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Piano, Salvatore Silvio (2018) Bacterial or fungal infections in patients with cirrhosis: epidemiology across the world, definition of sepsis and predictors of post discharge outcomes. [Ph.D. thesis]

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Abstract (english)

Background and aims: Bacterial infections are frequently observed in patients with cirrhosis and confers a poor survival. In recent years an increase in mortality rate has been observed in patients with cirrhosis. In addition, an increase in the prevalence of multi drug (MDR) bacterial infections has been described, reducing the efficacy of commonly used antibiotics such as third generation cephalosporins. In this thesis we conducted 3 studies aimed to: a) provide data about epidemiology of infections across countries and continents; b) assess the ability of the new criteria for sepsis (Sepsis-3) in predicting poor outcomes in patients with cirrhosis and bacterial infections; c) to assess predictor of early readmission (within 30 days) and mid-term survival (6 months) after discharge for bacterial infections
Methods: For the first study, we conducted a prospective, multicenter, intercontinental, cross sectional study including patients with cirrhosis and bacterial/fungal infections (1,302 patients). For the second study, we conducted a prospective cross sectional study in two cohort of patients (primary cohort [259 patients] and validation cohort [197 patients]). For the third study, patients discharged after a hospitalization for bacterial/fungal infections were followed up for 6 months (199 patients). In all the 3 studies, demographic, clinical, laboratory and microbiological characteristics were collected at inclusion in the study and during the follow up.
Results: In the first study we showed several differences among countries in the prevalence and the type of MDR bacterial infections, that were more prevalent in Indian or other Asian centers as well as in Southern American centers. These findings were associated with a significantly lower probability of microbiological susceptibility to antibiotic regimens suggested by the current guidelines. Remarkably, some infections were poorly treated even in countries with a low prevalence of MDR bacteria. The second study showed that Sepsis-3 criteria and quick SOFA have a significantly greater discrimination for in-hospital mortality (AUROC=0.784 and 0.732, respectively) than SIRS (AUROC=0.606;p<0.01 for both). Sepsis-3 had higher incidence of acute-on-chronic liver failure, septic shock and transfer to ICU than those without Sepsis-3. Similar results were observed in the validation cohort. In the third study, 69 patients (35%) were readmitted within 30 days from discharge. C-reactive protein (CRP) value at discharge (OR=1.91;p=0.022), diagnosis of acute-on-chronic liver failure during the hospital stay (OR=2.48;p=0.008) and the hospitalization in the last 30 days previous to the admission/inclusion in the study (OR=1.50;p=0.042) were found to be independent predictors of readmission. CRP at discharge was also found to be an independent predictor of 6 month mortality (HR=1.85;p=0.001) as well as age (HR=1.05;p=0.001), MELD score (HR=1.13;p<0.001), refractory ascites (HR=2.22;p=0.007) and diabetes (HR=2.41;p=0.010). Patients with a CRP>10 mg/l at discharge had a significantly higher probability of being readmitted within 30 days (44 vs 24%; p=0.007) and a significantly lower probability of 6-month survival (62 vs 88%;p<0.001) than those with a CRP≤10 mg/L
Conclusions: The first studies allowed to clarify the different epidemiology of bacterial infections in different centers suggesting different approach for the empirical treatment. The second study suggests that Sepsis-3 criteria and qSOFA are reliable tools to define the severity of infections and thus “sepsis” in patients with cirrhosis. Accordingly, an algorithm has been provided for the application of these criteria in patients with cirrhosis. Finally, the third study suggest that CRP levels may be potentially used to guide the antimicrobial stewardship in patients with cirrhosis and bacterial infections.

Abstract (italian)

Introduzione ed obiettivi: Le infezioni batteriche sono molto frequenti nei pazienti con cirrosi epatica e si associano ad una scarsa sopravvivenza. Negli ultimi anni è stato osservato un incremento nella prevalenza delle infezioni da germi multi-resistenti (MDR) in pazienti con cirrosi epatica con conseguente riduzione dell'efficacia degli antibiotici comunemente utilizzati in questi pazienti. In questa tesi sono stati condotti 3 studi clinici con l'obiettivo di: a) valutare l’epidemiologia delle infezioni batteriche in pazienti con cirrosi epatica nei diversi paesi e continenti; b) valutare l’accuratezza dei nuovi criteri diagnostici di sepsi (Sepsis-3) nel predire la mortalità in pazienti con cirrosi ed infezioni batteriche; c) valutare predittori di riammissione ospedaliera precoce (entro 30 giorni) e sopravvivenza a medio termine (6 mesi) dopo un episodio di infezione batterica.
Metodi: Per il primo studio, abbiamo condotto uno studio trasversale prospettico, multicentrico, intercontinentale includendo pazienti con cirrosi ed infezioni batteriche/fungine (1302 pazienti). Per il secondo studio, abbiamo condotto uno studio trasversale prospettico in 2 coorti di pazienti (coorte primaria [259 pazienti] e coorte di validazione [197 pazienti]). Per il terzo studio, abbiamo seguito per 6 mesi i pazienti dimessi dopo un ricovero per infezione batterica o fungina (199 pazienti). Nei 3 studi abbiamo raccolto variabili demografiche, cliniche, laboratoristiche e microbiologiche alla diagnosi di infezione e durante il seguimento.
Risultati: Nel primo studio abbiamo identificato numerose differenze tra i diversi paesi relativamente alla prevalenza e al tipo di infezioni sostenute da batteri MDR, che erano maggiormente isolati nei centri asiatici, in particolare indiani e nei centri sudamericani. Inoltre, queste differenze si associavano ad una ridotta suscettibilità agli schemi di terapia antibiotica suggeriti dalle attuali raccomandazioni internazionali. In particolare è importante evienziare come alcune infezioni fossero trattate in modo subottimale anche in paesi con una scarsa prevalenza di germi MDR. Nel secondo studio abbiamo evidenziato come i criteri Sepsis-3 ed il quick SOFA hanno una capacità di discriminazione per la mortalità ospedaliera (AUROC=0.784 e 0.732, rispettivamente) significativamente superiore ai criteri SIRS (AUROC 0.606; p<0.01 per entrambe le comparazioni). I pazienti con sepsi secondo i criteri Sepsis-3 avevano una maggiore incidenza di insufficienza epatica acuta su cronica (ACLF), shock settico e trasferimento in terapia intensiva rispetto a coloro che non avevano sepsi. Tali risultati sono stati confermati nella coorte di validazione. Nel terzo studio, 69 pazienti (35%) sono stati riospedalizzati entro 30 giorni dalla dimissione. I valori di proteina C reattiva (PCR) alla dimissione (OR=1.91; p=0.022), la diagnosi di ACLF durante il ricovero (OR=2.48;p=0.008) e l’ospedalizzazione negli ultimi 30 giorni prima del ricovero/inclusione nello studio (OR=1.50; p=0.042) sono risultati predittori indipendenti di riammissione ospedaliera precoce. I valori di PCR alla dimissione sono anche risultati predittori indipendenti di mortalità a 6 mesi (HR=1.85; p=0.001) così come l’età (HR=1.05;p=0.001), il punteggio MELD (HR=1.13;p<0.001), l’ascite refrattaria (HR=2.22;p=0.007) e la presenza di diabete (HR=2.41;p=0.010). I pazienti con una PCR>10 mg/l alla dimissione, avevano una probabilità di riammissione precoce significativamente maggiore (44 vs 24%; p=0.007) e una probabilità di sopravvivenza a 6 mesi significativamente inferiore (62 vs 88%; p<0.001) rispetto ai pazienti con una PCR≤10 mg/l.
Conclusioni: Il primo studio ha permesso di chiarire la differente epidemiologia delle infezioni batteriche nei diversi centri, suggerendo diversi approcci di terapia antibiotica empirica. Il secondo studio suggerisce che i criteri Sepsis-3 ed il quick SOFA sono affidabili per definire la severità dell’infezione batterica e quindi di “sepsi” nei pazienti con cirrosi epatica. In base a questi risultati abbiamo proposto un algoritmo per l’applicazione di questi criteri in pazienti con cirrosi epatica. Infine, il terzo studio suggerisce che la PCR possa essere potenzialmente utilizzata per guidare la durata della terapia antibiotica in pazienti con cirrosi epatica ed infezioni batteriche.

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EPrint type:Ph.D. thesis
Tutor:Angeli, Paolo
Ph.D. course:Ciclo 30 > Corsi 30 > SCIENZE CLINICHE E SPERIMENTALI
Data di deposito della tesi:13 January 2018
Anno di Pubblicazione:11 January 2018
Key Words:Cirrosi epatica, infezioni batteriche, epidemiologia, sepsi, insufficienza epatica acuta su cronica, liver cirrhosis, bacterial infections, epidemiology, sepsis, acute on chronic liver failure, stewardship
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/12 Gastroenterologia
Area 06 - Scienze mediche > MED/09 Medicina interna
Area 06 - Scienze mediche > MED/17 Malattie infettive
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:10686
Depositato il:09 Nov 2018 14:41
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