Journal Of Hepatology

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Journal of HepatologyPREDICT identifies Precipitating Events with Impact on Clinical Course and Outcomeof Acutely Decompensated Cirrhosis.--Manuscript Draft-Manuscript Number:Article Type:Original ArticleSection/Category:Cirrhosis and Liver FailureKeywords:Chronic liver disease, Non-elective admission, acute complications, Outcome, Riskfactors.First Author:Jonel TrebickaCorresponding Author:Jonel TrebickaGoethe-Universitat Frankfurt am MainFrankfurt am Main, GERMANYOrder of Authors:Jonel TrebickaJavier FernandezMaria PappPaolo CaraceniWim LalemanCarmine GambinoIlaria GiovoFrank Erhard UshcnerChristian JansenCesar JimenezRajeshwar MookerjeeThierry GustotAgustin AlbillosRafael BanaresPeter JarcuskaChristian SteibThomas ReibergerJuan AcevedoPietro GattiDebbie ShawcrossStefan ZeuzemAlexander ZipprichSalvatore PianoThomas BergTony BrunsFlemming Bendtsenminneke CoenraadManuela MerliPowered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

Rudolf StauberHeinz ZollerJose Presa RamosCristina SoleGerman SorianoAndrea de GottardiHenning GroenbaekFaouzi SalibaTrautwein ChristianHaluk Tarik KaniSven FrancqueStephen RyderPierre NahonManuel Romero GomezHans Van VlierbergheClaire FrancozMichael MannsElisabet GarciaManuel TufoniAlex AmorosMarco PavesiCristina SanchezMichael PraktiknjoAnna CurtoCarla PitarchAntonella PutignanoEsau MorenoWilliam BernalFerran AquilarJoan ClariaPaolo PonzoZsuzsanna VitalisGiacomo ZaccheriniBoglarka BaloghAlexander GerbesVictor VargasCarlo AlessandriaMauro BernardiPere GinesRichard MoreauPaolo AngeliPowered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

Rajiv JalanVicente ArroyoAbstract:Introduction: Acute decompensation (AD) of cirrhosis may present without acute-onchronic liver failure (ACLF) (AD-No ACLF), or with ACLF-phenotype (AD-ACLF)defined by organ failure(s). Precipitating events (PEs) may induce AD.This multicenter, prospective, observational PREDICT Study analyzes andcharacterizes the PEs leading to both AD-phenotypes.Patients and Methods: The PREDICT study included 1273 non-electively hospitalizedpatients with AD (No-ACLF 1071; ACLF 202). Medical history, clinical and laboratorydata were carefully collected at enrolment and during 90-days follow up, focused onthe characteristics of PEs, specifically induction of organ dysfunction/failure and/orsystemic inflammation, chronology, intensity, and relationship to outcome in both ADphenotypes.Results: Among 16 events explored as potential PEs, four types of events were PEsconsistently related to AD, including proven bacterial infections, severe alcoholichepatitis, gastrointestinal (GI) bleeding with shock and toxic encephalopathy. Amongpatients in the AD-No ACLF cohort and the AD-ACLF cohort with PEs (38% and 71%,respectively), almost all (96% and 97%, respectively) showed proven bacterial infectionand severe alcoholic hepatitis, either alone or in combination with other PEs.Interestingly, in both AD-phenotypes, proven bacterial infections and severe alcoholichepatitis had a similar effect on survival, and the number of PEs was associated withsignificantly increased 90-day mortality, in parallel with surrogates of systemicinflammation proving the validity of the definition of PEs.Conclusions: This study identified PEs that significantly impact the clinical course andprognosis of patients with AD and specific preventive and therapeutic strategies tothese events are required to improve outcome in decompensated cirrhosis.Opposed Reviewers:Patrick Kamathkamath.patrick@mayo.edoConflict of interestGuadalupe Garcia-Tsaoguadalupe.garcia-tsao@yale.edoConflict of interestPhilippe MathurinPhilippe.MATHURIN@chrulille.frConflict of interestShiv Sarinshivsarin@gimail.comconflict of interestJaime Boschjaume.bosch@idibaps.eduConflict of InterestJuan-Carlos Garcia-PaganJCGARCIA@clinic.eduConflict of interestPowered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

Cover LetterDear Professor Paolo Angeli,We are delighted to submit the second investigation of our Europeaninternational multicenter observational prospective study PREDICT entitled:“PREDICT identifies Precipitating Events with Impact on Clinical Courseand Outcome of Acutely Decompensated Cirrhosis.” for your kindconsideration in the most prestigious Journal of Hepatology.This study identified precipitating events that significantly impact the clinicalcourse and prognosis of patients with acutely decompensated cirrhosis. Thispaper may pave the path for specific preventive and therapeutic strategies tothese events in order to improve outcome in decompensated cirrhosis.Since this paper addresses an important and practical issue, we hope that itwill be found suitable for publication in the most prestigious Journal ofHepatology.Sincerely yoursJonel Trebicka on behalf of the authors

ManuscriptClick here to view linked ReferencesTrebicka et al.PRECIPITANTS OF AD AND ACLFTitle 3545556575859606162636465PREDICT identifies Precipitating Events with Impact on Clinical Course andOutcome of Acutely Decompensated Cirrhosis. (117/120)Authors:Jonel Trebicka1,2, Javier Fernandez1,4, Maria Papp5, Paolo Caraceni6, WimLaleman13, Carmine Gambino7, Ilaria Giovo8, Frank Erhard Uschner2, ChristianJansen3, Cesar Jimenez9, Rajeshwar Mookerjee10, Thierry Gustot11, AgustinAlbillos12, Rafael Bañares14, Peter Jarcuska15, Christian Steib16, Thomas Reiberger17,Juan Acevedo18, Pietro Gatti19, Debbie Shawcross20, Stefan Zeuzem2, AlexanderZipprich21, Salvatore Piano7, Thomas Berg22, Tony Bruns23,34, Flemming Bendtsen24,Minneke Coenraad25, Manuela Merli26, Rudolf Stauber27, Heinz Zoller28, José PresaRamos29, Cristina Solé4, Germán Soriano30, Andrea de Gottardi31, HenningGronbaek32, Faouzi Saliba33, Christian Trautwein34, Haluk Tarik Kani35, SvenFrancque36, Stephen Ryder37, Pierre Nahon38, Manuel Romero-Gomez39, Hans VanVlierberghe40, Claire Francoz41,42, Michael Manns43, Elisabet Garcia1, ManuelTufoni6, Alex Amoros1, Marco Pavesi1, Cristina Sanchez1, Michael Praktiknjo3, AnnaCurto1, Carla Pitarch1, Antonella Putignano11, Esau Moreno1, William Bernal20,Ferran Aguilar1, Joan Clària1,4, Paola Ponzo8, Zsuzsanna Vitalis5, GiacomoZaccherini6, Boglarka Balogh5, Alexander Gerbes16, Victor Vargas9, CarloAlessandria8, Mauro Bernardi6, Pere Ginès4, Richard Moreau1,41,42, Paolo Angeli1,7,Rajiv Jalan1,10, and Vicente Arroyo1 for the PREDICT STUDY group of the EASLCLIF CONSORTIUMAffiliations:1EuropeanFoundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain

PRECIPITANTS OF AD AND 4849505152535455565758596061626364653of Internal Medicine I, Goethe University Frankfurt, Frankfurt Germany,Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany,4HospitalClinic of Barcelona, University of Barcelona, CIBEReHD, IDIBAPS,Barcelona, Spain,5Universityof Debrecen, Faculty of Medicine, Institute of Medicine, Department ofGastroenterology, Debrecen, Hungary,6Universityof Bologna, Bologna, Italy,7Universityof Padova, Padova, Italy,8A.O.U.9LiverCittà della Salute e della Scienza Torino, Torino, Italy,Unit, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, CIBEREHD,Barcelona, Spain10UCLMedical School,Royal Free Hospital, London, United Kingdom,11C.U.B.Erasme, Bruxelles, Belgium,12Departmentof Gastroenterology, Hospital Universitario Ramón y Cajal, IRYCIS,University of Alcalá, CIBEREHD, Madrid, Spain,13Department of Gastroenterology and Hepatology, Section of Liver andBiliopancreatic disorders, University of Leuven, Leuven, Belgium14 HospitalGeneral Universitario Gregorio Marañón. Facultad de Medicina(Universidad Complutense of Madrid), CIBERehd, Madrid, Spain15PavolJozef Safarik University in Kosice, Kosice, Slovakia,16Departmentof Medicine II, Liver Centre Munich, University Hospital, LMU, Munich,Germany,17MedicalUniversity of Vienna, Vienna, Austria,18University19Internal20King'sHospitals Plymouth NHS Trust, Plymouth, UK,Medicine PO Ostuni, ASL Brindisi, Italy,College Hospital, London, United Kingdom,2

PRECIPITANTS OF AD AND pital Halle-Wittenberg, Halle(Saale), Germany,of Hepatology, Department of Medicine II, Leipzig UniversityMedical Center, Leipzig, Germany,23JenaUniversity Hospital, Jena, Germany,24Gastrounit,Medical Section, Hvidovre Hospital and Department of ClinicalMedicine, University of Copenhagen, Copenhagen, Denmark25LeidenUniversity Medical Center, Leiden, Netherlands,26UniversitáSapienza Roma, Roma, Italy,27MedicalUniversity of Graz, Graz, Austria,28MedicalUniversity of Innsbruck, Innsbruck, Austria,29CHTMAD30HospitalVila Real-Blueclinical, Vila Real, Portugal,de la Santa Creu i Sant Pau and CIBERehd, Barcelona, Spain,31UniversityClinic of Visceral Surgery and Medicine-Inselspital, Bern and EnteOspedaliero Cantonale, Universita della Svizzera Italiana, Lugano, Switzerland,32AarhusUniversity Hospital, Aarhus, Denmark,33AP-HPHôpital Paul Brousse, Centre Hépato-Biliaire, Universite Paris Saclay,INSERM Unit 1193, Villejuif, France,34AachenUniversity Hospital, Aachen, Germany,35MarmaraUniversity, Kadiköy, Turkey,36University37NIHRHospital Antwerp, Antwerpen, Belgium,Biomedical Research Centre at Nottingham University Hospitals NHS Trustand the University of Nottingham, Nottingham, United Kingdom,38AP-HP,Hôpital Jean Verdier, Service d’Hépatologie, Bondy; Université Paris 13,Sorbonne Paris Cité, “Equipe labellisée Ligue Contre le Cancer”, Saint-Denis;Inserm, UMR-1162, “Génomique fonctionnelle des tumeurs solides”, Paris, France,39Virgendel Rocío University Hospital, Sevilla, Spain,3

PRECIPITANTS OF AD AND 50515253545556575859606162636465University Hospital, Ghent, Belgium,41APHP,Hôpital Beaujon, Service d’Hépatologie, Clichy, France,42Inserm,Université de Paris, Centre de Recherche sur L Inflammation, Paris,France,43Hannover44MunsterMedical School, Hannover, Germany,University Hospital, Münster, Germany,45University46Hôpitauxof Basel-St Gall Cantonal Hospital, Switzerland,Universitaires de Genève, Genève, Switzerland47Universityof Birmingham, Birmingham, UKAuthors in bold share last authorship.4

PRECIPITANTS OF AD AND 647484950515253545556575859606162636465Miriam Maschmeier1, David Semela2, Laure Elkrief3, Ahmed Elsharkawy4, TamasTornai5, Istvan Tornai5, Istvan Altorjay5, Agnese Antognoli6, Maurizio Baldassarre6,Martina Gagliardi6, Eleonora Bertoli7, Sara Mareso7, Alessandra Brocca7, DanielaCampion8, Giorgio Maria Saracco8, Martina Rizzo8, Jennifer Lehmann9, AlessandraPohlmann9, Maximilian J. Brol9, Johannes Chang9, Robert Schierwagen18, ElsaSolà10, Nesrine Amari11, Miguel Rodriguez12, Frederik Nevens13, Ana Clemente14,Martin Janicko15, Daniel Markwardt16, Mattias Mandorfer17, Christoph Welsch18,Tanja M. Welzel18, Emanuela Ciraci19, Vish Patel20, Cristina Ripoll21, Adam Herber22,Paul Horn23, Karen Vagner Danielsen24, Lise Lotte Gluud24, Jelte Schaapman25,Oliviero Riggio26, Florian Rainer27, Jörg Tobiasch Moritz28, Mónica Mesquita29,Edilmar Alvarado-Tapias30, Osagie Akpata31, Luise Aamann32, Didier Samuel33,Sylvie Tresson33, Pavel Strnad34, Roland Amathieu35, Macarena Simón-Talero36,Francois Smits11, Natalie van den Ende13, Javier Martinez12, Rita Garcia14, HaraldRupprechter17, Cornelius Engelmann22, Osman Cavit Özdogan375

PRECIPITANTS OF AD AND ersity Hospital, Münster, Germany,2University3Hôpitauxof Basel-St Gall Cantonal Hospital, Switzerland,Universitaires de Genève, Genève, Switzerland4Universityof Birmingham, Birmingham, UK5Universityof Debrecen, Faculty of Medicine, Institute of Medicine, Department ofGastroenterology, Debrecen, Hungary,6Universityof Bologna, Bologna, Italy,7Universityof Padova, Padova, Italy,8A.O.U.Città della Salute e della Scienza Torino, Torino, Italy,9University10Hospital11C.U.B.Hospital Bonn, Bonn, Germany,Clinic of Barcelona, Barcelona, Spain,Erasme, Bruxelles, Belgium,12Departmentof Gastroenterology, Hospital Universitario Ramón y Cajal, IRYCIS,University of Alcalá, CIBEREHD, Madrid, Spain,13Departmentof Gastroenterology and Hepatology, Section of Liver andBiliopancreatic disorders, University of Leuven, Leuven, Belgium,14 HospitalGeneral Universitario Gregorio Marañón. Facultad de Medicina(Universidad Complutense of Madrid), CIBERehd, Madrid, Spain15PavolJozef Safarik University in Kosice, Kosice, Slovakia,16Departmentof Medicine II, Liver Centre Munich, University Hospital, LMU, Munich,Germany17MedicalUniversity of Vienna, Vienna, Austria,18Department19Internal20King'sof Internal Medicine I, Goethe University Frankfurt, Frankfurt Germany,Medicine PO Ostuni, ASL Brindisi, Italy,College Hospital, London, United Kingdom,6

PRECIPITANTS OF AD AND pital Halle-Wittenberg, Halle(Saale), Germany,of Hepatology, Department of Medicine II, Leipzig UniversityMedical Center, Leipzig, Germany,23JenaUniversity Hospital, Jena, Germany,24Gastrounit,Medical Section, Hvidovre Hospital and Department of ClinicalMedicine, University of Copenhagen, Copenhagen, Denmark25LeidenUniversity Medical Center, Leiden, Netherlands,26UniversitáSapienza Roma, Roma, Italy,27MedicalUniversity of Graz, Graz, Austria,28MedicalUniversity of Innsbruck, Innsbruck, Austria,29CHTMAD30Hospital31UCLVila Real-Blueclinical, Vila Real, Portugal,de la Santa Creu i Sant Pau and CIBERehd, Barcelona, Spain,Medical School,Royal Free Hospital, London, United Kingdom,32AarhusUniversity Hospital, Aarhus, Denmark,33AP-HPHôpital Paul Brousse, Centre Hépato-Biliaire, Universite Paris Saclay,INSERM Unit 1193, Villejuif, France,34AachenUniversity Hospital, Aachen, Germany,35AP-HP,Hôpital Jean Verdier, Service d’Hépatologie, Bondy; Université Paris 13,Sorbonne Paris Cité, “Equipe labellisée Ligue Contre le Cancer”, Saint-Denis;Inserm, UMR-1162, “Génomique fonctionnelle des tumeurs solides”, Paris, France,36Liver Unit, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona,CIBEREHD, Barcelona, Spain37MarmaraUniversity, Kadiköy, Turkey,Short title: PRECIPITANTS OF AD AND ACLF7

PRECIPITANTS OF AD AND ACLFAcknowledgements: The authors are very grateful to the patients, their families 545556575859606162636465the personal of the hospitals for making this possible. In addition a special thank youis dedicated to Mrs. Yolanda Godoy, Dr. Anna Bosch, Dr. Josep-Maria Torner, ssistanceintheaccomplishment of the study. We thank Marites Abans, Paul Sauerbruch, GudrunHack, Nadine Köstlmaier, Kristin Gehrmann for technical and administrativeassistance.Keywords: Chronic liver disease, Non-elective admission, acute complications,Outcome, Risk factors.Data availability: The data of this paper will be partly available upon request, but themajority of the data are unsuitable to post and partly data confidential.Corresponding author: Professor Dr. med. Jonel Trebicka, MD, PhD, EuropeanFoundation for Study of Chronic Liver Failure, EF-Clif, Travesera de Gracia 11, 7thFloor, 08021 Barcelona, SpainAbbreviations: AD (acute decompensation), ACLF (acute-on-chronic liver eaminotransferase),IQR(Interquartile Range), CLIF (chronic liver failure), CRP (C reactive protein), GI(gastrointestinal), OF (organ failure), CIF (cumulative incidence of function), MELD(model of end-stage liver disease), PE (precipitating event), SD (Standard Deviation),SDC (stable decompensated cirrhosis), UDC (unstable decompensated cirrhosis),WBC (white blood cell count)8

PRECIPITANTS OF AD AND ACLFFinancial support: The study was supported by the European Foundation for 545556575859606162636465Study of Chronic Liver Failure (EF-Clif). The EF-Clif is a non-profit privateorganization. The EF-Clif receives unrestricted donations from Cellex Foundation andGrifols. EF-Clif is partner, contributor and coordinator in several EU Horizon 2020program projects. JT was appointed as visiting Professor in EF-Clif for the executionof the study by a grant from Cellex Foundation. The funders had no influence onstudy design, data collection and analysis, decision to publish or preparation of themanuscript.Conflict of Interest: None of the authors have conflicts of interest for the reportedstudy.Author contributions: JT, JF, WL, JC, RJ, RM, PG, PA, VA: study concept anddesign, acquisition of data, analysis and interpretation of data, drafting of themanuscript, funding recipient, administrative, technical and material support, studysupervision; EG, AA, AC, CP, MP, CS, AC, AM, FA: acquisition of data, analysis ofdata, technical and material support; TT, MB, PA, CA, FEU, CJ, MST, TG, AA, WL,ES, RB, MJ, CS, TR, JA, PG, WB, SZ, CR, TB, AS, LLG, MC, OR, RS, HZ, AC,GSP, AdG, HG, FS, CT, OCÖ, FS, SR, RA, MRG, HVV, CF, MM, MP, PC, SP, IG,MP, VV, RM, ZV, MB, EB: acquisition of data, interpretation of data, critical revisionof the manuscript regarding important intellectual contentTables and Figures: 5 Tables, 3 FiguresWord count (inclusive of abstract, main text, references, figure legends): 6,7999

PRECIPITANTS OF AD AND 950515253545556575859606162636465Introduction: Acute decompensation (AD) of cirrhosis may present withoutacute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF-phenotype (ADACLF) defined by organ failure(s). Precipitating events (PEs) may induce AD. Thismulticenter, prospective, observational PREDICT Study (NCT03056612) analyzesand characterizes the PEs leading to both AD-phenotypes.Patients and Methods: The PREDICT study included 1273 non-electivelyhospitalized patients with AD (No-ACLF 1071; ACLF 202). Medical history, clinicaland laboratory data were carefully collected at enrolment and during 90-days followup, focused on the characteristics of PEs, specifically induction of ,chronology,intensity,andrelationship to outcome in both AD phenotypes.Results: Among 16 events explored as potential PEs, four types of eventswere PEs consistently related to AD, including proven bacterial infections, ingwithshockandtoxicencephalopathy. Among patients in the AD-No ACLF cohort and the AD-ACLF cohortwith PEs (38% and 71%, respectively), almost all (96% and 97%, respectively)showed proven bacterial infection and severe alcoholic hepatitis, either alone or incombination with other PEs. Interestingly, in both AD-phenotypes, proven bacterialinfections and severe alcoholic hepatitis had a similar effect on survival, and thenumber of PEs was associated with significantly increased 90-day mortality, inparallel with surrogates of systemic inflammation proving the validity of the definitionof PEs.Conclusions: This study identified PEs that significantly impact the clinicalcourse and prognosis of patients with AD and specific preventive and therapeuticstrategies to these events are required to improve outcome in decompensatedcirrhosis.word count (max. 250): 25010

PRECIPITANTS OF AD AND 7484950515253545556575859606162636465Acute decompensation of cirrhosis (hereafter called AD) defines the acutedevelopment of ascites, hepatic encephalopathy, gastrointestinal hemorrhage orbacterial infections, or any combination of these. In 2013, the CANONIC studyidentified the syndrome of acute-on-chronic liver failure (ACLF), the most severephenotype of AD, in 20% of 1343 consecutive patients non-electively hospitalized forthe treatment of an episode of AD [1]. ACLF was characterized by single or multipleorgan failure and high 28-day mortality rate (30%).In 2020, the PREDICT study, the second largest prospective observationalinvestigation in 1273 hospitalized patients with AD, showed that patients withoutACLF (AD-No ACLF phenotype) comprised 3 distinct sub-phenotypes definedaccording to ACLF development and readmission within 3 months after AD [2]. Inbrief, pre-ACLF patients developed ACLF and showed high short-term (90-day)mortality (67%); unstable decompensated cirrhosis (UDC) patients did not developACLF, but required readmission(s) and showed significant short-term mortality rate(35%); while stable decompensated cirrhosis (SDC) patients presented anuncomplicated course during the 3-month follow-up period and showed low 1-yearmortality (9%).In the traditional view, the development of AD is initiated by an acuteworsening of stable cirrhosis through different pathophysiological mechanismsconsidered as precipitating events (PEs). The evidence from the CANONIC and thePREDICT studies challenges this view [1, 2], and suggests that AD manifests mainlyas a result of systemic inflammation, inducing multiple organ dysfunction andpresents with different clinical phenotypes [3, 4]. Indeed, systemic inflammationincreases across the sub-phenotypes of AD-no ACLF (SDC, UDC and pre-ACLF),and reaches its maximum in patients with AD-ACLF [5, 6]. Moreover, in AD-ACLF11

PRECIPITANTS OF AD AND ACLFphenotype, the grade of systemic inflammation correlated with the number of 53545556575859606162636465failures, clinical course severity and prognosis [3, 4]. Therefore, for a PE to be ofimportance, it should have the ability to impair end-organ function.Despite that AD-ACLF phenotype frequently develops in close chronologicalrelationship with PEs, the critical time-period prior to AD-ACLF has not yet beenexplored in detail. Moreover, so far, there are no specific criteria for the diagnosis ofPEs. Consequently, many clinical relevant aspects of PEs remain ill-defined.The current study is the second investigation derived from the PREDICTstudy. It was aimed to provide the rationale for the diagnosis of PEs and toinvestigate the impact of the type and number of PEs on early clinical course andprognosis in patients hospitalized with AD-No ACLF and AD-ACLF phenotypes.12

PRECIPITANTS OF AD AND ACLFPATIENTS AND 5253545556575859606162636465PatientsThe PREDICT study (ClinicalTrials.gov number, NCT03056612) is ective,observationalstudyperformed in 48 university hospitals from 15 countries and promoted by theEuropean Foundation for the Study of Chronic Liver Failure. The design of the studyhas been reported in detail elsewhere [2]. Briefly, 1071 patients with AD-No ACLFphenotype and 202 with AD-ACLF phenotype non-electively hospitalized fortreatment were enrolled from March 2017 to July 2018. The diagnosis of cirrhosiswas based on previous liver biopsy findings or a composite of clinical signs andlaboratory test results and imaging. Diagnostic criteria of AD were based on thepresence of ascites, encephalopathy, gastrointestinal hemorrhage or infections (thelatter only in patients with prior decompensation) or any combination of these at nonelective hospital admission. Diagnosis of ACLF at enrolment or during follow-up wasperformed according to the EASL-CLIF criteria [1, 7]. Organ failure and organdysfunction were defined according to the Chronic Liver Failure (CLIF)- Consortiumorgan failure (OF) score [8].The stratification of patients who had the AD-No ACLF phenotype into the ADpre-ACLF, AD-UDC and AD-SDC sub-phenotypes was performed using previouslydescribed criteria [2]. Therefore, patients included in the PREDICT study werestratified into four different groups (Fig. 1). 1. AD-ACLF: included 202 patients withACLF at enrolment; 2. AD-Pre ACLF: included 218 patients without ACLF atenrolment that developed the ACLF during a 3-month follow-up period afterenrolment; 3. AD-UDC: included 233 patients who did not develop ACLF during the3-month follow-up period, but required at least one hospital readmission; 4. AD-SDC:13

PRECIPITANTS OF AD AND ACLFIncluded 620 patients who did not develop ACLF or required hospital 950515253545556575859606162636465during the 3-month follow-up period.Study DesignThe PREDICT study [2] was designed to explore in detail two important timeperiods during the clinical course of AD. The first period covered the first 90-day priorto hospital admission, paying particular attention to the first two weeks prior toadmission, which is the period in which most PEs can develop. The second period,the “follow-up period”, covered the first 3 months after admission, and was the periodin which the early clinical course of patients with ACLF-phenotype and AD-No ACLFsub-phenotypes was assessed.Pre-specified clinical and standard laboratory data were obtained at enrolmentand during follow-up visits. The design of the PREDICT study is described in detailelsewhere [2].Data obtained at enrolment.Most patients were enrolled within the first or second day of hospitaladmission. Two categories of pre-specified information were obtained at enrolment.The first category included the general characteristics and demographic data,specific data related to the AD episode, physical examination, standard laboratoryanalysis at enrolment, and results from the bacteriological cultures routinelyperformed in patients with suspected bacterial infections.The second category of pre-specified data obtained at enrolment were relatedto the past medical history. The electronic Case Report Form (eCRF) of thePREDICT study was specifically designed to capture the characteristics of anypotential PE prior to enrolment, including severity and temporal relationship to the14

PRECIPITANTS OF AD AND ACLFonset of the 545556575859606162636465Data obtained during follow-upAfter enrolment, patients were closely followed-up for a period of 3 monthswith frequent pre-specified sequential visits and laboratory determinations. Data onliver transplantation or death and causes of death were prospectively collected 3, 6and 12 months after enrolment in all patients.Identification of PEs of AD-No ACLF and AD-ACLFIn order to identify the PE a Adjudication Committee of the PREDICT study,which included JT, JF, RM and VA was nominated to elaborate the list of potentialPEs, and the general principles and specific criteria for diagnosis. This Committeeidentified relevant and “true” PEs (hereafter just called as PEs), highly probable ofprecipitating both phenotypes of AD according to the criteria defined below. TheAdjudication Committee proposed the following events as potential precipitantsaccording to prior experience by the CANONIC study and other investigation:bacterial infections, alcoholic hepatitis, GI bleeding, drug-induced organ injury,therapeutic interventions.General principles for PE identificationTo provide the PREDICT study with a reliable method to identify PEs, thefollowing general principles were agreed: of AD-ACLF, specific diagnostic criteriawere developed based on the following principles:1. PEs should consist of events that have the potential to induce impairment in thefunction of the liver and/or other organs, either by direct organ injury (e.g., tissue15

PRECIPITANTS OF AD AND 647484950515253545556575859606162636465or, antpathophysiological mechanisms (e.g., immune responses to microbial or endogenouscause).2. When assessing the potential of hepatotoxic, nephrotoxic or neurotoxic drugs asbeing PEs, the lack of liver, kidney or brain dysfunction or failure, respectively, asdefined by the CLIF-C OF score [8] rule out drug-induced organ toxicity as a PE.3. As suggested by the results of the CANONIC study [1, 7], clinically identifiable,relevant and true PEs should have a higher prevalence among patients with ADACLF than among those with AD-no ACLF.4. PEs should precede or coincide with the onset of AD-ACLF. The time period betweenthe PE and the onset of AD-ACLF, however, is heterogeneous, depending on the PE.5. Any event developing after the onset of AD-ACLF is a complication or a coincidentalevent but not a PE.Specific criteria for the identification of PEs from the list proposed by the adjudicationcomiteeBacterial infections. Infections were considered potential PEs if they werediagnosed at the time of or solved within the 48-hour period that preceded the onsetof AD. Infections occurring before AD but solved before this 48-hour time frame wereconsidered as unrelated events. Previous data have shown that the cytokineresponse to bacterial infections, even efficiently treated, may last up to 48 hours and16

PRECIPITANTS OF AD AND ACLFmay induce the onset of AD [9]. When infections were diagnosed between the first123456789101112

Jonel Trebicka1,2, Javier Fernandez1,4, Maria Papp5, Paolo Caraceni6, Wim Laleman 13 , Carmine Gambino 7 , Ilaria Giovo 8 , Frank Erhard Uschner 2 , Christian Jansen 3 , Cesar Jimenez

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