|
1
|
Varghese G, Jamwal A, Sarawat D, Singh S, Tejan N, Patel SS, Sahu C. Bacterial resistance profile and its association with poor outcome among cirrhosis patients attending a tertiary care referral center in northern India. Indian J Gastroenterol 2025; 44:198-207. [PMID: 39921835 DOI: 10.1007/s12664-024-01712-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 11/11/2024] [Indexed: 02/10/2025]
Abstract
BACKGROUND AND OBJECTIVE The epidemiological connections, predisposing factors and clinical outcomes of infections by drug-resistant bacteria in cirrhosis are poorly documented. Thus, this study was conducted to assess the risk factors, complications and patterns of bacterial resistance among these patients. METHODS This retrospective observational study was conducted from March 1, 2021, to July 31, 2023, at a tertiary care centre in Uttar Pradesh. Patients of cirrhosis aged ≥ 18 years with microbial infection were included in the study. Samples, as indicated, were sent to the microbiology lab for culture and sensitivity. The patient's clinical history, details regarding bacterial culture and antibiotic sensitivity results were extracted from the hospital information system (HIS) and entered into an excel sheet. Univariate analysis of the variables was done and the statistical significance of these variables was determined using the p-value. A p-value of < 0.05 was considered significant. RESULTS During the study period, 765 patients were diagnosed with cirrhosis, of which 248 (32%) had a positive bacterial culture report. Among them, 206 (83.1%) patients recovered and were discharged in stable condition. Among the cirrhotic patients, the most common infection was spontaneous bacterial peritonitis (49.5%), followed by bacteremia (39.1%), lower respiratory tract infections (6.4%), urinary tract infections (2.9%) and skin and soft tissue infections (2%). Escherichia coli (28%) was the most common gram-negative bacteria. Multidrug-resistant organism infections were seen in 134 (54%) patients. Multidrug-resistant (MDR) infection (31.4%) and extensively drug-resistant (XDR) infection (22.6%) were significantly associated with poor outcomes among these patients. Carbapenem-resistant organisms (22.6%) were the predominant resistant patterns seen among the gram-negative isolates in cirrhosis patients. The mortality rate among these cirrhotic patients with bacterial infection was 16.9%. CONCLUSIONS MDR and XDR bacterial infections in cirrhotic patients are an emerging threat that has a detrimental effect on prognosis. Thus, it is critical to assess strategies to prevent the development of antibiotic resistance in cirrhosis.
Collapse
Affiliation(s)
- Gerlin Varghese
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Ashima Jamwal
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Deepika Sarawat
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Surender Singh
- Department of Hepatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India.
| | - Nidhi Tejan
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Sangram Singh Patel
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Chinmoy Sahu
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226 014, India.
| |
Collapse
|
|
2
|
Schulz MS, Angeli P, Trebicka J. Acute and non-acute decompensation of liver cirrhosis (47/130). Liver Int 2025; 45:e15861. [PMID: 38426268 DOI: 10.1111/liv.15861] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 12/18/2023] [Accepted: 01/19/2024] [Indexed: 03/02/2024]
Abstract
In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.
Collapse
Affiliation(s)
- Martin S Schulz
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Paolo Angeli
- European Foundation for Study of Chronic Liver Failure, Barcelona, Spain
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
- European Foundation for Study of Chronic Liver Failure, Barcelona, Spain
| |
Collapse
|
|
3
|
Juanola A, Tiwari N, Solé C, Adebayo D, Wong F, Ginès P. Organ dysfunction and failure in liver disease. Liver Int 2025; 45:e15622. [PMID: 37222263 DOI: 10.1111/liv.15622] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 05/15/2023] [Indexed: 05/25/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a complex syndrome defined by the existence of different organ failures (OFs) in patients with chronic liver disease, mainly cirrhosis. Several definitions have been proposed to define the syndrome, varying in the grade of the subjacent liver disease, the type of precipitants and the organs considered in the definition. Liver, coagulation, brain, kidney, circulatory and pulmonary are the six types of OFs proposed in the different classifications, with different prevalence worldwide. Irrespective of the definition used, patients who develop ACLF present a hyperactive immune system, profound haemodynamic disturbances and several metabolic alterations that finally lead to organ dysfunction. These disturbances are triggered by different factors such as bacterial infections, alcoholic hepatitis, gastrointestinal bleeding or hepatitis B virus flare, among others. Because patients with ACLF present high short-term mortality, a prompt recognition is needed to start treatment of the trigger event and specific organ support. Liver transplantation is also feasible in carefully selected patients and should be evaluated.
Collapse
Affiliation(s)
- Adrià Juanola
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
| | - Neha Tiwari
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Cristina Solé
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
- Department of Gastroenterology and Hepatology, Parc Tauli Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Danielle Adebayo
- Department of Gastroenterology, Royal Berkshire NHS Foundation Trust, Reading, UK
| | - Florence Wong
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Pere Ginès
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
4
|
Piano S, Mahmud N, Caraceni P, Tonon M, Mookerjee RP. Mechanisms and treatment approaches for ACLF. Liver Int 2025; 45:e15733. [PMID: 37715608 DOI: 10.1111/liv.15733] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/03/2023] [Accepted: 09/02/2023] [Indexed: 09/17/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF.
Collapse
Affiliation(s)
- Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine - DIMED, University and Hospital of Padova, Padova, Italy
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Leonard Davis Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
- Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine - DIMED, University and Hospital of Padova, Padova, Italy
| | - Rajeshwar Prosad Mookerjee
- Institute for Liver and Digestive Health, University College London, London, UK
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark
| |
Collapse
|
|
5
|
Karvellas CJ, Gustot T, Fernandez J. Management of the acute on chronic liver failure in the intensive care unit. Liver Int 2025; 45:e15659. [PMID: 37365997 DOI: 10.1111/liv.15659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/01/2023] [Accepted: 06/15/2023] [Indexed: 06/28/2023]
Abstract
Acute on chronic liver failure (ACLF) reflects the development of organ failure(s) in a patient with cirrhosis and is associated with high short-term mortality. Given that ACLF has many different 'phenotypes', medical management needs to take into account the relationship between precipitating insult, organ systems involved and underlying physiology of chronic liver disease/cirrhosis. The goals of intensive care management of patients suffering ACLF are to rapidly recognize and treat inciting events (e.g. infection, severe alcoholic hepatitis and bleeding) and to aggressively support failing organ systems to ensure that patients may successfully undergo liver transplantation or recovery. Management of these patients is complex since they are prone to develop new organ failures and infectious or bleeding complications. ICU therapy parallels that applied in the general ICU population in some complications but differs in others. Given that liver transplantation in ACLF is an emerging and evolving field, multidisciplinary teams with expertise in critical care and transplant medicine best accomplish management of the critically ill ACLF patient. The focus of this review is to identify the common complications of ACLF and to describe the proper management in critically ill patients awaiting liver transplantation in our centres, including organ support, prognostic assessment and how to assess when recovery is unlikely.
Collapse
Affiliation(s)
- Constantine J Karvellas
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
| | - Thierry Gustot
- Department of Gastroenterology, Hepato-Pancreatology and Digestive Oncology, H.U.B., CUB Hôpital Erasme, Brussels, Belgium
| | - Javier Fernandez
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Barcelona, Spain
- EF CLIF, EASL-CLIF Consortium, Barcelona, Spain
| |
Collapse
|
|
6
|
McGettigan B, Hernandez-Tejero M, Malhi H, Shah V. Immune Dysfunction and Infection Risk in Advanced Liver Disease. Gastroenterology 2025:S0016-5085(24)05694-4. [PMID: 39927926 DOI: 10.1053/j.gastro.2024.08.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 02/11/2025]
Abstract
The risk of microbial infections is increased in cirrhosis and other forms of advanced liver disease such as alcohol-associated hepatitis. Such infections may precipitate new or further decompensation and death, especially in patients with clinical features of acute-on-chronic liver failure. The severe immune dysfunction or "immune paralysis" caused by advanced liver disease is associated with high short-term mortality. However, the pathogenic mechanisms underlying immune dysfunction and immunodeficiency are incompletely understood. Evidence to date suggests a complex, dynamic process that perturbs the physiological roles of the liver as a master regulator of systemic immunity and protector against noxious effects of exogenous molecules in the portal vein flowing from the gut. Thus, in cirrhosis and severe alcohol-associated hepatitis, the ability of hepatocytes and intrahepatic immune cells to balance normal context-dependent dichotomous responses of tolerance vs immune activation is lost. Contributing factors include loss of the gut barrier with translocation of microbial products through the portal vein, culminating in development of functional defects in innate and adaptive immune cells, and generation of immune-regulatory myeloid cells that permit microbial colonization and infection. This review addresses key evidence supporting the paradigm of immune dysfunction as a risk for microbial infections and identifies potential therapeutic targets for intervention. The primary focus is on cirrhosis-associated immune dysfunction and alcohol-associated liver disease, because the bulk of available data are from these 2 conditions.
Collapse
Affiliation(s)
- Brett McGettigan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Maria Hernandez-Tejero
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
| |
Collapse
|
|
7
|
Dirchwolf M, Gomez Perdiguero G, Cairo F, Vazquez C, Notari L, Murga MD, Elizondo M, Bessone F, Agozino M, Brutti J, Zerega AR, Pages J, Stieben TE, Calzetta P, Arufe D, González Ballerga E, Giunta D, Smud A, Osso Sanchez B, Navarro L, Palazzo A, Valverde M, Gadano A, Marciano S. Towards evidence-based empiric antibiotic recommendations for spontaneous infections in patients with cirrhosis. Dig Liver Dis 2025; 57:394-400. [PMID: 39107169 DOI: 10.1016/j.dld.2024.07.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/24/2024] [Accepted: 07/21/2024] [Indexed: 08/09/2024]
Abstract
BACKGROUND With the emergence of multidrug-resistant infections, healthcare professionals must evaluate the effectiveness of empiric antibiotic treatments. AIMS To assess the antibiotic susceptibility patterns of microorganisms causing spontaneous infections in patients with cirrhosis and to evaluate the suitability of empiric antibiotic treatments based on major clinical guidelines. METHODS This cross-sectional study utilized two datasets from prospective studies of patients with cirrhosis and culture-positive spontaneous bacterial infections in Argentina and Uruguay. We estimated susceptibility to commonly used antibiotics and assessed coverage following European and American recommendations. RESULTS We analyzed 238 episodes of culture-positive spontaneous infections in 229 patients. When implementing the recommendations for empiric treatment of community-acquired spontaneous infections, ceftazidime would result in 39 % coverage, whereas ceftriaxone would reach 70 %. Cefepime, which is not included in the recommendations, would have provided coverage of 74 %. Using ertapenem for nosocomial infections would have only covered 56 % of these episodes, whereas meropenem or imipenem reached 73 % coverage. Only the combination of meropenem or imipenem plus vancomycin would achieve a coverage surpassing 85 % in healthcare-associated or nosocomial spontaneous bacterial infections. CONCLUSIONS Our study uncovers inadequate coverage in specific clinical scenarios when adhering to recommendations, underscoring the necessity of guidelines based on local epidemiological data.
Collapse
Affiliation(s)
- Melisa Dirchwolf
- Liver Unit, Hospital Privado de Rosario, Presidente Roca 2440, CP 200, Santa Fe, Argentina.
| | - Gonzalo Gomez Perdiguero
- Liver Unit, Hospital Italiano de Buenos Aires. Tte. Gral. Juan Domingo Perón 4190, CP 1199, Buenos Aires, Argentina
| | - Fernando Cairo
- Liver Unit, Solid Organ Transplant Service, El Cruce Hospital. Av. Calchaquí 5401, CP 1888, Buenos Aires, Argentina
| | - Carolina Vazquez
- Internal Medicine, Critical Care Unit, Italiano Hospital of Buenos Aires. Tte. Gral. Juan Domingo Perón 4190, CP 1199, Buenos Aires, Argentina
| | - Lorena Notari
- Liver Unit, Police Medical Hospital Churruca Visca. Uspallata 3400, CP 1437, Buenos Aires, Argentina
| | - Maria Dolores Murga
- Liver Unit, Angel C. Padilla Hospital. Juan Bautista Alberdi 550, CP 4000, Tucuman, Argentina
| | - Martin Elizondo
- Bi-Institutional Unit for Complex Hepatic Diseases (Militar Hospital - Clinical Hospital), Liver Transplant Program. Av 8 octubre 3020, CP 11600, Montevideo, Uruguay
| | - Fernando Bessone
- Liver Unit, Centenario Hospital of Rosario. Urquiza 3100, CP 2000, Santa Fe, Argentina
| | - Marina Agozino
- Liver and Gastroenterology Unit, Guemes Sanatorio. Av Cordoba 3933, CP 1188, Buenos Aires, Argentina
| | - Julia Brutti
- Liver Unit, Alemán Hospital. Av. Pueyrredón 1640, CP 1118, Buenos Aires, Argentina
| | | | - Josefina Pages
- Liver Unit, Austral University Hospital. Av. Pres. Juan Domingo Peron 1500, CP 1629, Buenos Aires, Argentina
| | - Teodoro Eduardo Stieben
- Liver Unit, San Martin Hospital of Parana. Pres. Juan Domingo Perón 450, CP 3100, Entre Rios, Argentina
| | - Pablo Calzetta
- Liver and Gastroenterology Unit, Juan A. Fernández Hospital. Av. Cerviño 3356, CP 1425, Buenos Aires, Argentina
| | - Diego Arufe
- Liver Unit, Sagrado Corazón Sanatorio. Bartolomé Mitre 1955, CP 1039, Buenos Aires, Argentina
| | - Esteban González Ballerga
- Liver and Gastroenterology Unit, Hospital Clinica Jose de San Martin Clinica. Av. Córdoba 2351, CP 1120, Buenos Aires, Argentina
| | - Diego Giunta
- Instituto Universitario del Hospital Italiano, Buenos Aires. Argentina. Potosí 4265, CP 1199, Buenos Aires, Argentina
| | - Astrid Smud
- Infectious Diseases Service, Italiano Hospital of Buenos Aires, Tte. Gral. Juan Domingo Perón 4190, CP 1199, Buenos Aires, Argentina
| | - Brenda Osso Sanchez
- Liver Unit, Police Medical Hospital Churruca Visca. Uspallata 3400, CP 1437, Buenos Aires, Argentina
| | - Lucia Navarro
- Liver Unit, Solid Organ Transplant Service, El Cruce Hospital. Av. Calchaquí 5401, CP 1888, Buenos Aires, Argentina
| | - Ana Palazzo
- Liver Unit, Angel C. Padilla Hospital. Juan Bautista Alberdi 550, CP 4000, Tucuman, Argentina
| | - Marcelo Valverde
- Bi-Institutional Unit for Complex Hepatic Diseases (Militar Hospital - Clinical Hospital), Liver Transplant Program. Av 8 octubre 3020, CP 11600, Montevideo, Uruguay
| | - Adrian Gadano
- Liver Unit, Hospital Italiano de Buenos Aires. Tte. Gral. Juan Domingo Perón 4190, CP 1199, Buenos Aires, Argentina
| | - Sebastián Marciano
- Liver Unit, Hospital Italiano de Buenos Aires. Tte. Gral. Juan Domingo Perón 4190, CP 1199, Buenos Aires, Argentina
| |
Collapse
|
|
8
|
Choudhury A, Kulkarni AV, Arora V, Soin AS, Dokmeci AK, Chowdhury A, Koshy A, Duseja A, Kumar A, Mishra AK, Patwa AK, Sood A, Roy A, Shukla A, Chan A, Krag A, Mukund A, Mandot A, Goel A, Butt AS, Sahney A, Shrestha A, Cárdenas A, Di Giorgio A, Arora A, Anand AC, Dhawan A, Jindal A, Saraya A, Srivastava A, Kumar A, Kaewdech A, Pande A, Rastogi A, Valsan A, Goel A, Kumar A, Singal AK, Tanaka A, Coilly A, Singh A, Meena BL, Jagadisan B, Sharma BC, Lal BB, Eapen CE, Yaghi C, Kedarisetty CK, Kim CW, Panackel C, Yu C, Kalal CR, Bihari C, Huang CH, Vasishtha C, Jansen C, Strassburg C, Lin CY, Karvellas CJ, Lesmana CRA, Philips CA, Shawcross D, Kapoor D, Agrawal D, Payawal DA, Praharaj DL, Jothimani D, Song DS, Kim DJ, Kim DS, Zhongping D, Karim F, Durand F, Shiha GE, D'Amico G, Lau GK, Pati GK, Narro GEC, Lee GH, Adali G, Dhakal GP, Szabo G, Lin HC, Li H, Nair HK, Devarbhavi H, Tevethia H, Ghazinian H, Ilango H, Yu HL, Hasan I, Fernandez J, George J, Behari J, Fung J, Bajaj J, Benjamin J, Lai JC, Jia J, Hu JH, Chen JJ, Hou JL, Yang JM, Chang J, Trebicka J, Kalf JC, Sollano JD, Varghese J, Arab JP, Li J, Reddy KR, Raja K, Panda K, Kajal K, Kumar K, Madan K, Kalista KF, Thanapirom K, Win KM, Suk KT, Devadas K, Lesmana LA, Kamani L, Premkumar M, Niriella MA, Al Mahtab M, Yuen MF, Sayed MHE, Alla M, Wadhawan M, Sharma MK, Sahu M, Prasad M, Muthiah MD, Schulz M, Bajpai M, Reddy MS, Praktiknjo M, Yu ML, Prasad M, Sharma M, Elbasiony M, Eslam M, Azam MG, Rela M, Desai MS, Vij M, Mahmud N, Choudhary NS, Marannan NK, Ormeci N, Saraf N, Verma N, Nakayama N, Kawada N, Oidov Baatarkhuu, Goyal O, Yokosuka O, Rao PN, Angeli P, Parikh P, Kamath PS, Thuluvath PJ, Lingohr P, Ranjan P, Bhangui P, Rathi P, Sakhuja P, Puri P, Ning Q, Dhiman RK, Kumar R, Vijayaraghavan R, Khanna R, Maiwall R, Mohanka R, Moreau R, Gani RA, Loomba R, Mehtani R, Rajaram RB, Hamid SS, Palnitkar S, Lal S, Biswas S, Chirapongsathorn S, Agarwal S, Sachdeva S, Saigal S, Kumar SE, Violeta S, Singh SP, Mochida S, Mukewar S, Alam S, Lim SG, Alam S, Shalimar, Venishetty S, Sundaram SS, Shetty S, Bhatia S, Singh SA, Kottilil S, Strasser S, Shasthry SM, Maung ST, Tan SS, Treeprasertsuk S, Asthana S, Manekeller S, Gupta S, Acharya SK, K C S, Maharshi S, Asrani S, Dadhich S, Taneja S, Giri S, Singh S, Chen T, Gupta T, Kanda T, Tanwandee T, Piratvishuth T, Spengler U, Prasad VGM, Midha V, Rakhmetova V, Arroyo V, Sood V, Br VK, Wong VWS, Pamecha V, Singh V, Dayal VM, Saraswat VA, Kim WR, Jafri W, Gu W, Jun WY, Qi X, Chawla YK, Kim YJ, Shi Y, Abbas Z, Kumar G, Shiina S, Wei L, Omata M, Sarin SK. Acute-on-chronic liver failure (ACLF): the 'Kyoto Consensus'-steps from Asia. Hepatol Int 2025; 19:1-69. [PMID: 39961976 PMCID: PMC11846769 DOI: 10.1007/s12072-024-10773-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 12/29/2024] [Indexed: 02/23/2025]
Abstract
Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the 'Golden Therapeutic Window', the 'transplant window', and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The 'Kyoto APASL Consensus' presented below carries the final recommendations along with the relevant background information and areas requiring future studies.
Collapse
Affiliation(s)
- Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - A S Soin
- Medanta-The Medicity Hospital, Gurugram, Haryana, India
| | | | - Abhijeet Chowdhury
- Institute of Post-Graduate Medical Education and Research (IPGMER), Kolkata, West Bengal, India
| | - Abraham Koshy
- VPS Lakeshore Hospital and Research Center Ltd, Kochi, Kerala, India
| | - Ajay Duseja
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Ajay Kumar
- Govind Ballabh Pant Hospital, New Delhi, India
| | - Ajay Kumar Mishra
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | | | - Ajit Sood
- Dayanand Medical College, Ludhiana, India
| | - Akash Roy
- Apollo Multispeciality Hospital, Kolkata, India
| | - Akash Shukla
- Seth G S Medical College and K E M Hospital, Mumbai, Maharashtra, India
- Sir HN Reliance Foundation Hospital, Girgaon, Mumbai, Maharashtra, India
| | - Albert Chan
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | | | - Amar Mukund
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Amit Goel
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | | | | | | | - Andrés Cárdenas
- Univerity of Barcelona Institut d'Investigacions Biomèdiques August Pi-Sunyer, Barcelona, Spain
| | | | - Anil Arora
- Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
| | - Anil Chandra Anand
- Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, Orissa, India
| | | | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Anoop Saraya
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Anshu Srivastava
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | - Anupam Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Apurva Pande
- Fortis Hospital, Greater Noida, Uttar Pradesh, India
| | - Archana Rastogi
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Arun Valsan
- Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Ashish Goel
- Christian Medical College (CMC), Vellore, India
| | - Ashish Kumar
- Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
| | - Ashwani K Singal
- University of Louisville School of Medicine, Trager Transplant Center and Jewish Hospital, Louisville, KY, USA
| | | | - Audrey Coilly
- Centre Hepato-Biliaire, Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - Ayaskanta Singh
- IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
| | - Babu Lal Meena
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | - Bikrant Bihari Lal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - C E Eapen
- Christian Medical College (CMC), Vellore, India
| | - Cesar Yaghi
- Saint Joseph University, Hôtel-Dieu de France University Medical Center, Beirut, Lebanon
| | | | | | | | - Chen Yu
- Capital Medical University, Beijing, China
| | - Chetan R Kalal
- Nanavati Max Super Specialty Hospital, Mumbai, Maharashtra, India
| | - Chhagan Bihari
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Chitranshu Vasishtha
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Christian Jansen
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | - Chun Yen Lin
- Linkou Medical Centre, Chang Gung Memorial Hospital, Keelung, Taiwan
| | | | - Cosmas Rinaldi Adithya Lesmana
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Medistra Hospital, Jakarta, Indonesia
| | | | | | | | | | | | | | | | | | | | - Dong-Sik Kim
- Korea University College of Medicine, Seoul, Republic of Korea
| | | | - Fazal Karim
- Sir Salimullah Medical College, Mitford Hospital, Dhaka, Bangladesh
| | - Francois Durand
- Université de Paris, AP-HP, C, DMU DIGEST, Centre de Référence Des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de Recherche Sur L'inflammation, Inserm, Paris, France
| | | | - Gennaro D'Amico
- Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
- Clinica La Maddalena, Palermo, Italy
| | - George K Lau
- Humanity and Health Medical Center, Hongkong, SAR, China
| | | | - Graciela Elia Castro Narro
- Hospital Médica Sur, Mexico City, Mexico
- Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubiran",, Mexico City, Mexico
- Latin-American Association for the Study of the Liver (ALEH), Santiago de Chile, Chile
| | - Guan-Huei Lee
- National University Hospital, National University of Singapore, Singapore, Singapore
| | - Gupse Adali
- University of Health Sciences, Ümraniye, Istanbul, Turkey
| | | | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - H C Lin
- Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hai Li
- School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hari Kumar Nair
- Ernakulam Medical Center (EMC), Kinder Multispeciality Hospital, Kochi, Kerala, India
| | | | - Harshvardhan Tevethia
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | | | - Irsan Hasan
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | - J Fernandez
- University of Barcelona, IDIBAPS and CIBEREHD, Barcelona, Spain
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Jaideep Behari
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - James Fung
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | | | - Jaya Benjamin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Jennifer C Lai
- University of California, San Francisco, San Francisco, CA, USA
| | - Jidong Jia
- Capital Medical University, Beijing, China
| | - Jin Hua Hu
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Jin Jun Chen
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jin Lin Hou
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jin Mo Yang
- The Catholic University of Korea, Seoul, Korea
| | - Johannes Chang
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jonel Trebicka
- Medizinische Klinik B, Universitätsklinikum Münster, Münster, Germany
| | - Jörg C Kalf
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jose D Sollano
- Department of Medicine, Cardinal Santos Medical Center, Manila, Philippines
| | - Joy Varghese
- Gleneagles Global Hospital, Chennai, Tamil Nadu, India
| | - Juan Pablo Arab
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Schulich School of Medicine, Western University, London, ON, Canada
| | - Jun Li
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | | | - Kaiser Raja
- King's College Hospital London, Dubai, United Arab Emirates
| | - Kalpana Panda
- IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
| | - Kamal Kajal
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Karan Kumar
- Mahatma Gandhi Medical College, Jaipur, Rajasthan, India
| | - Kaushal Madan
- Max Super Specialty Hospital Saket, New Delhi, India
| | - Kemal Fariz Kalista
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | | | - Khin Maung Win
- University of Medicine, Yangon Ministry of Health, Yangon, Myanmar
| | - Ki Tae Suk
- Hallym University, Chuncheon, Republic of Korea
| | | | | | - Lubna Kamani
- Liaquat National Hospital, Karachi, Sindh, Pakistan
| | - Madhumita Premkumar
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Mamun Al Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Man Fung Yuen
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | | | - Manasa Alla
- Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | | | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Manoj Sahu
- IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
| | - Manya Prasad
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Mark Dhinesh Muthiah
- National University Hospital, National University of Singapore, Singapore, Singapore
| | - Martin Schulz
- Goethe University Clinic Frankfurt, Frankfurt, Germany
| | - Meenu Bajpai
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | - Ming Lung Yu
- Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, National Sun Yet-Sen University, Kaohsiung, Taiwan
| | | | - Mithun Sharma
- Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | | | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Mohd Golam Azam
- Endocrine and Metabolic Disorder (BIRDEM) Shahbad, Bangladesh Institute of Research and Rehabilitation in Diabetes, Dhaka, Bangladesh
| | - Mohd Rela
- Dr. Rela Institute and Medical Centre, Chennai, India
| | - Moreshwar S Desai
- Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Mukul Vij
- Dr. Rela Institute and Medical Centre, Chennai, India
| | - Nadim Mahmud
- University of Pennsylvania, Philadelphia, PA, USA
| | | | | | - Necati Ormeci
- İstanbul Health and Technology University, Istanbul, Turkey
| | - Neeraj Saraf
- Medanta-The Medicity Hospital, Gurugram, Haryana, India
| | - Nipun Verma
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Norifumi Kawada
- Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Oidov Baatarkhuu
- Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | | | - Osamu Yokosuka
- Graduate School of Medicine, Chiba University, Chuo-Ku, Chiba, Japan
| | - P N Rao
- Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | - Paolo Angeli
- Department of Medicine (DIMED), University of Padova, Padua, Italy
| | | | | | | | - Philipp Lingohr
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Piyush Ranjan
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | - Pravin Rathi
- Topi Wala National (TN) Medical College and BYL Nair Charitable Hospital, Mumbai, India
| | | | - Puneet Puri
- Virginia Commonwealth University, Richmond, VA, USA
| | - Qin Ning
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - R K Dhiman
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | - Rahul Kumar
- Changi General Hospital, Singapore, Singapore
| | - Rajan Vijayaraghavan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Rajeev Khanna
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Ravi Mohanka
- Sir HN Reliance Foundation Hospital, Girgaon, Mumbai, Maharashtra, India
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
- Centre de Recherche Sur L'Inflammation (CRI), INSERM and Université Paris-Cité, Paris, France
- Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Beaujon, Service d'Hépatologie, Clichy, France
| | - Rino Alvani Gani
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | - Rohit Loomba
- University of California, San Diego, La Jolla, CA, USA
| | - Rohit Mehtani
- Amrita Institute of Medical Sciences and Research Centre, Faridabad, Haryana, India
| | | | - S S Hamid
- Aga Khan University Hospital, Karachi, Pakistan
| | | | - Sadhna Lal
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Sagnik Biswas
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | - Samagra Agarwal
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | - Sanjiv Saigal
- Max Super Specialty Hospital Saket, New Delhi, India
| | | | | | - Satender Pal Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Saurabh Mukewar
- Midas Multispeciality Hospital Pvt. Ltd, Nagpur, Maharashtra, India
| | - Seema Alam
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Seng Gee Lim
- National University Hospital, National University of Singapore, Singapore, Singapore
| | - Shahinul Alam
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Shalimar
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | | | - Shiran Shetty
- Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shobna Bhatia
- National Institute of Medical Sciences, Jaipur, India
| | | | - Shyam Kottilil
- University of Maryland School of Medicine, Baltimore, USA
| | | | - S M Shasthry
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Soek Siam Tan
- Selayang Hospital, University of Malaysia, Batu Caves, Selangor, Malaysia
| | | | | | | | - Subhash Gupta
- Max Super Specialty Hospital Saket, New Delhi, India
| | | | - Sudhamshu K C
- Bir Hospital, National Academy of Medical Sciences, Kathmandu, Nepal
| | - Sudhir Maharshi
- Sawai Man Singh (SMS) Medical College and Hospital, Jaipur, Rajasthan, India
| | - Sumeet Asrani
- Baylor Simmons Transplant Institute, Dallas, TX, USA
| | - Sunil Dadhich
- Dr Sampuranand Medical College (SNMC), Jodhpur, Rajasthan, India
| | - Sunil Taneja
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Suprabhat Giri
- Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, Orissa, India
| | - Surender Singh
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | - Tao Chen
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tarana Gupta
- Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Tatsuo Kanda
- Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | | | | | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - V G Mohan Prasad
- Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | | | | | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Vikrant Sood
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Vinay Kumar Br
- Mazumdar Shaw Medical Centre, Bangalore, Karnataka, India
| | | | - Viniyendra Pamecha
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Virendra Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India
| | - Vishwa Mohan Dayal
- Indira Gandhi Institute of Medical Sciences, (IGIMS), Bely Road Patna, Bihar, India
| | | | - WRay Kim
- Stanford University, Stanford, CA, USA
| | - Wasim Jafri
- Aga Khan University Hospital, Karachi, Pakistan
| | - Wenyi Gu
- Goethe University Clinic Frankfurt, Frankfurt, Germany
| | - Wong Yu Jun
- Changi General Hospital, Singapore, Singapore
| | - Xiaolong Qi
- Medical School, Zhongda Hospital, Southeast University, Nanjing, China
| | - Yogesh K Chawla
- Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, Orissa, India
| | - Yoon Jun Kim
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yu Shi
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Zaigham Abbas
- Ziauddin University Hospital Karachi, Karachi, Pakistan
| | - Guresh Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Lai Wei
- Changgung Hospital, Tsinghua University, Beijing, China
| | - Masao Omata
- Yamanashi Central Hospital, Yamanashi, Japan
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India.
| |
Collapse
|
|
9
|
Haedge F, Bruns T. Antibiotics in decompensated liver disease - who, when and for how long? Expert Rev Gastroenterol Hepatol 2025; 19:111-130. [PMID: 39921440 DOI: 10.1080/17474124.2025.2464044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
INTRODUCTION Bacterial infections are a leading cause of hospitalization and mortality in patients with decompensated cirrhosis. Antibiotic prophylaxis in cirrhotic patients has demonstrated significant short-term reductions in bacterial infections in randomized controlled trials, but at the cost of drug resistance and with uncertain survival benefits. AREAS COVERED This review examines antibiotic use in cirrhosis, focusing on patients most likely to benefit from antibiotic prophylaxis, management strategies for infections through risk-based antibiotic selection and timely treatment initiation, challenges posed by the emergence of multidrug-resistant organisms, and principles of antimicrobial stewardship. EXPERT OPINION The efficacy of prophylaxis has decreased over time, and current registry data have questioned its use, emphasizing the need for better risk-based individualized strategies. When bacterial infections occur, the efficacy of antimicrobial therapies depends heavily on local epidemiological patterns and individual patient risk factors, necessitating tailored antibiotic selection based on regional resistance data and specific clinical scenarios. Nosocomial infections, colonization with multidrug-resistant organisms, and prior exposure to systemic antibiotics are key risk factors that should guide empirical therapy selection. Until evidence-based algorithms are available, clinicians should continue to adopt individualized approaches, guided by available evidence, local specificities, and antimicrobial stewardship principles to optimize patient outcomes.
Collapse
Affiliation(s)
- Frederic Haedge
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| |
Collapse
|
|
10
|
Torres S, El Maimouni C, Herrera G, Fernandez J. Spontaneous candidemia: A real infection in advanced cirrhosis. J Hepatol 2024; 81:e267-e268. [PMID: 39218221 DOI: 10.1016/j.jhep.2024.08.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Affiliation(s)
- Sonia Torres
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | | | | | - Javier Fernandez
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain.
| |
Collapse
|
|
11
|
Venkatakrishnan G, Amma BSPT, Menon RN, Rajakrishnan H, Surendran S. Infections in acute liver failure - Assessment, prevention, and management. Best Pract Res Clin Gastroenterol 2024; 73:101958. [PMID: 39709213 DOI: 10.1016/j.bpg.2024.101958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/22/2024] [Indexed: 12/23/2024]
Abstract
Infections in acute liver failure (ALF) increase the associated morbidity and mortality, and often hamper the possibility of transplantation. Two-thirds of the infections in ALF are bacterial while one-third is fungal. High suspicion for infection is essential whenever there is clinical deterioration. Multi-drug resistant infections are frequently encountered with prolonged ICU stay, invasive lines, ventilation and renal replacement therapy. Since most of the infections in ALF are nosocomial, prevention of infections is crucial by infection control practices in the ICU. Although markers such as CRP, procalcitonin (for bacterial infections), 1,3-beta-D glucan, and galactomannan (fungal infections) aid in the diagnosis, the gold standard is blood culture. Therapy for respiratory infections must be based on BAL or mini-BAL culture. In this article, we discuss the common infections occurring in ALF, methods for early diagnosis and recommended prophylactic, pre-emptive as well as therapeutic options for treating infections in ALF.
Collapse
Affiliation(s)
- Guhan Venkatakrishnan
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Binoj S Pillai Thankamony Amma
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Ramachandran N Menon
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Haritha Rajakrishnan
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Sudhindran Surendran
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India.
| |
Collapse
|
|
12
|
Silvey S, Patel N, Liu J, Tafader A, Nadeem M, Dhaliwal G, O'Leary JG, Patton H, Morgan TR, Rogal S, Bajaj JS. A Machine Learning Algorithm Avoids Unnecessary Paracentesis for Exclusion of SBP in Cirrhosis in Resource-limited Settings. Clin Gastroenterol Hepatol 2024; 22:2442-2450.e8. [PMID: 38906441 PMCID: PMC11588556 DOI: 10.1016/j.cgh.2024.06.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/04/2024] [Accepted: 06/12/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND & AIMS Despite the poor prognosis associated with missed or delayed spontaneous bacterial peritonitis (SBP) diagnosis, <15% get timely paracentesis, which persists despite guidelines/education in the United States. Measures to exclude SBP non-invasively where timely paracentesis cannot be performed could streamline this burden. METHODS Using Veterans Health Administration Corporate Data Warehouse (VHA-CDW) we included patients with cirrhosis between 2009 and 2019 who underwent timely paracentesis and collected relevant clinical information (demographics, cirrhosis severity, medications, vitals, and comorbidities). XGBoost-models were trained on 75% of the primary cohort, with 25% reserved for testing. The final model was further validated in 2 cohorts: Validation cohort #1: In VHA-CDW, those without prior SBP who received 2nd early paracentesis, and Validation cohort #2: Prospective data from 276 non-electively admitted University hospital patients. RESULTS Negative predictive values (NPVs) at 5%,10%, and 15% probability cutoffs were examined. Primary cohort: n = 9643 (mean age, 63.1 ± 8.7 years; 97.2% men; SBP, 15.0%) received first early paracentesis. Testing-set NPVs for SBP were 96.5%, 93.0%, and 91.6% at the 5%, 10%, and 15% probability thresholds, respectively. In Validation cohort #1: n = 2844 (mean age, 63.14 ± 8.37 years; 97.1% male; SBP, 9.7%) with NPVs were 98.8%, 95.3%, and 94.5%. In Validation cohort #2: n = 276 (mean age, 56.08 ± 9.09; 59.6% male; SBP, 7.6%) with NPVs were 100%, 98.9%, and 98.0% The final machine learning model showed the greatest net benefit on decision-curve analyses. CONCLUSIONS A machine learning model generated using routinely collected variables excluded SBP with high NPV. Applying this model could ease the need to provide paracentesis in resource-limited settings by excluding those unlikely to have SBP.
Collapse
Affiliation(s)
- Scott Silvey
- Department of Population Health, Virginia Commonwealth University, Richmond, Virginia
| | - Nilang Patel
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia
| | - Jinze Liu
- Department of Population Health, Virginia Commonwealth University, Richmond, Virginia
| | - Asiya Tafader
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia
| | - Mahum Nadeem
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia
| | - Galvin Dhaliwal
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia
| | - Jacqueline G O'Leary
- Department of Medicine, University of Texas Southwestern and Dallas VA Medical Center, Dallas, Texas
| | - Heather Patton
- Department of Medicine, University of California San Diego and San Diego VA Medical Center, San Diego, California
| | - Timothy R Morgan
- Medical Service, VA Long Beach Healthcare Center, Long Beach, California
| | - Shari Rogal
- Department of Medicine, University of Pittsburgh Medical Center and Pittsburgh VA Medical Center, Pittsburgh, Pennsylvania
| | - Jasmohan S Bajaj
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia.
| |
Collapse
|
|
13
|
Cao Z, Wong F, Choudhury AK, Kamath PS, Topazian M, Torre A, Hayes PC, George J, Idilman R, Seto WK, Desalegn H, Alvares-da-Silva MR, Bush BJ, Thacker LR, Xie Q, Bajaj JS. Global prevalence and characteristics of infections and clinical outcomes in hospitalised patients with cirrhosis: a prospective cohort study for the CLEARED Consortium. Lancet Gastroenterol Hepatol 2024; 9:997-1009. [PMID: 39243795 DOI: 10.1016/s2468-1253(24)00224-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 06/30/2024] [Accepted: 07/03/2024] [Indexed: 09/09/2024]
Abstract
BACKGROUND Infections have a poor prognosis in inpatients with cirrhosis. We aimed to determine regional variations in infections and their association with clinical outcomes in a global cohort of inpatients with cirrhosis. METHODS In this prospective cohort study initiated by the CLEARED Consortium, we enrolled adults (aged >18 years) with cirrhosis who were non-electively admitted to 98 hospitals from 26 countries or regions across six continents between Nov 5, 2021, and Dec 10, 2022. Data at admission, during hospitalisation, and for 30 days after discharge were collected through patient reports and chart reviews. Collected data included demographics; country and country income level per World Bank classifications (high-income countries [HICs], upper-middle-income countries [UMICs], and low-income or lower-middle-income countries [L-LMICs]); comorbidities; characteristics related to cirrhosis and the infections, including types, culture results, and drug resistance profile; antibiotic use; and disease course while hospitalised and for 30 days post-discharge. The primary outcome was in-hospital death or hospice referral in those with versus those without an admission infection (defined by the presence of infection on or within 48 h of admission). Multivariable log-binomial regression for in-hospital death or hospice referral was performed to identify risk factors. FINDINGS Of 4550 patients screened, 4238 patients (mean age 56·1 years [SD 13·3]; 2711 [64·0%] male and 1527 [36·0%] female) with complete data were enrolled. 1351 (31·9%) had admission infections. A higher proportion of patients in L-LMICs had infections (318 [41·7%] of 762 vs 444 [58·3%] without infection) than in UMICs (588 [30·6%] of 1922 vs 1334 [69·4%]) or HICs (445 [28·6%] of 1554 vs 1109 [71·4%]). Patients with admission infections had worse severity of cirrhosis and were more likely to have had an infection or been hospitalised in the preceding 6 months. The most common specific infection types were spontaneous bacterial peritonitis (391 [28·9%] of 1351), pneumonia (233 [17·2%]), and urinary tract infections (193 [14·3%]). 549 (40·6%) patients were culture-positive for bacterial or fungal infections, with the lowest culture-positive rates in Africa and mainland China. Most of the isolated organisms were Gram-negative (345 [63%] of 549), then Gram-positive (157 [29%]), and then fungi or mixed (47 [9%]), with Escherichia coli, Klebsiella pneumoniae, and Enterococcus spp being the top three isolated pathogens. The overall rate of drug resistance was 40% (220 of 549 with positive cultures), being highest in UMICs. The most used empirical antimicrobials were third-generation cephalosporins (453 [37%] of 1241), followed by the broad-spectrum β-lactams and β-lactamase inhibitors (289 [23%]). De-escalation was observed in 62 (20%) of 304 patients who had their antibiotics changed. Patients with versus without admission infections had a higher rate of in-hospital death or hospice transfer (299 [22·1%] of 1351 vs 232 [8·0%] of 2887; p<0·0001), a result replicated in multivariable analysis (adjusted risk ratio 1·75 [95% CI 1·42-2·06]; p<0·0001). Older age, self-reported female gender, not being in a HIC, lactulose use, and higher MELD-Na score were also associated with in-hospital death or hospice transfer on multivariable analysis. INTERPRETATION In the CLEARED Consortium cohort of inpatients with cirrhosis, the rates and types of infections, causative organisms, and culture-positivity varied substantially across regions, and infections were associated with a higher mortality risk. Culture positivity, which guides appropriate antibiotic use, was low. Taking a global perspective, considering regional variations in infections, drug resistance, and resources, could help to alleviate disparities in burden and outcomes. FUNDING US Department of Veterans Affairs, the Richmond Institute for Veterans Research, the National Natural Science Foundation of China, Shanghai Rising-Star Program, the National Council for Scientific and Technological Development of Brazil, and Shanghai Municipal Key Clinical Specialty.
Collapse
Affiliation(s)
- Zhujun Cao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Florence Wong
- Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Ashok K Choudhury
- Department of Hepatology, Institute for Liver and Biliary Sciences, New Delhi, India
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Mark Topazian
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; Gastroenterology and Hepatology Unit, St Paul's Hospital, Millennium Medical College, Addis Ababa, Ethiopia
| | - Aldo Torre
- Department of Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Peter C Hayes
- Hepatology, Division of Health Sciences, Deanery of Clinical Sciences, University of Edinburgh, Edinburgh, UK
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, NSW, Australia
| | - Ramazan Idilman
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Hailemichael Desalegn
- Gastroenterology and Hepatology Unit, St Paul's Hospital, Millennium Medical College, Addis Ababa, Ethiopia
| | - Mario Reis Alvares-da-Silva
- Department of Hepatology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Brian J Bush
- Department of Population Health, Virginia Commonwealth University, Richmond, VA, USA
| | - Leroy R Thacker
- Department of Population Health, Virginia Commonwealth University, Richmond, VA, USA
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition and Richmond VA Medical Center, Virginia Commonwealth University, Richmond, VA, USA.
| |
Collapse
|
|
14
|
Pompili E, Iannone G, Carrello D, Zaccherini G, Baldassarre M, Caraceni P. Managing Multiorgan Failure in Acute on Chronic Liver Failure. Semin Liver Dis 2024; 44:492-509. [PMID: 39442531 DOI: 10.1055/a-2448-0664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Acute-on-chronic liver failure (ACLF) is defined as a clinical syndrome that develops in patients with chronic liver disease characterized by the presence of organ failure and high short-term mortality, although there is still no worldwide consensus on diagnostic criteria. Management of ACLF is mainly based on treatment of "precipitating factors" (the most common are infections, alcohol-associated hepatitis, hepatitis B flare, and bleeding) and support of organ failure, which often requires admission to the intensive care unit. Liver transplantation should be considered in patients with ACLF grades 2 to 3 as a potentially life-saving treatment. When a transplant is not indicated, palliative care should be considered after 3 to 7 days of full organ support in patients with at least four organ failures or a CLIF-C ACLF score of >70. This review summarizes the current knowledge on the management of organ failure in patients with ACLF, focusing on recent advances.
Collapse
Affiliation(s)
- Enrico Pompili
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giulia Iannone
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Daniele Carrello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Maurizio Baldassarre
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| |
Collapse
|
|
15
|
Ferrarese A, Senzolo M, Sasset L, Bassi D, Cillo U, Burra P. Multidrug-resistant bacterial infections in the liver transplant setting. Updates Surg 2024; 76:2521-2529. [PMID: 38918314 PMCID: PMC11602820 DOI: 10.1007/s13304-024-01903-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024]
Abstract
Bacterial infections pose a life-threatening complication in patients with decompensated liver cirrhosis and acute-on-chronic liver failure. An increasing prevalence of infections caused by multidrug-resistant organisms (MDROs) has been observed in these patients, significantly impacting prognosis. A growing body of evidence has identified the most common risk factors for such infections, enabling the development of preventive strategies and therapeutic interventions. MDRO infections may also occur after liver transplantation (most commonly in the early post-operative phase), affecting both graft and patient survival. This review provides an overview of MDRO infections before and after liver transplantation, discussing epidemiological aspects, risk factors, prevention strategies, and novel therapeutic approaches. Furthermore, it examines the implications of MDRO infections in the context of prioritizing liver transplantation for the most severe patients, such as those with acute-on-chronic liver failure.
Collapse
Affiliation(s)
- Alberto Ferrarese
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy.
| | - Marco Senzolo
- Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Lolita Sasset
- Infectious Disease Unit, Padua University Hospital, Padua, Italy
| | - Domenico Bassi
- Hepato-Biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
| | - Umberto Cillo
- Hepato-Biliary-Pancreatic Surgery and Liver Transplantation Unit, Padua University Hospital, Padua, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
- Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| |
Collapse
|
|
16
|
Clària J, Aguilar F, Lozano JJ, Jiménez-Gracia L, Nieto JC, Romero-Grimaldo B, Marcos-Fa X, Giarracco E, Weiss E, Trebicka J, Hernàndez I, Fernandez J, Casulleras M, López-Vicario C, Muldur S, Hopke A, Vlagea A, Aransay AM, Marchese D, Bernardi M, Jalan R, Angeli P, Magri G, Cerutti A, Irimia D, Heyn H, Arroyo V, Moreau R. Albumin reprograms the B cell transcriptional landscape and improves neutrophil antimicrobial function in patients with decompensated cirrhosis. JHEP Rep 2024; 6:101184. [PMID: 39434891 PMCID: PMC11490805 DOI: 10.1016/j.jhepr.2024.101184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 07/26/2024] [Accepted: 07/31/2024] [Indexed: 10/23/2024] Open
Abstract
Background & Aims Patients with acutely decompensated (AD) cirrhosis are immunocompromised and particularly susceptible to infections. This study investigated the immunomodulatory actions of albumin by which this protein may lower the incidence of infections. Methods Blood immunophenotyping was performed in 11 patients with AD cirrhosis and 10 healthy volunteers (HV). Bulk and single-cell RNA sequencing (scRNA-seq) and flow cytometry were performed in peripheral blood mononuclear cells (PBMCs) from 20 patients with AD cirrhosis and 34 HV exposed to albumin. Albumin's effects on degranulation, phagocytosis, chemotaxis, and swarming of neutrophils from six patients with AD cirrhosis and nine HV were assessed by measuring myeloperoxidase enzymatic activity, the engulfment of fluorescent-labeled Escherichia coli and zymosan, and interactions of neutrophils with Candida albicans at single-cell resolution in microfluidic chambers, respectively. Whole blood RNA sequencing (RNA-seq) analyses were performed in 49 patients admitted for severe AD cirrhosis, of whom 30 received albumin during hospitalization. Results Compared with HV, patients with AD cirrhosis showed severe lymphopenia and defective neutrophil antimicrobial function. Bulk and scRNA-seq analyses revealed significantly (false discovery rate [FDR] <0.05) increased signatures related to B cells, myeloid cells, and CD4+ T cells in PBMCs incubated with albumin. Changes in the B cell population were confirmed by flow cytometry. Neutrophils exposed to albumin also exhibited augmented chemotactic and degranulation responses, enhanced phagocytosis, and increased pathogen-restrictive swarming. RNA-seq data analysis in patients who had received albumin revealed specific upregulation of signatures related to B cells and neutrophils together with transcriptional changes in CD4+ T cells (FDR <0.05). Conclusions The finding that albumin promotes the transcriptional reprogramming and expansion of the B cell compartment and improves neutrophil antimicrobial functions indicates mechanisms that may lower the incidence of infections in patients with severe AD cirrhosis receiving albumin therapy. Impact and implications Patients with acutely decompensated cirrhosis receiving albumin as treatment have a lower incidence of infections. The reason for this protection is currently unknown, but the present study provides data that support the ability of albumin to boost the antimicrobial functions of immune cells in these patients. Moreover, these findings encourage the design of controlled clinical studies specifically aimed at investigating the effects of albumin administration on the immune system.
Collapse
Affiliation(s)
- Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Hospital Clínic-IDIBAPS, Barcelona, Spain
- CIBER of Hepatic and Digestive Diseases (CIBERehd); Barcelona, Spain
- Universitat de Barcelona, Barcelona, Spain
| | - Ferran Aguilar
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
| | - Juan-José Lozano
- CIBER of Hepatic and Digestive Diseases (CIBERehd); Barcelona, Spain
| | - Laura Jiménez-Gracia
- Universitat de Barcelona, Barcelona, Spain
- Centre Nacional d’Anàlisi Genòmica (CNAG), Barcelona, Spain
| | - Juan C. Nieto
- Universitat de Barcelona, Barcelona, Spain
- Centre Nacional d’Anàlisi Genòmica (CNAG), Barcelona, Spain
| | - Berta Romero-Grimaldo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Hospital Clínic-IDIBAPS, Barcelona, Spain
- CIBER of Hepatic and Digestive Diseases (CIBERehd); Barcelona, Spain
| | - Xavi Marcos-Fa
- Translational Clinical Research Program, Institute “Hospital del Mar” for Medical Investigations (IMIM), Barcelona, Spain
| | - Emma Giarracco
- Translational Clinical Research Program, Institute “Hospital del Mar” for Medical Investigations (IMIM), Barcelona, Spain
| | - Emmanuel Weiss
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Cité, Centre de Recherche sur l’Inflammation (CRI), Paris, France
- Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Beaujon, Département d’Anesthésie et de Réanimation, DMU Parabol, Clichy, France
| | - Jonel Trebicka
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Inmaculada Hernàndez
- Universitat de Barcelona, Barcelona, Spain
- Centre Nacional d’Anàlisi Genòmica (CNAG), Barcelona, Spain
- Institute for Research in Biomedicine (IRB), Barcelona, Spain
| | - Javier Fernandez
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Hospital Clínic-IDIBAPS, Barcelona, Spain
| | - Mireia Casulleras
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Hospital Clínic-IDIBAPS, Barcelona, Spain
| | - Cristina López-Vicario
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Hospital Clínic-IDIBAPS, Barcelona, Spain
- CIBER of Hepatic and Digestive Diseases (CIBERehd); Barcelona, Spain
| | - Sinan Muldur
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical School, Boston, MA, USA
| | - Alex Hopke
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Ana M. Aransay
- CIBER of Hepatic and Digestive Diseases (CIBERehd); Barcelona, Spain
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Parque Tecnológico de Bizkaia, Derio, Spain
| | - Domenica Marchese
- Universitat de Barcelona, Barcelona, Spain
- Centre Nacional d’Anàlisi Genòmica (CNAG), Barcelona, Spain
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rajiv Jalan
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Liver Failure Group, Institute for Liver Disease Health, University College London, Royal Free Hospital, London, UK
| | - Paolo Angeli
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine – DIMED, University of Padova, Padova, Italy
| | - Giuliana Magri
- Immunology Unit, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Andrea Cerutti
- Translational Clinical Research Program, Institute “Hospital del Mar” for Medical Investigations (IMIM), Barcelona, Spain
- Catalan Institute for Research and Advanced Studies (ICREA); Barcelona, Spain
| | - Daniel Irimia
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Shriners Burns Hospital, Harvard Medical School, Boston, MA, USA
| | - Holger Heyn
- Universitat de Barcelona, Barcelona, Spain
- Centre Nacional d’Anàlisi Genòmica (CNAG), Barcelona, Spain
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), European Association for the Study of the Liver (EASL)–CLIF Consortium, and Grifols Chair, Barcelona, Spain
- Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Cité, Centre de Recherche sur l’Inflammation (CRI), Paris, France
- Assistance Publique – Hôpitaux de Paris (AP-HP), Hôpital Beaujon, Service d’Hépatologie, Clichy, France
| |
Collapse
|
|
17
|
Marciano S, Piano S, Singh V, Caraceni P, Maiwall R, Alessandria C, Fernandez J, Kim DJ, Kim SE, Soares E, Marino M, Vorobioff J, Merli M, Elkrief L, Vargas V, Krag A, Singh S, Elizondo M, Anders MM, Dirchwolf M, Mendizabal M, Lesmana CRA, Toledo C, Wong F, Durand F, Gadano A, Giunta DH, Angeli P. Development and external validation of a model to predict multidrug-resistant bacterial infections in patients with cirrhosis. Liver Int 2024; 44:2915-2928. [PMID: 39148354 DOI: 10.1111/liv.16063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/11/2024] [Accepted: 07/28/2024] [Indexed: 08/17/2024]
Abstract
With the increasing rate of infections caused by multidrug-resistant organisms (MDRO), selecting appropriate empiric antibiotics has become challenging. We aimed to develop and externally validate a model for predicting the risk of MDRO infections in patients with cirrhosis. METHODS We included patients with cirrhosis and bacterial infections from two prospective studies: a transcontinental study was used for model development and internal validation (n = 1302), and a study from Argentina and Uruguay was used for external validation (n = 472). All predictors were measured at the time of infection. Both culture-positive and culture-negative infections were included. The model was developed using logistic regression with backward stepwise predictor selection. We externally validated the optimism-adjusted model using calibration and discrimination statistics and evaluated its clinical utility. RESULTS The prevalence of MDRO infections was 19% and 22% in the development and external validation datasets, respectively. The model's predictors were sex, prior antibiotic use, type and site of infection, MELD-Na, use of vasopressors, acute-on-chronic liver failure, and interaction terms. Upon external validation, the calibration slope was 77 (95% CI .48-1.05), and the area under the ROC curve was .68 (95% CI .61-.73). The application of the model significantly changed the post-test probability of having an MDRO infection, identifying patients with nosocomial infection at very low risk (8%) and patients with community-acquired infections at significant risk (36%). CONCLUSION This model achieved adequate performance and could be used to improve the selection of empiric antibiotics, aligning with other antibiotic stewardship program strategies.
Collapse
Affiliation(s)
- Sebastián Marciano
- Liver Unit and Research Department, Hospital Italiano Buenos Aires, Buenos Aires, Argentina
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| | - Virendra Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Paolo Caraceni
- Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Rakhi Maiwall
- Institute of Liver and Biliary Sciences, New Delhi, India
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Turin, Italy
| | - Javier Fernandez
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain
- Institut d'Investigacions Biomèdiques August-PiSunyer, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Catalonia, Spain
- European Foundation of Chronic Liver Failure (EF-Clif), Barcelona, Catalonia, Spain
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Sung Eun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Anyang City, Republic of Korea
| | - Elza Soares
- Gastroenterology Division, Medicine Department, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Mónica Marino
- Liver Unit, Hospital Dr. Carlos B. Udaondo, Buenos Aires, Argentina
| | | | - Manuela Merli
- Department of translation and precision medicine, University of Rome Sapienza, Rome, Italy
| | - Laure Elkrief
- Service de Transplantation, Service d'Hépato-gastroentérologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Victor Vargas
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, CIBERehd, Barcelona, Spain
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Shivaram Singh
- Department of Gastroenterology, S.C.B. Medical College, Cuttack, India
| | - Martín Elizondo
- Bi-Institutional Liver Transplant Unit Center (Hospital de Clínicas-Military Hospital), Montevideo, Uruguay
| | - Maria M Anders
- Liver Unit, Hospital Aleman Buenos Aires, Buenos Aires, Argentina
| | | | | | - Cosmas R A Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia
- Medical Faculty, Universitas Indonesia, Jakarta, Indonesia
- Digestive Disease & GI Oncology Centre, Medistra Hospital, Jakarta, Indonesia
| | - Claudio Toledo
- Gastroenterology Unit, Hospital Valdivia, Universidad Austral de Chile, Valdivia, Chile
| | - Florence Wong
- Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Francois Durand
- Hepatology & Liver Intensive Care, Hospital Beaujon, University Paris Diderot, Paris, France
| | - Adrián Gadano
- Liver Unit and Research Department, Hospital Italiano Buenos Aires, Buenos Aires, Argentina
| | - Diego H Giunta
- Hospital Italiano Buenos Aires University, Buenos Aires, Argentina
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy
| |
Collapse
|
|
18
|
Ferguson Toll J, Solà E, Perez MA, Piano S, Cheng A, Subramanian AK, Kim WR. Infections in decompensated cirrhosis: Pathophysiology, management, and research agenda. Hepatol Commun 2024; 8:e0539. [PMID: 39365139 PMCID: PMC11458171 DOI: 10.1097/hc9.0000000000000539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 08/01/2024] [Indexed: 10/05/2024] Open
Abstract
Bacterial infections in patients with cirrhosis lead to a 4-fold increase in mortality. Immune dysfunction in cirrhosis further increases the risk of bacterial infections, in addition to alterations in the gut microbiome, which increase the risk of pathogenic bacteria. High rates of empiric antibiotic use contribute to increased incidence of multidrug-resistant organisms and further increases in mortality. Despite continous advances in the field, major unknowns regarding interactions between the immune system and the gut microbiome and strategies to reduce infection risk and improve mortality deserve further investigation. Here, we highlight the unknowns in these major research areas and make a proposal for a research agenda to move toward improving disease progression and outcomes in patients with cirrhosis and infections.
Collapse
Affiliation(s)
- Jessica Ferguson Toll
- Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Elsa Solà
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA
| | | | - Salvatore Piano
- Department of Medicine, University Hospital of Padova, Padova, Italy
| | - Alice Cheng
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Aruna K. Subramanian
- Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - W. Ray Kim
- Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| |
Collapse
|
|
19
|
Incicco S, Angeli P, Piano S. Infectious Complications of Portal Hypertension. Clin Liver Dis 2024; 28:525-539. [PMID: 38945641 DOI: 10.1016/j.cld.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Patients with cirrhosis and clinically significant portal hypertension are at high risk of developing bacterial infections (BIs) that are the most common trigger of acute decompensation and acute-on-chronic liver failure. Furthermore, after decompensation, the risk of developing BIs further increases in an ominous vicious circle. BIs may be subtle, and they should be ruled out in all patients at admission and in case of deterioration. Timely administration of adequate empirical antibiotics is the cornerstone of treatment. Herein, we reviewed current evidences about pathogenesis, clinical implications and management of BIs in patients with cirrhosis and portal hypertension.
Collapse
Affiliation(s)
- Simone Incicco
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy.
| |
Collapse
|
|
20
|
Piano S, Bunchorntavakul C, Marciano S, Rajender Reddy K. Infections in cirrhosis. Lancet Gastroenterol Hepatol 2024; 9:745-757. [PMID: 38754453 DOI: 10.1016/s2468-1253(24)00078-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 05/18/2024]
Abstract
Cirrhosis is an immune dysfunction state, and as such, patients with cirrhosis are susceptible to bacterial, fungal, and viral infections. Because of infection, these patients have a propensity to develop multiorgan failure, which is associated with high mortality. Bacterial infections are the most prevalent type of infection in patients with cirrhosis, with the prevalence of bacterial infections in patients admitted for an acute decompensating event ranging from 24% to 29%. Together with invasive fungal infections, bacterial infections are the most severe. Multidrug-resistant organisms have been evolving at a rapid and alarming rate around the world, which presents enormous challenges. The development of effective measures for the prevention, early detection, and treatment of infections in patients with cirrhosis is challenging, given the rising incidence of infections in this patient population.
Collapse
Affiliation(s)
- Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine, University and Hospital of Padova, Padova, Italy
| | | | - Sebastian Marciano
- Department of Clinical Investigation, Italian Hospital, Buenos Aires, Argentina
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
|
21
|
Fernández J, Blasi A, Hidalgo E, Karvellas CJ. Bridging the critically ill patient with acute to chronic liver failure to liver transplantation. Am J Transplant 2024; 24:1348-1361. [PMID: 38548058 DOI: 10.1016/j.ajt.2024.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/16/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024]
Abstract
Liver transplantation (LT) has emerged as an effective therapy for severe forms of acute-on-chronic liver failure (ACLF), an entity characterized by the development of multiorgan failure and high short-term mortality. The aim of critical care management of ACLF patients is to rapidly treat precipitating events and aggressively support failing organs to ensure that patients may successfully undergo LT or, less frequently, recover. Malnutrition and sarcopenia are frequently present, adversely impacting the prognosis of these patients. Management of critical care patients with ACLF is complex and requires the participation of different specialties. Once the patient is stabilized, a rapid evaluation for salvage LT should be performed because the time window for LT is often narrow. The development of sepsis and prolonged organ support may preclude LT or diminish its chances of success. The current review describes strategies to bridge severe ACLF patients to LT, highlights the minimal evaluation required for listing and the currently suggested contraindications to proceed with LT, and addresses different aspects of management during the perioperative and early posttransplant period.
Collapse
Affiliation(s)
- Javier Fernández
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Spain; EF Clif, EASL-CLIF Consortium, Barcelona, Spain.
| | - Annabel Blasi
- Anesthesiology Department, Hospital Clínic, and University of Barcelona, Spain
| | - Ernest Hidalgo
- Hepatolobiliary Surgery Department, Hospital Vall d'Hebron, Barcelona, Spain
| | - Constantine J Karvellas
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada; Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
| |
Collapse
|
|
22
|
Igna R, Muzica C, Zenovia S, Minea H, Girleanu I, Huiban L, Trifan A. The value of presepsin and procalcitonin as prognostic factors for mortality in patients with alcoholic liver cirrhosis and acute on chronic liver failure. Arch Clin Cases 2024; 11:61-68. [PMID: 39015298 PMCID: PMC11250657 DOI: 10.22551/2024.43.1102.10290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2024] Open
Abstract
Background: Acute on chronic liver failure (ACLF) is typically characterized by a rapid progression of liver failure in patients with liver cirrhosis and it is triggered by a precipitant factor, usually a bacterial infection (BI). Considering the low accuracy of the inflammation biomarkers in liver cirrhosis, presepsin and procalcitonin have demonstrated a good diagnostic performance for BI. Understanding the key prognostic factors that influence patient outcomes can significantly impact clinical decision-making and improve patient care in ACLF which can lead to lower mortality rates. Aim: To evaluate the prognostic factors associated with 30-day mortality in patients with alcohol-related liver cirrhosis and ACLF. Methods: This retrospective study on 227 patients diagnosed with ACLF and alcohol-related liver cirrhosis analyzed the prognostic role of presepsin and procalcitonin serum levels. Results: The survival analysis according to the grade of ACLF showed that more than 80% of patients with ACLF grade 1 survived after 30 days, with a mean estimated time of death of 29 ±0.44 days (95 % CI: 28.17-29.92) compared to ACLF grade 2 (24.9±1.064 days; 95 % CI: 22.82-26.99) and ACLF grade 3 (21.05±1.17 days; 95 % CI: 18.75-23.34), with a mean overall survival on entire cohort of 25.69±0.52 days (95 % CI: 24.65-26.73). Presepsin (OR: 4.008, CI 95:3.130-6.456, p=0.001) and procalcitonin (OR: 3.666, CI 95:2.312-5.813, p=0.001) were the most significant factors associated with 30-day mortality. In ACLF grade 2, presepsin provides a better prediction of mortality at the cutoff value of 1050 pg/mL (Sensitivity 72%, Specificity 69%) than procalcitonin (AUC=0.727 95% CI 0.594-0.860, p<0.002) whereas in ACLF grade 3, a cutoff of 1450 pg/mL (Sensitivity 89%, Specificity 91%) presepsin had a more significant accuracy of mortality prediction (AUC=0.93 95% CI 0.81-0.99, p<0.001) than procalcitonin (AUC=0.731 95% CI 0.655-0.807, p<0.001). Conclusion: ACLF is associated with a high mortality rate and the risk of death increases with the grade of ACLF. Presepsin and procalcitonin serum levels are good prognostic factors for 30-day mortality and should be used in clinical practice to stratify the risk and provide and early and efficient treatment in patients with ACLF.
Collapse
Affiliation(s)
- Răzvan Igna
- Intensive Care Unit, “Sf. Spiridon” University Hospital, Iasi, Romania
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Cristina Muzica
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” University Hospital, Iasi, Romania
| | - Sebastian Zenovia
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” University Hospital, Iasi, Romania
| | - Horia Minea
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” University Hospital, Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” University Hospital, Iasi, Romania
| | - Laura Huiban
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” University Hospital, Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” University Hospital, Iasi, Romania
| |
Collapse
|
|
23
|
Carelli S, Posteraro B, Torelli R, De Carolis E, Vallecoccia MS, Xhemalaj R, Cutuli SL, Tanzarella ES, Dell'Anna AM, Lombardi G, Cammarota F, Caroli A, Grieco DL, Sanguinetti M, Antonelli M, De Pascale G. Prognostic value of serial (1,3)-β-D-glucan measurements in ICU patients with invasive candidiasis. Crit Care 2024; 28:236. [PMID: 38997712 PMCID: PMC11241937 DOI: 10.1186/s13054-024-05022-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 07/06/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND To determine whether a decrease in serum (1,3)-β-D-glucan (BDG) was associated with reduced mortality and to investigate the performance of BDG downslope in predicting clinical outcome in invasive candidiasis. METHODS Observational cohort study in ICU patients over a ten-year period (2012-2022) in Italy. Proven invasive candidiasis with at least 2 BDG determinations were considered. RESULTS In the study population of 103 patients (age 47 [35-62] years, SAPS II score 67 [52-77]) 68 bloodstream and 35 intrabdominal infections were recorded. Serial measurements showed that in 54 patients BDG decreased over time (BDG downslope group) while in 49 did not (N-BDG downslope group). Candida albicans was the pathogen most frequently isolated (61%) followed by C. parapsilosis (17%) and C. glabrata (12%), in absence of any inter-group difference. Invasive candidiasis related mortality was lower in BDG downslope than in N-BDG downslope group (17% vs 53%, p < 0.01). The multivariate Cox regression analysis showed the association of septic shock at infection occurrence and chronic liver disease with invasive candidiasis mortality (HR [95% CI] 3.24 [1.25-8.44] p = 0.02 and 7.27 [2.33-22.66] p < 0.01, respectively) while a BDG downslope was the only predictor of survival (HR [95% CI] 0.19 [0.09-0.43] p < 0.01). The area under the receiver operator characteristic curve for the performance of BDG downslope as predictor of good clinical outcome was 0.74 (p = 0.02) and our model showed that a BDG downslope > 70% predicted survival with both specificity and positive predictive value of 100%. CONCLUSIONS A decrease in serum BDG was associated with reduced mortality and a steep downslope predicted survival with high specificity in invasive candidiasis.
Collapse
Affiliation(s)
- Simone Carelli
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy.
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Brunella Posteraro
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Riccardo Torelli
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Elena De Carolis
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Maria Sole Vallecoccia
- Anesthesia and Intensive Care Unit, Department of Emergency and Critical Care, Santa Maria Nuova Hospital, Florence, Italy
| | - Rikardo Xhemalaj
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Salvatore Lucio Cutuli
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Eloisa Sofia Tanzarella
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Maria Dell'Anna
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gianmarco Lombardi
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Fabiola Cammarota
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandro Caroli
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Domenico Luca Grieco
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maurizio Sanguinetti
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Massimo Antonelli
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gennaro De Pascale
- Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
| |
Collapse
|
|
24
|
Campello E, Zanetto A, Radu CM, Toffanin S, Shalaby S, Gavasso S, Rizzo S, Perin N, Angeli P, Burra P, Senzolo M, Simioni P. Profiling plasma alterations of extracellular vesicles in patients with acutely decompensated cirrhosis and bacterial infection. Liver Int 2024; 44:1610-1623. [PMID: 38517208 DOI: 10.1111/liv.15889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 02/08/2024] [Accepted: 02/19/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND Extracellular vesicles (EVs) modulate inflammation, coagulation and vascular homeostasis in decompensated cirrhosis. AIM To characterize the profile of plasmatic EVs in patients with decompensated cirrhosis and bacterial infections and evaluate the association between EVs and the development of hemostatic complications. METHODS We measured the levels of EVs using high-sensitivity flow cytometry and phospholipid-dependent clotting time (PPL) in a prospective cohort of hospitalized patients with acutely decompensated cirrhosis with versus without bacterial infections. A separate cohort of patients with bacterial infections without cirrhosis was also enrolled. We measured endothelium-, tissue factor (TF)-bearing, platelet- and leukocyte-derived EVs. In patients with infections, EVs were reassessed upon resolution of infection. Bleeding and thrombotic complications were recorded during 1-year follow-up. RESULTS Eighty patients with decompensated cirrhosis were recruited (40 each with and without bacterial infections). Electron microscopy confirmed the presence of plasma EVs. Despite no difference in total EVs and PPL, patients with cirrhosis and infection had significantly higher TF+ EVs, P-Selectin+ EVs (activated platelet-derived), CD14+ EVs (monocyte/macrophages derived) and CD14+ TF+ EVs versus those with cirrhosis without infection. Upon infection resolution, levels of these EVs returned to those without infection. Patients with infections showed a significant association between reduced P-Selectin+ EVs and bleeding complications (HR 8.0 [95%CI 1.3-48.1]), whereas high levels of leukocyte-derived EVs (CD45+) and CD14+ EVs were significantly associated with thrombotic complications (HR 16.4 [95%CI 1.7-160] and 10.9 [95%CI 1.13-106], respectively). Results were confirmed in a validation cohort. CONCLUSION Bacterial infections are associated with particular alterations of plasma EVs profile in decompensated cirrhosis. Bacterial infections trigger the release of EVs originating from various cell types, which may tip the precarious hemostatic balance of patients with acutely decompensated cirrhosis towards hyper- or hypocoagulability.
Collapse
Affiliation(s)
- Elena Campello
- Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Claudia M Radu
- Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Serena Toffanin
- Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Sabrina Gavasso
- Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Stefania Rizzo
- Cardiovascular Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padova University Hospital, Padova, Italy
| | - Nicola Perin
- Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, Padova University Hospital, Padova, Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Paolo Simioni
- Thrombotic and Hemorrhagic Diseases Unit, General Internal Medicine, Department of Medicine, Padova University Hospital, Padova, Italy
| |
Collapse
|
|
25
|
Tantia P, Aggarwal P, Acharya S, Kumar S, Kothari M, Kadam A, Patil R. Exploring Haematological Complications in Cirrhosis of the Liver: A Comprehensive Review. Cureus 2024; 16:e65319. [PMID: 39184703 PMCID: PMC11344626 DOI: 10.7759/cureus.65319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
Various chronic liver diseases inevitably end up with cirrhosis of the liver, and this comes with a whole range of haematological complications. Therefore, this detailed review has discussed pathophysiology, clinical manifestations, diagnostic measures, and treatment plans for these anomalies. Closely related are conditions such as anaemia, thrombocytopenia, coagulopathy, leukopenia, and haemolytic disorders, which are known to contribute to morbidity and mortality in cirrhotic patients significantly. Therefore, we need to understand the causes of these problems to find ways of helping our patients better. For this reason, multidisciplinary management will be key in ensuring proper monitoring, timely intervention, and preventive measures for haematological abnormalities in cirrhosis. Additionally, there have been tremendous advancements in therapeutic options, like adjunctive therapies or haematopoietic growth factors, which hold much promise regarding patient outcomes. This article emphasizes the proactive management of haematological complications associated with cirrhosis while highlighting the need for further research coupled with collaboration aimed at strengthening prevention strategies, diagnostic methods, and curative interventions.
Collapse
Affiliation(s)
- Parav Tantia
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Parth Aggarwal
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sourya Acharya
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sunil Kumar
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Manjeet Kothari
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Abhinav Kadam
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Rajvardhan Patil
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| |
Collapse
|
|
26
|
Velarde-Ruiz Velasco JA, Crespo J, Montaño-Loza A, Aldana-Ledesma JM, Cano-Contreras AD, Cerda-Reyes E, Fernández Pérez NJ, Castro-Narro GE, García-Jiménez ES, Lira-Vera JE, López-Méndez YI, Meza-Cardona J, Moreno-Alcántar R, Pérez-Escobar J, Pérez-Hernández JL, Tapia-Calderón DK, Higuera-de-la-Tijera F. Position paper on perioperative management and surgical risk in the patient with cirrhosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:418-441. [PMID: 39003101 DOI: 10.1016/j.rgmxen.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/02/2024] [Indexed: 07/15/2024]
Abstract
INTRODUCTION Management of the patient with cirrhosis of the liver that requires surgical treatment has been relatively unexplored. In Mexico, there is currently no formal stance or expert recommendations to guide clinical decision-making in this context. AIMS The present position paper reviews the existing evidence on risks, prognoses, precautions, special care, and specific management or procedures for patients with cirrhosis that require surgical interventions or invasive procedures. Our aim is to provide recommendations by an expert panel, based on the best published evidence, and consequently ensure timely, quality, efficient, and low-risk care for this specific group of patients. RESULTS Twenty-seven recommendations were developed that address preoperative considerations, intraoperative settings, and postoperative follow-up and care. CONCLUSIONS The assessment and care of patients with cirrhosis that require major surgical or invasive procedures should be overseen by a multidisciplinary team that includes the anesthesiologist, hepatologist, gastroenterologist, and clinical nutritionist. With respect to decompensated patients, a nephrology specialist may be required, given that kidney function is also a parameter involved in the prognosis of these patients.
Collapse
Affiliation(s)
- J A Velarde-Ruiz Velasco
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - J Crespo
- Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - A Montaño-Loza
- División de Gastroenterología y Hepatología, Hospital de la Universidad de Alberta, Alberta, Canada
| | - J M Aldana-Ledesma
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - A D Cano-Contreras
- Instituto de Investigaciones Médico Biológicas, Universidad Veracruzana, Veracruz, Veracruz, Mexico
| | | | | | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - E S García-Jiménez
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - J E Lira-Vera
- Servicio de Gastroenterología y Hepatología, Hospital Central «Dr. Ignacio Morones Prieto», San Luis Potosí, San Luis Potosí, Mexico
| | - Y I López-Méndez
- Departamento de Gastroenterología, Medica Sur, Mexico City, Mexico
| | - J Meza-Cardona
- Departamento de Gastroenterología, Hospital Español, Mexico City, Mexico
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades «Dr. Bernando Sepúlveda», UMAE Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - J Pérez-Escobar
- Servicio de Gastroenterología y Unidad de Trasplante Hepático, Hospital Juárez de México, Mexico City, Mexico
| | - J L Pérez-Hernández
- Servicio de Gastroenterología y Hepatología, Hospital General de México «Dr. Eduardo Liceaga», Mexico City, Mexico
| | - D K Tapia-Calderón
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - F Higuera-de-la-Tijera
- Servicio de Gastroenterología y Hepatología, Hospital General de México «Dr. Eduardo Liceaga», Mexico City, Mexico.
| |
Collapse
|
|
27
|
Rigo-Bonnin R, Amador A, Núñez-Gárate M, Mas-Bosch V, Padullés A, Cobo-Sacristán S, Castellote J. Medición de la concentración de ertapenem en el plasma y líquido ascítico mediante UHPLC-MS/MS. Aplicación en pacientes cirróticos con peritonitis bacteriana espontánea. ADVANCES IN LABORATORY MEDICINE 2024; 5:181-188. [PMID: 38939206 PMCID: PMC11206186 DOI: 10.1515/almed-2023-0122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
Objetivos La peritonitis bacteriana espontánea es una complicación frecuente y grave de los pacientes cirróticos con ascitis. Actualmente, los antibióticos carbapenémicos son el tratamiento de elección en pacientes con peritonitis nosocomiales o relacionadas con el sistema sanitario. Pese a ello, los estudios de eficacia del ertapenem en pacientes cirróticos con peritonitis bacteriana espontánea son limitados y la farmacocinética y farmacodinamia de este antibiótico continúa siendo desconocida. Así, el objetivo de este estudio es desarrollar y validar procedimientos de medida basados en la cromatografía líquida de alta y rápida eficacia acoplada a la espectrometría de masas en tándem (UHPLC-MS/MS) para medir las concentraciones de ertapenem en el plasma y en el líquido ascítico. Métodos El pretratamiento de las muestras se realiza utilizando una precipitación de proteínas con acetonitrilo. La separación cromatográfica se lleva a cabo en una columna C18 de fase inversa Acquity®-UPLC®-BEHTM (2,1 × 100 mm id, 1,7 µm) utilizando un gradiente no lineal de agua/acetonitrilo que contiene un 0,1 % de ácido fórmico y an un flujo de 0,4 mL/min. El ertapenem y su patrón interno (ertapenem-D4) son detectados mediante espectrometría de masas en tándem en las modalidades de ionización mediante electroespray positiva y de monitorización múltiple de reacción utilizando, como transiciones de masa, 476,2→346,0/432,2 para el ertapenem y 480,2→350,0 para su patrón interno. Resultados No se observan interferencias ni contaminación por arrastre significativas. Las imprecisiones, los sesgos relativos absolutos, así como los efectos matriz y recuperaciones normalizadas son ≤14,5 %, ≤9,3 %, (92,8−104,5) % y (98,8−105,8) %, respectivamente. Los procedimientos de medida cromatográficos son lineales entre (0,50−100) mg/L. Conclusiones Los procedimientos de medida basados en la UHPLC-MS/MS desarrollados y validados podrían ser de utilidad para realizar estudios farmacocinéticos y farmacodinámicos en sujetos con cirrosis hepática que presentan peritonitis bacteriana espontánea tratados con ertapenem.
Collapse
Affiliation(s)
- Raúl Rigo-Bonnin
- Laboratorio Clínico, Hospital Universitario de Bellvitge, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, España
| | - Alberto Amador
- Servicio de Farmacia, Hospital Universitario de Bellvitge, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, España
| | - María Núñez-Gárate
- Laboratorio Clínico, Hospital Universitario de Bellvitge, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, España
| | - Virgínia Mas-Bosch
- Laboratorio Clínico, Hospital Universitario de Bellvitge, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, España
| | - Ariadna Padullés
- Unidad de Hepatología y Trasplante Hepático, Servicio de Aparato Digestivo, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, España
| | - Sara Cobo-Sacristán
- Unidad de Hepatología y Trasplante Hepático, Servicio de Aparato Digestivo, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, España
| | - José Castellote
- Servicio de Farmacia, Hospital Universitario de Bellvitge, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, España
| |
Collapse
|
|
28
|
Rigo-Bonnin R, Amador A, Núñez-Gárate M, Mas-Bosch V, Padullés A, Cobo-Sacristán S, Castellote J. Determination of ertapenem in plasma and ascitic fluid by UHPLC-MS/MS in cirrhotic patients with spontaneous bacterial peritonitis. ADVANCES IN LABORATORY MEDICINE 2024; 5:173-180. [PMID: 38939197 PMCID: PMC11206183 DOI: 10.1515/almed-2023-0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/12/2023] [Indexed: 06/29/2024]
Abstract
Objectives Spontaneous bacterial peritonitis is a frequent severe complication in cirrhotic patients with ascites. Carbapenem antibiotics are currently the treatment of choice for patients with hospital-acquired or healthcare-related infections. However, there is limited evidence available on the efficacy of ertapenem in cirrhotic patients with spontaneous bacterial peritonitis. As a result, the pharmacokynetics and pharmacodynamics of this antibiotic are still unknown. The objective of this study was to develop and validate measurement procedures based on liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to determine ertapenem concentrations in plasma and ascitic fluid. Methods Samples were pretreated by acetronile protein-precipitation. Chromatographic separation is performed on a C18 reversed-phase Acquity®-UPLC®-BEHTM column (2.1 × 100 mm id, 1.7 µm) using a non-linear gradient of water/acetonitrile containing 0.1 % of formic acid at a flow rate of 0.4 mL/min. Ertapenem and its internal standard (ertapenem-D4) are detected by tandem mass spectrometry using positive electrospray ionization and multiple reaction monitoring, and using 476.2 → 346.0/432.2 as mass transition for ertapenem and 480.2 → 350.0 for its internal standard. Results No significant interferences or carry-over contamination were observed. Imprecisions, absolute relative bias, matrix effects and normalized recoveries were ≤14.5 %, ≤9.3 % (92.8-104.5) % and (98.8-105.8) %, respectively. Chromatographic measurement procedures were linear from (0.50-100) mg/L. Conclusions The measurement procedures based on UHPLC-MS/MS developed and validated in this study could be useful in pharmacokynetic and pharmacodynamic studies in subjects with liver cirrhosis who develop spontaneous bacterial peritonitis treated with ertapenem.
Collapse
Affiliation(s)
- Raúl Rigo-Bonnin
- Clinical Laboratory, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Alberto Amador
- Service of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - María Núñez-Gárate
- Clinical Laboratory, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Virgínia Mas-Bosch
- Clinical Laboratory, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Ariadna Padullés
- Unit of Hepatology and Liver Transplant, Service of Gastroenterology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Sara Cobo-Sacristán
- Unit of Hepatology and Liver Transplant, Service of Gastroenterology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - José Castellote
- Service of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| |
Collapse
|
|
29
|
Kosuta I, Premkumar M, Reddy KR. Review article: Evaluation and care of the critically ill patient with cirrhosis. Aliment Pharmacol Ther 2024; 59:1489-1509. [PMID: 38693712 DOI: 10.1111/apt.18016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/21/2024] [Accepted: 04/12/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND The increase in prevalence of liver disease globally will lead to a substantial incremental burden on intensive care requirements. While liver transplantation offers a potential life-saving intervention, not all patients are eligible due to limitations such as organ availability, resource constraints, ongoing sepsis or multiple organ failures. Consequently, the focus of critical care of patients with advanced and decompensated cirrhosis turns to liver-centric intensive care protocols, to mitigate the high mortality in such patients. AIM Provide an updated and comprehensive understanding of cirrhosis management in critical care, and which includes emergency care, secondary organ failure management (mechanical ventilation, renal replacement therapy, haemodynamic support and intensive care nutrition), use of innovative liver support systems, infection control, liver transplantation and palliative and end-of life care. METHODS We conducted a structured bibliographic search on PubMed, sourcing articles published up to 31 March 2024, to cover topics addressed. We considered data from observational studies, recommendations of society guidelines, systematic reviews, and meta-analyses, randomised controlled trials, and incorporated our clinical expertise in liver critical care. RESULTS Critical care management of the patient with cirrhosis has evolved over time while mortality remains high despite aggressive management with liver transplantation serving as a crucial but not universally available resource. CONCLUSIONS Implementation of organ support therapies, intensive care protocols, nutrition, palliative care and end-of-life discussions and decisions are an integral part of critical care of the patient with cirrhosis. A multi-disciplinary approach towards critical care management is likely to yield better outcomes.
Collapse
Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Madhumita Premkumar
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
30
|
Trad N, Mohamed G, Bizid S, Abdallah HB, Bouali R, Abdelli MN. Clinical impact of multidrug-resistant bacterial infections in patients with cirrhosis. Future Sci OA 2024; 10:FSO945. [PMID: 38813115 PMCID: PMC11131343 DOI: 10.2144/fsoa-2023-0160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 11/17/2023] [Indexed: 05/31/2024] Open
Abstract
Aim: Recently, the emergency of multidrug-resistant organisms (MDRO) has complicated the management of bacterial infections (BI) in cirrhosis. We aimed to assess their clinical impact on patients with decompensated cirrhosis. Methods: A retrospective study included consecutive cirrhotic patients hospitalized for acute decompensation (AD) between January 2010 and December 2019. Results: A total of 518 AD admissions in 219 patients were included, with 260 BI episodes (50.2%). MDRO prevalence was 38.2% of the total isolates. Recent antibiotic use (OR = 4.91), nosocomial infection (OR = 2.95), and healthcare-associated infection (OR = 3.45) were their main risk factors. MDROs were associated with empiric treatment failure (OR = 23.42), a higher prevalence of sepsis (OR = 4.93), ACLF (OR = 3.42) and mortality. Conclusion: The clinical impact of MDROs was pejorative, with an increased risk of empiric treatment failure, organ failure and death.
Collapse
Affiliation(s)
- Nouha Trad
- Gastroenterology department, Principal Military Hospital of Instruction of Tunis, Faculty of medicine of Tunis, University Tunis El Manar Tunis, Tunisia
| | - Ghanem Mohamed
- Gastroenterology department, Principal Military Hospital of Instruction of Tunis, Faculty of medicine of Tunis, University Tunis El Manar Tunis, Tunisia
| | - Sondes Bizid
- Gastroenterology department, Principal Military Hospital of Instruction of Tunis, Faculty of medicine of Tunis, University Tunis El Manar Tunis, Tunisia
| | - Hatem Ben Abdallah
- Gastroenterology department, Principal Military Hospital of Instruction of Tunis, Faculty of medicine of Tunis, University Tunis El Manar Tunis, Tunisia
| | - Riadh Bouali
- Gastroenterology department, Principal Military Hospital of Instruction of Tunis, Faculty of medicine of Tunis, University Tunis El Manar Tunis, Tunisia
| | - Mohamed Nabil Abdelli
- Gastroenterology department, Principal Military Hospital of Instruction of Tunis, Faculty of medicine of Tunis, University Tunis El Manar Tunis, Tunisia
| |
Collapse
|
|
31
|
Wu P, Lee PC, Chang TE, Hsieh YC, Chiou JJ, Lin CH, Huang YL, Lin YT, Huo TI, Schnabl B, Lee KC, Hou MC. Fecal Carriage of Multidrug-Resistant Organisms Increases the Risk of Hepatic Encephalopathy in Cirrhotic Patients: Insights from Gut Microbiota and Metabolite Features. RESEARCH SQUARE 2024:rs.3.rs-4328129. [PMID: 38766152 PMCID: PMC11100873 DOI: 10.21203/rs.3.rs-4328129/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Background Impact of fecal colonization by multidrug-resistant organisms (MDROs) on changes in gut microbiota and associated metabolites, as well as its role in cirrhosis-associated outcomes, has not been thoroughly investigated. Methods Eighty-eight cirrhotic patients and 22 healthy volunteers were prospectively enrolled with analysis conducted on plasma metabolites, fecal MDROs, and microbiota. Patients were followed for a minimum of one year. Predictive factors for cirrhosis-associated outcomes were identified using Cox proportional hazards regression models, and risk factors for fecal MDRO carriage were assessed using logistic regression model. Correlations between microbiota and metabolic profiles were evaluated through Spearman's rank test. Results Twenty-nine (33%) cirrhotic patients exhibited MDRO carriage, with a notably higher rate of hepatic encephalopathy (HE) in MDRO carriers (20.7% vs. 3.2%, p = 0.008). Cox regression analysis identified higher serum lipopolysaccharide levels and fecal MDRO carriage as predictors for HE development. Logistic regression analysis showed that MDRO carriage is an independent risk factor for developing HE. Microbiota analysis showed a significant dissimilarity of fecal microbiota between cirrhotic patients with and without MDRO carriage (p = 0.033). Thirty-two metabolites exhibiting significantly different expression levels among healthy controls, cirrhotic patients with and without MDRO carriage were identified. Six of the metabolites showed correlation with specific bacterial taxa expression in MDRO carriers, with isoaustin showing significantly higher levels in MDRO carriers experiencing HE compared to those who did not. Conclusion Fecal MDRO carriage is associated with altered gut microbiota, metabolite modulation, and an elevated risk of HE occurrence within a year.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Yi-Long Huang
- National Yang Ming Chiao Tung University - Yangming Campus
| | | | | | | | | | | |
Collapse
|
|
32
|
Revelli L, Dirchwolf M. Editorial: Terlipressin and MDRO colonisation in cirrhosis-Is there a causal link? Aliment Pharmacol Ther 2024; 59:1284-1285. [PMID: 38652777 DOI: 10.1111/apt.17940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
LINKED CONTENTThis article is linked to Mücke et al paper. To view this article, visit https://doi.org/10.1111/apt.17899
Collapse
Affiliation(s)
- Luciano Revelli
- Liver Unit, Hospital Privado de Rosario, Santa Fe, Argentina
| | | |
Collapse
|
|
33
|
Maiwall R, Piano S, Singh V, Caraceni P, Alessandria C, Fernandez J, Soares EC, Kim DJ, Kim SE, Marino M, Vorobioff J, Ribeiro Barea RDC, Merli M, Elkrief L, Vargas V, Krag A, Singh SP, Lesmana LA, Toledo C, Marciano S, Verhelst X, Wong F, Intagliata N, Rabinowich L, Colombato L, Kim SG, Gerbes A, Durand F, Roblero JP, Bhamidimarri KR, Maevskaya M, Fassio E, Kim HS, Hwang JS, Gines P, Bruns T, Gadano A, Angeli P, Sarin SK. Determinants of clinical response to empirical antibiotic treatment in patients with cirrhosis and bacterial and fungal infections-Results from the ICA "Global Study" (EABCIR-Global Study). Hepatology 2024; 79:1019-1032. [PMID: 38047909 DOI: 10.1097/hep.0000000000000653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 06/30/2023] [Indexed: 12/05/2023]
Abstract
BACKGROUND The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites "Global Study." METHODS Patients hospitalized with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures. RESULTS From October 2015 to September 2016, 1302 patients were included at 46 centers. A clinical response was achieved in only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR = 1.16; 95% CI = 1.02-1.31), blood leukocyte count (OR = 1.39;95% CI = 1.09-1.77), serum albumin (OR = 0.70; 95% CI = 0.55-0.88), nosocomial infections (OR = 1.96; 95% CI = 1.20-2.38), pneumonia (OR = 1.75; 95% CI = 1.22-2.53), and ineffective treatment according to antibiotic susceptibility test (OR = 5.32; 95% CI = 3.47-8.57). Patients with a lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55% vs. 96%; p < 0.001), a higher incidence of second infections (29% vs. 15%; p < 0.001), shock (35% vs. 7%; p < 0.001) and new organ failures (52% vs. 19 %; p < 0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival ( subdistribution = 0.20; 95% CI = 0.14-0.27). CONCLUSIONS Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with a high degree of inflammation, low serum albumin levels, and severe liver impairment.
Collapse
Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine, DIMED, University of Padova, Padova, Italy
| | - Virendra Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Turin, Italy
| | - Javier Fernandez
- Liver ICU, Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
- Institut d'Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHED), Barcelona, Spain
- European Foundation of Chronic Liver Failure (EF-Clif), Barcelona, Spain
| | - Elza Cotrim Soares
- Gastroenterology Division, Medicine Department, Faculty of Medical Sciences, University of Campinas (UNICAMP). Campinas, São Paulo, Brazil
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Sung Eun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Anyang city, Republic of Korea
| | - Monica Marino
- Liver Unit, Hospital Dr. Carlos B. Udaondo, Buenos Aires, Argentina
| | | | | | - Manuela Merli
- Gastroenterology and Hepatology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Laure Elkrief
- Service de Transplantation, Service d'Hépato-gastroentérologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | - Victor Vargas
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, CIBERehd, Barcelona. Spain
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | | | | | - Claudio Toledo
- Gastroenterology Unit, Hospital Valdivia, Universidad Austral de Chile, Valdivia, Chile
| | - Sebastian Marciano
- Liver Unit and Department of Research, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Florence Wong
- Division of Gastroenterology, Department of Medicine, University of Toronto, Ontario, Canada
| | - Nicolas Intagliata
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA
| | - Liane Rabinowich
- Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center and Tel-Aviv University, Tel-Aviv, Israel
| | - Luis Colombato
- Gastroenterology Department, Buenos Aires British Hospital, Argentine Catholic University (UCA), Buenos Aires, Argentina
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea
| | - Alexander Gerbes
- Department of Medicine II, Liver Centre Munich, University Hospital, LMU Munich, Germany
| | - Francois Durand
- Hepatology & Liver Intensive Care, Hospital Beaujon, Clichy, University Paris Diderot, Paris, France
| | - Juan Pablo Roblero
- Departamento de Medicina, Universidad de Chile Campus Centro, Hospital Clínico San Borja Arriarán, Santiago, Chile
| | | | | | - Eduardo Fassio
- Liver Unit, Hospital Nacional Prof. Alejandro Posadas, El Palomar, Buenos Aires, Argentina
| | - Hyoung Su Kim
- Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Republic of Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Pere Gines
- Liver ICU, Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
- Institut d'Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHED), Barcelona, Spain
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Adrian Gadano
- Liver Unit and Department of Research, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine, DIMED, University of Padova, Padova, Italy
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| |
Collapse
|
|
34
|
Lin HR, Liao QX, Lin XX, Zhou Y, Lin JD, Xiao XJ. Development of a nomogram for predicting in-hospital mortality in patients with liver cirrhosis and sepsis. Sci Rep 2024; 14:9759. [PMID: 38684696 PMCID: PMC11059344 DOI: 10.1038/s41598-024-60305-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 04/21/2024] [Indexed: 05/02/2024] Open
Abstract
In this study, we aimed to investigate the risk factors associated with in-hospital mortality in patients with cirrhosis and sepsis, establish and validate the nomogram. This retrospective study included patients diagnosed with liver cirrhosis and sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV). Models were compared by the area under the curve (AUC), integrated discriminant improvement (IDI), net reclassification index (NRI) and decision curve analysis (DCA). A total of 1,696 patients with cirrhosis and sepsis were included in the final cohort. Our final model included the following 9 variables: age, heartrate, total bilirubin (TBIL), glucose, sodium, anion gap (AG), fungal infections, mechanical ventilation, and vasopressin. The nomogram were constructed based on these variables. The AUC values of the nomograms were 0.805 (95% CI 0.776-0.833), which provided significantly higher discrimination compared to that of SOFA score [0.684 (95% CI 0.647-0.720)], MELD-Na [0.672 (95% CI 0.636-0.709)] and ABIC [0.674(95% CI 0.638-0.710)]. We established the first nomogram for predicting in-hospital mortality in patients with liver cirrhosis and sepsis based on these factors. This nomogram can performs well and facilitates clinicians to identify people at high risk of in-hospital mortality.
Collapse
Affiliation(s)
- Hai-Rong Lin
- Department of Intensive Care Unit, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350004, China
- Department of Intensive Care Unit, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Qiu-Xia Liao
- Department of Intensive Care Unit, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350004, China
- Department of Intensive Care Unit, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xin-Xin Lin
- Department of Intensive Care Unit, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350004, China
- Department of Intensive Care Unit, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Ye Zhou
- Department of Intensive Care Unit, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350004, China
- Department of Intensive Care Unit, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Jian-Dong Lin
- Department of Intensive Care Unit, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350004, China
- Department of Intensive Care Unit, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xiong-Jian Xiao
- Department of Intensive Care Unit, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350004, China.
- Department of Intensive Care Unit, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
| |
Collapse
|
|
35
|
Sehrawat SS, Premkumar M. Critical care management of acute liver failure. Indian J Gastroenterol 2024; 43:361-376. [PMID: 38578565 DOI: 10.1007/s12664-024-01556-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/12/2024] [Indexed: 04/06/2024]
Abstract
The management of acute liver failure (ALF) in modern hepatology intensive care units (ICU) has improved patient outcomes. Critical care management of hepatic encephalopathy, cerebral edema, fluid and electrolytes; prevention of infections and organ support are central to improved outcomes of ALF. In particular, the pathogenesis of encephalopathy is multifactorial, with ammonia, elevated intra-cranial pressure and systemic inflammation playing a central role. Although ALF remains associated with high mortality, the availability of supportive care, including organ failure support such as plasma exchange, timely mechanical ventilation or continuous renal replacement therapy, either conservatively manages patients with ALF or offers bridging therapy until liver transplantation. Thus, appropriate critical care management has improved the likelihood of patient recovery in ALF. ICU care interventions such as monitoring of cerebral edema, fluid status assessment and interventions for sepsis prevention, nutritional support and management of electrolytes can salvage a substantial proportion of patients. In this review, we discuss the key aspects of critical care management of ALF.
Collapse
Affiliation(s)
- Surender Singh Sehrawat
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.
| |
Collapse
|
|
36
|
Li Q, Zhou X, Yang R, Shen X, Li G, Zhang C, Li P, Li S, Xie J, Yang Y. Carbapenem-resistant Gram-negative bacteria (CR-GNB) in ICUs: resistance genes, therapeutics, and prevention - a comprehensive review. Front Public Health 2024; 12:1376513. [PMID: 38601497 PMCID: PMC11004409 DOI: 10.3389/fpubh.2024.1376513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/20/2024] [Indexed: 04/12/2024] Open
Abstract
Intensive care units (ICUs) are specialized environments dedicated to the management of critically ill patients, who are particularly susceptible to drug-resistant bacteria. Among these, carbapenem-resistant Gram-negative bacteria (CR-GNB) pose a significant threat endangering the lives of ICU patients. Carbapenemase production is a key resistance mechanism in CR-GNB, with the transfer of resistance genes contributing to the extensive emergence of antimicrobial resistance (AMR). CR-GNB infections are widespread in ICUs, highlighting an urgent need for prevention and control measures to reduce mortality rates associated with CR-GNB transmission or infection. This review provides an overview of key aspects surrounding CR-GNB within ICUs. We examine the mechanisms of bacterial drug resistance, the resistance genes that frequently occur with CR-GNB infections in ICU, and the therapeutic options against carbapenemase genotypes. Additionally, we highlight crucial preventive measures to impede the transmission and spread of CR-GNB within ICUs, along with reviewing the advances made in the field of clinical predictive modeling research, which hold excellent potential for practical application.
Collapse
Affiliation(s)
- Qi Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoshi Zhou
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Rou Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoyan Shen
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Pharmacy, Chengdu Qingbaijiang District People's Hospital, Chengdu, China
| | - Guolin Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Changji Zhang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Pengfei Li
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shiran Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jingxian Xie
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yong Yang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| |
Collapse
|
|
37
|
Khan S, Hong H, Bass S, Wang Y, Wang XF, Sims OT, Koval CE, Kapoor A, Lindenmeyer CC. Comparison of fungal vs bacterial infections in the medical intensive liver unit: Cause or corollary for high mortality? World J Hepatol 2024; 16:379-392. [PMID: 38577538 PMCID: PMC10989308 DOI: 10.4254/wjh.v16.i3.379] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/17/2024] [Accepted: 02/26/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Due to development of an immune-dysregulated phenotype, advanced liver disease in all forms predisposes patients to sepsis acquisition, including by opportunistic pathogens such as fungi. Little data exists on fungal infection within a medical intensive liver unit (MILU), particularly in relation to acute on chronic liver failure. AIM To investigate the impact of fungal infections among critically ill patients with advanced liver disease, and compare outcomes to those of patients with bacterial infections. METHODS From our prospective registry of MILU patients from 2018-2022, we included 27 patients with culture-positive fungal infections and 183 with bacterial infections. We compared outcomes between patients admitted to the MILU with fungal infections to bacterial counterparts. Data was extracted through chart review. RESULTS All fungal infections were due to Candida species, and were most frequently blood isolates. Mortality among patients with fungal infections was significantly worse relative to the bacterial cohort (93% vs 52%, P < 0.001). The majority of the fungal cohort developed grade 2 or 3 acute on chronic liver failure (ACLF) (90% vs 64%, P = 0.02). Patients in the fungal cohort had increased use of vasopressors (96% vs 70%, P = 0.04), mechanical ventilation (96% vs 65%, P < 0.001), and dialysis due to acute kidney injury (78% vs 52%, P = 0.014). On MILU admission, the fungal cohort had significantly higher Acute Physiology and Chronic Health Evaluation (108 vs 91, P = 0.003), Acute Physiology Score (86 vs 65, P = 0.003), and Model for End-Stage Liver Disease-Sodium scores (86 vs 65, P = 0.041). There was no significant difference in the rate of central line use preceding culture (52% vs 40%, P = 0.2). Patients with fungal infection had higher rate of transplant hold placement, and lower rates of transplant; however, differences did not achieve statistical significance. CONCLUSION Mortality was worse among patients with fungal infections, likely attributable to severe ACLF development. Prospective studies examining empiric antifungals in severe ACLF and associations between fungal infections and transplant outcomes are critical.
Collapse
Affiliation(s)
- Sarah Khan
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH 44195, United States.
| | - Hanna Hong
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Stephanie Bass
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Yifan Wang
- Department of Quantitative Health Sciences/Biostatistics Section, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Xiao-Feng Wang
- Department of Quantitative Health Sciences/Biostatistics Section, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Omar T Sims
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Christine E Koval
- Department of Infectious Disease, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Aanchal Kapoor
- Department of Critical Care Medicine, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Christina C Lindenmeyer
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH 44195, United States
| |
Collapse
|
|
38
|
Mani I, Alexopoulou A. Spontaneous bacterial peritonitis- Is hepatocellular carcinoma an aggravating prognostic factor? Am J Med Sci 2024; 367:153-154. [PMID: 38135275 DOI: 10.1016/j.amjms.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 12/18/2023] [Indexed: 12/24/2023]
Affiliation(s)
- Iliana Mani
- 2nd Department of Internal Medicine, Medical School, National & Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Alexandra Alexopoulou
- 2nd Department of Internal Medicine, Medical School, National & Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece.
| |
Collapse
|
|
39
|
Huang Y, Guo X, Wu Y, Chen X, Feng L, Xie N, Shen G. Nanotechnology's frontier in combatting infectious and inflammatory diseases: prevention and treatment. Signal Transduct Target Ther 2024; 9:34. [PMID: 38378653 PMCID: PMC10879169 DOI: 10.1038/s41392-024-01745-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 12/27/2023] [Accepted: 01/11/2024] [Indexed: 02/22/2024] Open
Abstract
Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases, which continuously pose one of the most serious threats to human health, attributed to factors such as the emergence of new pathogens, increasing drug resistance, changes in living environments and lifestyles, and the aging population. Despite rapid advancements in mechanistic research and drug development for these diseases, current treatments often have limited efficacy and notable side effects, necessitating the development of more effective and targeted anti-inflammatory therapies. In recent years, the rapid development of nanotechnology has provided crucial technological support for the prevention, treatment, and detection of inflammation-associated diseases. Various types of nanoparticles (NPs) play significant roles, serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability. NPs can also directly combat pathogens and inflammation. In addition, nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases. This review categorizes and characterizes different types of NPs, summarizes their applications in the prevention, treatment, and detection of infectious and inflammatory diseases. It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects. In conclusion, nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.
Collapse
Affiliation(s)
- Yujing Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xiaohan Guo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yi Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xingyu Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Lixiang Feng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Na Xie
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
| | - Guobo Shen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
| |
Collapse
|
|
40
|
Lacy MG, Filippov E, Nematollahi S. Controlling infections in hospitalized pretransplant candidates. Curr Opin Organ Transplant 2024; 29:56-63. [PMID: 37991047 DOI: 10.1097/mot.0000000000001120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023]
Abstract
PURPOSE OF REVIEW Infections in hospitalized patients awaiting solid organ transplantation can pose complicated diagnostic and therapeutic challenges. Goals of management include stabilizing the patient, treating or controlling infections, and decreasing the risk of reactivation of infection after transplant. RECENT FINDINGS Groups such as The Organ Procurement and Transplantation Network, American Society of Transplantation Infectious Diseases Community of Practice and the European Society of Clinical Microbiology and Infectious Diseases have updated their guidelines on screening and treatment of infection in transplant candidates. There are also recent developments in therapeutic options for tuberculosis, COVID-19, Clostridioides difficile colitis, bloodstream infections, and other common infections. SUMMARY Ideally, antimicrobial therapy should be complete prior to transplantation. In situations in which completion of therapy prior to transplant is not feasible, therapy may need to be prolonged or modified. In most situations, infections can be managed similarly to the general population, although some infections, particularly fungal and mycobacterial, require a different management approach. We review disease- and organ-specific management.
Collapse
Affiliation(s)
- Marian G Lacy
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona
| | - Evgenii Filippov
- Department of Medicine, Sinai Hospital of Baltimore, Baltimore, Maryland, USA
| | - Saman Nematollahi
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona
| |
Collapse
|
|
41
|
Cuyàs B, Huerta A, Poca M, Alvarado-Tapias E, Brujats A, Román E, Guarner C, Escorsell À, Soriano G. Impact of the COVID-19 pandemic on the incidence and type of infections in hospitalized patients with cirrhosis: a retrospective study. Sci Rep 2024; 14:2718. [PMID: 38302563 PMCID: PMC10834517 DOI: 10.1038/s41598-024-52452-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 01/18/2024] [Indexed: 02/03/2024] Open
Abstract
Infections are a major cause of morbidity and mortality in cirrhosis, especially those caused by multi-drug resistant bacteria. During the COVID-19 pandemic, the incidence and type of infection in these patients may have been influenced by the restrictive measures implemented. We aimed to compare the infections in patients with cirrhosis hospitalized before the COVID-19 pandemic versus those hospitalized during the pandemic. We retrospectively compared infections in patients with cirrhosis hospitalized in the hepatology unit during the pre-pandemic period (3/2019-2/2020) with infections in patients hospitalized during the pandemic (3/2020-2/2021). Baseline characteristics, type of infections, type of bacteria, antimicrobial resistance and mortality were evaluated. There were 251 hospitalizations in 170 patients during the pre-pandemic period and 169 hospitalizations in 114 patients during the pandemic period. One or more infections were identified in 40.6% of hospitalizations during the pre-pandemic period and 43.8% of hospitalizations during the pandemic, P = 0.52. We found 131 infections in the pre-pandemic period and 75 infections during the pandemic. The percentage of nosocomial infections decreased in the pandemic period (25.3% vs. 37.4% in the pre-pandemic period, P = 0.06). We found a non-significant trend to a higher incidence of infections by multi-drug resistant organisms (MDRO) in the pandemic period than in the pre-pandemic period (6.5% vs. 4%). The incidence of infections was similar in both periods. However, during the pandemic, we observed a trend to a lower incidence of nosocomial infections with a higher incidence of MDRO infections.
Collapse
Affiliation(s)
- Berta Cuyàs
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Anna Huerta
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
| | - Maria Poca
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Edilmar Alvarado-Tapias
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Anna Brujats
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Eva Román
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Escola Universitària d'Infermeria EUI-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Carlos Guarner
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Àngels Escorsell
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - German Soriano
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Institut de Recerca Sant Pau, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
42
|
Ichita C, Shimizu S, Goto T, Haruki U, Itoh N, Iwagami M, Sasaki A. Effectiveness of antibiotic prophylaxis for acute esophageal variceal bleeding in patients with band ligation: A large observational study. World J Gastroenterol 2024; 30:238-251. [PMID: 38314133 PMCID: PMC10835525 DOI: 10.3748/wjg.v30.i3.238] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/12/2023] [Accepted: 01/03/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Esophageal variceal bleeding is a severe complication associated with liver cirrhosis and typically necessitates endoscopic hemostasis. The current standard treatment is endoscopic variceal ligation (EVL), and Western guidelines recommend antibiotic prophylaxis following hemostasis. However, given the improvements in prognosis for variceal bleeding due to advancements in the management of bleeding and treatments of liver cirrhosis and the global concerns regarding the emergence of multidrug-resistant bacteria, there is a need to reassess the use of routine antibiotic prophylaxis after hemostasis. AIM To evaluate the effectiveness of antibiotic prophylaxis in patients treated for EVL. METHODS We conducted a 13-year observational study using the Tokushukai medical database across 46 hospitals. Patients were divided into the prophylaxis group (received antibiotics on admission or the next day) and the non-prophylaxis group (did not receive antibiotics within one day of admission). The primary outcome was composed of 6-wk mortality, 4-wk rebleeding, and 4-wk spontaneous bacterial peritonitis (SBP). The secondary outcomes were each individual result and in-hospital mortality. A logistic regression with inverse probability of treatment weighting was used. A subgroup analysis was conducted based on the Child-Pugh classification to determine its influence on the primary outcome measures, while sensitivity analyses for antibiotic type and duration were also performed. RESULTS Among 980 patients, 790 were included (prophylaxis: 232, non-prophylaxis: 558). Most patients were males under the age of 65 years with a median Child-Pugh score of 8. The composite primary outcomes occurred in 11.2% of patients in the prophylaxis group and 9.5% in the non-prophylaxis group. No significant differences in outcomes were observed between the groups (adjusted odds ratio, 1.11; 95% confidence interval, 0.61-1.99; P = 0.74). Individual outcomes such as 6-wk mortality, 4-wk rebleeding, 4-wk onset of SBP, and in-hospital mortality were not significantly different between the groups. The primary outcome did not differ between the Child-Pugh subgroups. Similar results were observed in the sensitivity analyses. CONCLUSION No significant benefit to antibiotic prophylaxis for esophageal variceal bleeding treated with EVL was detected in this study. Global reassessment of routine antibiotic prophylaxis is imperative.
Collapse
Affiliation(s)
- Chikamasa Ichita
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Department of Health Data Science, Yokohama City University, Yokohama 236-0027, Kanagawa, Japan
| | - Sayuri Shimizu
- Department of Health Data Science, Yokohama City University, Yokohama 236-0027, Kanagawa, Japan
| | - Tadahiro Goto
- Department of Health Data Science, Yokohama City University, Yokohama 236-0027, Kanagawa, Japan
- TXP Research, TXP Medical Co., Ltd., Chiyoda-ku 101-0042, Tokyo, Japan
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Bunkyo-ku 113-0033, Tokyo, Japan
| | - Uojima Haruki
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Department of Genome Medical Sciences Project, Research Institute, National Center for Global Health and Medicine, Ichikawa 272-8516, Chiba, Japan
| | - Naoya Itoh
- Division of Infectious Diseases, Aichi Cancer Center, Nagoya 464-8681, Aichi, Japan
| | - Masao Iwagami
- Department of Health Services Research, Institute of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Akiko Sasaki
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| |
Collapse
|
|
43
|
Hernández-Évole H, Jiménez-Esquivel N, Pose E, Bataller R. Alcohol-associated liver disease: Epidemiology and management. Ann Hepatol 2024; 29:101162. [PMID: 37832648 DOI: 10.1016/j.aohep.2023.101162] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023]
Abstract
Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. Alcohol-associated hepatitis (AH) is a severe clinical presentation of ALD, which is characterized by abrupt jaundice and clinical decompensations of liver disease. AH occurs in a percentage of patients with underlying ALD and active alcohol consumption. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population. In this regard, alcohol cessation remains the first-line treatment in all stages of alcohol disease. In patients with advanced ALD nonresponding to medical therapy, liver transplantation is the only approach that improves prognosis, and it should be considered in patients with decompensated cirrhosis. In the last years, AH has emerged as a new indication of early liver transplantation in non-responders to medical therapy, with promising results in highly selected patients. In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.
Collapse
Affiliation(s)
- Helena Hernández-Évole
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Natalia Jiménez-Esquivel
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elisa Pose
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ramón Bataller
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
| |
Collapse
|
|
44
|
Bloom PP, Bajaj JS. The Current and Future State of Microbiome Therapeutics in Liver Disease. Am J Gastroenterol 2024; 119:S36-S41. [PMID: 38153225 DOI: 10.14309/ajg.0000000000002581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/31/2023] [Indexed: 12/29/2023]
Affiliation(s)
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| |
Collapse
|
|
45
|
Mendez-Sanchez N, Coronel-Castillo CE, Cordova-Gallardo J, Qi X. Antibiotics in Chronic Liver Disease and Their Effects on Gut Microbiota. Antibiotics (Basel) 2023; 12:1475. [PMID: 37887176 PMCID: PMC10603944 DOI: 10.3390/antibiotics12101475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 10/28/2023] Open
Abstract
Impairments in liver function lead to different complications. As chronic liver disease progresses (CLD), hypoalbuminemia and alterations in bile acid compositions lead to changes in gut microbiota and, therefore, in the host-microbiome interaction, leading to a proinflammatory state. Alterations in gut microbiota composition and permeability, known as gut dysbiosis, have important implications in CLD; alterations in the gut-liver axis are a consequence of liver disease, but also a cause of CLD. Furthermore, gut dysbiosis plays an important role in the progression of liver cirrhosis and decompensation, particularly with complications such as hepatic encephalopathy and spontaneous bacterial peritonitis. In relation to this, antibiotics play an important role in treating CLD. While certain antibiotics have specific indications, others have been subjected to continued study to determine whether or not they have a modulatory effect on gut microbiota. In contrast, the rational use of antibiotics is important, not only because of their disrupting effects on gut microbiota, but also in the context of multidrug-resistant organisms. The aim of this review is to illustrate the role of gut microbiota alterations in CLD, the use and impact of antibiotics in liver cirrhosis, and their harmful and beneficial effects.
Collapse
Affiliation(s)
- Nahum Mendez-Sanchez
- Unit Liver Research, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | | | - Jacqueline Cordova-Gallardo
- Department of Hepatology, Service of Surgery and Obesity Clinic, General Hospital “Dr. Manuel Gea González”, Mexico City 14080, Mexico
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China
| |
Collapse
|
|
46
|
Incicco S, Tonon M, Zeni N, Gambino C, Gagliardi R, Calvino V, Barone A, Zilio G, Feltracco P, Burra P, Cillo U, Angeli P, Piano S. Impact of bacterial infections prior to liver transplantation on post-transplant outcomes in patients with cirrhosis. JHEP Rep 2023; 5:100808. [PMID: 37534231 PMCID: PMC10393541 DOI: 10.1016/j.jhepr.2023.100808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/08/2023] [Accepted: 05/22/2023] [Indexed: 08/04/2023] Open
Abstract
Background & Aims Bacterial infections are frequent in patients with cirrhosis and increase the risk of death and drop-out from liver transplant (LT) waiting list. In patients with bacterial infections, LT is frequently delayed because of the fear of poor outcomes. We evaluated the impact of pre-LT infections on post-LT complications and survival. Methods From 2012 to 2018, consecutive patients transplanted at the Hospital of Padua were identified and classified in two groups: patients surviving an episode of bacterial infection within 3 months before LT (study group) and patients without infections before LT (control group). Post-LT outcomes (complications, new infections, survival) were collected. Results A total of 466 LT recipients were identified (study group n = 108; control group n = 358). After LT, the study group had a higher incidence of new bacterial (57% vs. 20%, p <0.001) and fungal infections (14% vs. 5%, p = 0.001) and of septic shock (8% vs. 2%, p = 0.004) than the control group. Along with the model for end-stage liver disease (MELD) score and alcohol-related cirrhosis, bacterial infection pre-LT was an independent predictor of post-LT infections (odds ratio = 3.92; p <0.001). Nevertheless, no significant difference was found in 1-year (88% vs. 89%, p = 0.579) and 5-year survival rates (76% vs. 75%, p = 0.829) between the study group and control group. Within the study group, no association was found between the time elapsed from infection improvement/resolution to LT and post-LT outcomes. Conclusions Patients with pre-LT infections have a higher risk of new bacterial and fungal infections and of septic shock after LT. However, post-LT survival is excellent. Therefore, as soon as the bacterial infection is improving/resolving, transplant should not be delayed, but patients with pre-transplant bacterial infections require active surveillance for infections after LT. Impact and Implications Bacterial infections increase mortality and delay transplant in patients with cirrhosis awaiting liver transplantation (LT). Little is known about the impact of adequately treated infections before LT on post-transplant complications and outcomes. The study highlights that pre-LT infections increase the risk of post-LT infections, but post-LT survival rates are excellent despite the risk. These findings suggest that physicians should not delay LT because of concerns about pre-LT infections, but instead should actively monitor these patients for infections after surgery.
Collapse
Affiliation(s)
- Simone Incicco
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Nicola Zeni
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Carmine Gambino
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Roberta Gagliardi
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Valeria Calvino
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Anna Barone
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Gianluca Zilio
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Paolo Feltracco
- Anesthesiology and Intensive Care Unit, Department of Medicine (DIMED), University and Hospital of Padova, Padua, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University and Hospital of Padova, Padua, Italy
| | - Umberto Cillo
- General Surgery 2-Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, Padua, Italy
| |
Collapse
|
|
47
|
Bhavsar-Burke I, Lindenmeyer CC. Cutting deep: Understanding the risks associated with postoperative infections in patients with cirrhosis. Liver Transpl 2023; 29:913-914. [PMID: 37204175 DOI: 10.1097/lvt.0000000000000177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 05/03/2023] [Indexed: 05/20/2023]
Affiliation(s)
- Indira Bhavsar-Burke
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
| | | |
Collapse
|
|
48
|
Clària J, Arroyo V, Moreau R. Roles of systemic inflammatory and metabolic responses in the pathophysiology of acute-on-chronic liver failure. JHEP Rep 2023; 5:100807. [PMID: 37600957 PMCID: PMC10432809 DOI: 10.1016/j.jhepr.2023.100807] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/17/2023] [Accepted: 05/24/2023] [Indexed: 08/22/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is the most severe form of acutely decompensated cirrhosis and is characterised by the presence of one or more organ failures, intense systemic inflammation, peripheral blood lymphopenia, and a high risk of death without liver transplantation within 28 days. Herein, we propose the hypothesis that intense systemic inflammation may lead to organ failures through five different non-mutually exclusive mechanisms. First, pathogen-associated molecular patterns and inflammatory mediators (i.e. cytokines and lipid mediators) stimulate the production of the vasorelaxant nitric oxide in the walls of splanchnic arterioles, leading to enhanced splanchnic and systemic vasodilation which, in turn, induces enhanced activity of endogenous vasoconstrictor systems causing renal vasoconstriction and acute kidney injury. Second, neutrophils that reach the systemic circulation are prone to adhere to the vascular endothelium. Cytokines and lipid mediators act on the endothelium in microvessels of vital organs, an effect that favours the migration of neutrophils (and probably other leukocytes) to surrounding tissues where neutrophils can cause tissue damage and thereby contribute to organ failure. Third, cytokines and lipid mediators promote the formation of microthrombi that impair microcirculation and tissue oxygenation. Fourth, acute inflammation stimulates intense peripheral catabolism of amino acids whose products may be metabotoxins that contribute to hepatic encephalopathy. Fifth, acute inflammatory responses, which include the production of a broad variety of biomolecules (proteins and lipids), and an increase in biomass (i.e., granulopoiesis requiring de novo nucleotide synthesis), among others, are energetically expensive processes that require large amounts of nutrients. Therefore, immunity competes with other maintenance programmes for energy. The brain stem integrates the energy demand of each organ system, with immunity considered a top priority. The brain stem may "decide" to make a trade-off which involves the induction of a dormancy programme that permits the shutdown of mitochondrial respiration and oxidative phosphorylation in peripheral organs. In the context of acutely decompensated cirrhosis, the consequence of a shutdown of mitochondrial respiration and ATP production would be a dramatic decrease in organ function.
Collapse
Affiliation(s)
- Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Grifols Chair, Barcelona, Spain
- Hospital Clínic-IDIBAPS, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Grifols Chair, Barcelona, Spain
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Grifols Chair, Barcelona, Spain
- INSERM, Université de Paris, Centre de Recherche sur l’Inflammation (CRI), Paris, France
- Assistance Publique – Hôpitaux de Paris (AP-HP), Hôpital Beaujon, Service d’Hépatologie, Clichy, France
| |
Collapse
|
|
49
|
Perricone G, Artzner T, De Martin E, Jalan R, Wendon J, Carbone M. Intensive care management of acute-on-chronic liver failure. Intensive Care Med 2023; 49:903-921. [PMID: 37552333 DOI: 10.1007/s00134-023-07149-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/21/2023] [Indexed: 08/09/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by an acute deterioration of the liver function associated with extrahepatic organ failures requiring intensive care support and associated with a high short-term mortality. ACLF has emerged as a major cause of mortality in patients with cirrhosis and chronic liver disease. ACLF has a unique pathophysiology in which systemic inflammation plays a key role; this provides the basis of novel therapies, several of which are now in clinical trials. Intensive care unit (ICU) therapy parallels that applied in the general ICU population in some organ failures but has peculiar differential characteristics in others. Critical care management strategies and the option of liver transplantation (LT) should be balanced with futility considerations in those with a poor prognosis. Nowadays, LT is the only life-saving treatment that can radically improve the long-term prognosis of patients with ACLF. This narrative review will provide insights on the current understanding of ACLF with emphasis on intensive care management.
Collapse
Affiliation(s)
- Giovanni Perricone
- Hepatology and Gastroenterology Unit, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162, Milan, Italy.
| | - Thierry Artzner
- Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France
| | - Eleonora De Martin
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Inserm UMR-S 1193, Université Paris-Saclay, Villejuif, France
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Julia Wendon
- Liver Intensive Therapy Unit, Division of Inflammation Biology, King's College London, London, UK
| | - Marco Carbone
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- European Reference Network On Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| |
Collapse
|
|
50
|
Abstract
Bacterial infections (BIs) are the most common precipitating event of acute-on-chronic liver failure (ACLF) and a frequent complication of ACLF. BIs aggravate the course of the syndrome and are associated with higher mortality rates. For this reason, BIs should be promptly diagnosed and treated in all patients with ACLF. The administration of an appropriate empirical antibiotic therapy improves survival in patients with BIs and ACLF and is the cornerstone of treatment. Due to the spread of antibiotic resistance worldwide, the empirical treatment should cover multi-drug-resistant organisms. Herein we reviewed the current evidence about the management of BIs in ACLF.
Collapse
Affiliation(s)
- Simone Incicco
- Department of Medicine (DIMED), Unit of Internal Medicine and Hepatology (UIMH), University Hospital of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - Paolo Angeli
- Department of Medicine (DIMED), Unit of Internal Medicine and Hepatology (UIMH), University Hospital of Padova, Via Giustiniani 2, Padova 35128, Italy
| | - Salvatore Piano
- Department of Medicine (DIMED), Unit of Internal Medicine and Hepatology (UIMH), University Hospital of Padova, Via Giustiniani 2, Padova 35128, Italy.
| |
Collapse
|