Fever and cirrhosis

(infection and cirrhosis)

Bacterial Infections in cirrhotics: dimension 20-50% of cirrhotics admitted to hospital have an infection Bacterial infections in cirrhosis are a major cause of:

Decompensation Death

Fernandez, Hepatology 2002; Arvaniti, Gastroenterology 2010; Fernandez, Hepatology 2012

Diagnosi di infezione batterica in cirrotici al ricovero

Pazienti con cirrosi: 536 Pazienti con cirrosi: 404 ricoveri in 361 pazienti

% Urinary tract 26.1

SBP 23.9

Bacteremia 18.5

Pneumonia 16.3

Soft tissue 4.3

Other 10.9

Multicenter Italian Database, unpublished

% Urinary tract 41 Ascites 23 Bacteremia 21 Pneumonia 17 Soft tissue Other -

Borzio et al, 2001

Some outcome measures

499 in-hospital patients with cirrhosis

Length of hospitalization (days): With bacterial infection 15.5 ± Without bacterial infection 9.9 ± 9.9

7.5 p=0.001 In-hospital mortality With bacterial infection 7 / 88 8.2% Without bacterial infection 11/411 2.7% p=0.03

Gaeta et al. Multicentre Italian database

Risk of death in patients with and without infection (in studies reporting complete information on mortality) Arvaniti V. et al. Gastroenterology 2010 ; 139 : 1246-1256

Mortality of patients with cirrhosis after infection

Parameter

Total mortality

- 1 mo - 3 mo - 12 mo

1978-1999 total mortality

- 1 mo - 3 mo - 12 mo

2000-2009 total mortality

- 1 mo - 3 mo - 12 mo N° of studies 178 51 27 40 89 21 18 25 89 29 9 14 N° of pataients 11.987

2449 1439 2154 4890 737 578 758 7132 1621 681 634 Median Mortality 38 % 30.3% 44 % 63 % 47.4 % 37.3 % 43 % 69.7% 32.3% 26 % 44% 60% Arvaniti V. et al. Gastroenterology 2010 ; 139 : 1246-1256

Case discussion

3 months before

Tot. Bilirubin Ascites 2.08 mg/dL NO

On admission

Tot. Bilirubin Ascites 3.5 mg/dL mild

Case discussion

3 months before

Tot. Bilirubin Ascites 2.08 mg/dL NO WBC Neutrophils 4900/µL 3050/µL

On admission

Tot. Bilirubin Ascites WBC Neutrophils 3.5 mg/dL mild 8400/ µL 5300/ µL

Il paziente con cirrosi è immunocompromesso

Bonnel, Clinical Gastroenterol Hepatol 2011

Infections occurring during Peg IFN+RBV treatment Ref. 1 Pts n.

255 2 3 4 319 119 30 5 case control 66 Type of Pts F3-F4 Metavir 17% F3-F4 Metavir 34% Cirrhosis 15% OLT listed (50% CTP A) Decompensated cirrhosis Infections 12% (24 / 100 pts / yr) 23% (41/100 pts / yr) 18% 13% Factors associated Neutropenia only in respiratory infection Age> 60 (not neutropenia) None with neutropenia n.a.

28% 0.45 / 1000pts / mo.

OR = 2.95 (0.93-9.3) CTP C; neutrophils < 900 1. Puoti et al., Antiviral Ther. 2008; 2 Antonini et al., Infection 2008.; 3. Soza et al. Hepatol. 2002 4 Forns et al., J. Hepatol. 2003;.; 5. Iacobellis et al. J. Hepatol 2007

Case discussion

3 months before

Tot. Bilirubin Ascites 2.08 mg/dL NO WBC Neutrophils 4900/µL 3050/µL Creatinine Cr Clearance 1.3 mg/dL 39.26 mL/min

On admission

Tot. Bilirubin Ascites WBC Neutrophils 3.5 mg/dL mild 8400/ µL 5300/ µL Creatinine Cr clearance 2.5 mg/dL 20.6 mL/min

Three-month probability of survival of patients with cirrhosis according to the cause of renal failure

Martin-Llahi. M. et al. Gastroenterology 2010

Renal failure and bacterial infections in patients with cirrhosis

Fasolato, Hepatology 2007

Case discussion

Urinalysis

Diuresis 600 ml/24h Natriuria 38.7 mEq/24h Cloruria 31.5 mEq/24h Kaliuria 25.0 mEq /24h Microalbuminuria (106 mg/24h) >35 Leukocytes x field 10 RBC x field

Case discussion

3 months before

Tot. Bilirubin Ascites 2.08 mg/dL NO WBC Neutrophils 4900/µL 3050/µL Creatinine Cr Clearance 1.3 mg/dL 39.26 mL/min CRP 0.25 mg/dL

On admission

Tot. Bilirubin Ascites WBC Neutrophils 3.5 mg/dL mild 8400/ µL 5300/ µL Creatinine Cr clearance CRP 2.5 mg/dL 20.6 mL/min 5 mg/dL

Enteric

bacteria overgrowth Portal vein Cirrhosis-associated immune dysfunction Other sources

Bacterem

ia

Translocation to limph nodes

Organ localization SBP

Mechanisms of bacterial (and their products) translocation

Portal hypertension Splancnic vasodilation Disruption of intestinal barrier permeability Increased sympathetic nerve activity Intestinal hypomobility and germ overgrow

Translocation

Transolacation is associated to increased plasma levels of cytokines (TNF α , IL-6,), MAP-K,

“Tempesta citochinica” provocata da prodotti batterici

From: Wong, Gut 2006

Bacterial translocation becomes clinically significant when it produces SBP, bacteremia, post-surgical infections

Bacterial peptides (Porins; HSP60;) are present in the ascites of afebrile patients with increased TNF α and IFN-gamma concentrations

Cano et al. J Mol Med, 2010, e-Pub

SBP –

A chronic inflammatory disease with flares?

bacterial translocation cytokine production nitric oxide production bacterial products which cause: inflammatory response SBP SBP

time

Clinical risk factors associated with the occurrence of bacterial infections in cirrhosis

variceal bleeding prior episode of SBP high Child–Pugh score low ascitic protein levels

Gines P,. Hepatology 1990;12:716–724; Gustot T, Hepatology 2009;50:2022–2033 Arvaniti V, Gastroenterology 2010;139:1246–1256; Foreman MG, Chest 2003;124: 1016–1020.

Susceptibility to spontaneous bacterial peritonitis are genetics the future ?

NOD2 (nucleotide-binding oligomerization domain) variants linked to impaired mucosal barrier may be genetic risk for SBP Mannose-binding lectin deficiency, inducing a defect in opsonophagocytosis of bacteria, confers a higher risk of bacterial infections in patients with cirrhosis Toll-like receptor (TLR)2 polymorphisms are associated with an increased susceptibility towards SBP

Appenrodt, Hepatology 2010; 51:1327-33; Altorjav I,. J Hepatol 2010;53:484–491 Nischalke HD,. J Hepatol. 2011; 55:1010-6.

Case discussion

3 months before

Tot. Bilirubin Ascites 2.08 mg/dL NO WBC Neutrophils 4900/µL 3050/µL Creatinine Cr Clearance 1.3 mg/dL 39.26 mL/min CRP 0.25 mg/dL

On admission

Tot. Bilirubin Ascites WBC Neutrophils 3.5 mg/dL mild 8400/ µL 5300/ µL Creatinine Cr clearance CRP Body temp 2.5 mg/dL 20.6 mL/min 5 mg/dL 37.5 °C

Deterioramento della funzione epatica Segni e sintomi tipici di infezione

Ittero Creat. clearance Encefalopatia Febbre (assente nel 30-50%) Leucocitosi neutrofila (relativa!)

Possibile esordio grave: febbre, coagulopatia, coma

Cazzaniga, J Hepatol 2009; 51:475-482; Wong, Gut 2005; 54:718-25; Fasolato, Hepatology 2007; 45:223-2

Absence of fever in cirrhotic patients with pneumonia

Pneumonia HIV negative (n = 79) T° < 37 26 (32,9%) T° > 37 53 (67,1%) (53) 14 (26,4%) 39 (73,6%) HIV positive (26) 12 (46,2%) 14 (53,8%) Gaeta, Puoti, in preparation

SIRS criteria: less diagnostic accuracy in cirrhosis ?

SIRS criteria In cirrhosis

• Hyperdynamic circulation leads to tachycardia • Beta-blockers cause a reduced heart rate • Hypersplenism decreases white blood cell count Cazzaniga M,. J Hepatol 2009;51:475–482. Thabut D, Hepatology 2007;46:1872–1882.

Therapy

The flow chart of empirical treatment

Infection considered

Microbiological investigations

Empirical treatment POS (40%) NEG (60%) Modify tx Continue empirical tx

Epidemiology classification

Community acquired the diagnosis of infection is made within 48 hours of hospitalization and the patient did not fulfill the criteria for HCA infection Health Care Associated the diagnosis is made within 48 hours of hospitalization in patients with any of the following criteria: (1) had attended a hospital or a hemodialysis clinic, or had received intravenous chemotherapy during the 30 days before infection; or (2) were hospitalized for at least 2 days, or had undergone surgery during the 180 days before infection; or (3) had resided in a nursing home or a long-term care facility.

Hospital Acquired the diagnosis of infection is made after more than 48 hours of hospital stay

Case discussion

Therapy

• Plasma expansion ( saline, albumin ) • Antibiotic therapy :

During the previous six months the patient had received :

• Quinolones • 3rd generation cephalosporins

given by GP for UTI and upper respiratory infection

Therapy was started with Meropenem 500mg/12h (according to creatinine clearance) and continued for 10 days

Systemic antibiotic exposure is a risk factor for bacterial resistance in cirrhosis

169 infectious episodes in 115 patients 70 culture positive infections 33 (47%) antibiotic resistant strains Independent risk factors for resistance Systemic antibiotics in the previous 30 days OR 13.5 (95% CI = 2.6 – 71.6) Nosocomial infection OR 4.2 (95% CI = 1.4 -12.5) Non-adsorbable antibiotics OR 0.4 (95% CI = 0.04 -2.8) Tandon et al. Clin Gastroenterol Hepatol 2012; 10:1291-98

Exposure to antibiotics in the 30 days before the development of infection

Tandon et al. Clin Gastroenterol Hepatol 2012; 10:1291-98

Prevalence of gram positive cocci in infections in cirrhotic patients

% 90 80 70 60 50 40 30 20 10 0 UTI SBP Bacteremia Tandon, Clin Gastroenterol Hepatol. 2012

Prevalence of E.coli with resistance to quinolones

Norfloxacin + Novella 1997 9/10 (90%) Campillo 1998 3/23 (13%) Fernandez 2002 24/37 (65%) Cereto 2003 9/13 (69 %) Norfloxacin 4/11 (36%) 8/42 (19 %) 39/135 (29%) 3/34 (31 %) tot 13/21 11/65 63/172 12/47

3rd generation cephalosporin susceptible

Incidence of 3rd-generation resistant episodes of SBP

Ariza et al, J Hepatol 2012; 56 : 825–832

Risk factors for SBP caused by a 3rd-generation cephalosporin-resistant microorganism

Ariza et al, J Hepatol 2012; 56 : 825–832

Prevalence of resistant strains among

Community acquired Health care associated Hospital acquired 7 – 33% 21 – 50% 40 – 80%

Merli, 2012; Ariza 2012

Prevalence of resistance to ESBL among

E. coli

isolates from bacteremias (

EARSS

2005) No data < 1% 1-5% 5-10% 10-25% >25%

Quale terapia per le infezioni sostenute da ESBL+?

Antibiotici ESBLs Cefalosporine di terza generazione Cefepime Fluorochinoloni Piperacillina/tazobactam Carbapenemici Tigeciclina Colistin – – +/– +/– +++ ++ (for carbapenem resistance)

Spontaneous Bacterial Peritonitis (SBP) by a 3rd-generation cephalosporin-resistant microorganism (MRCef) by the days after admission (circles) or days of contact with the health-care system (triangles)

Ariza et al, J Hepatol 2012; 56 : 825–832

Risk Factors of Infections by Multiresistant Bacteria in Cirrhosis * * * *

Fernandez, Hepatology 2012

Definitions of resistance

multidrug-resistant (MDR) The isolate is non-susceptible to at least 1 agent in ≥ 3 antimicrobial categories extensively-drug resistant (XDR) The isolate is non-susceptible to at least 1 agent in all but 2 or fewer antimicrobial categories pandrug-resistant (PDR) Non-susceptibility to all agents in all antimicrobial categories ECDC Expert Panel. Accessible at: http://ecdc.europa.eu/en/activities/diseaseprogrammes/ARHAI

Uso di albumina in pazienti cirrotici con infezioni

Guevara et al. J Hepatol 2012 vol. 57 j 759–765

Cause di febbre nel cirrotico

non solo batteri !!

INFLUENZA

L’Influenza può causare scompenso nel paziente cirrotico

(Duchini, Arch Intern Med, 2000)

Elevata mortalità da influenza H1N1 in pazienti cirrotici (3/21 cirrotici vs. 0/27 non cirrotici)

(Marzano, J Med Virol 2012)

Il vaccino anti-influenzale è sicuro ed immunogeno nei pazienti cirrotici o trapiantati di fegato

(Gaeta, Vaccine 2009)

Summary & Conclusions

Bacterial infection is one of the most frequent cause of decompensation and death in cirrhosis Immune defects, mainly acquired but also genetic, and bacterial translocation are the main mechanisms involved in its pathogenesis The prevalence of infections is likely to be underestimated in clinical practice due to the reduced diagnostic capacity of the standard diagnostic criteria Gram positive and MDR bacteria are increasing etiologic agents

Risk factors for 30-day mortality

Ariza et al, J Hepatol 2012; 56 : 825–832

Prevalence of gram positive/gram negative bacteria

% 70 60 50 40 30 20 10 0 Gram neg Gram pos All HA Merli, Clin Gastroenterol Hepatol 2010

LPS stimulates hyper-production of TNF-a from monocytes of cirrhotic patients

Fernandez J, J Hepatol 2012

Pazienti a rischio di infezione

• Cirrosi avanzata (Child-Pugh B/C) • Precedente episodio di peritonite batterica • Emorragia digestiva

Profilassi antibiotica nei pazienti con rischio elevato Norfloxacina 400 mg/die

Probabilità di sviluppo di peritonite batterica spontanea

(%)

100

P < 0.001

Placebo

50 0

Norfloxacin 100 200 300 400 J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.

days

Improved survival after variceal bleeding

80% 70% 60% 50% 40% 30% 20% 10% 0% year: Tx: 1980 •Ballon tamponade Child A Child B Child C 2000 •Vasoactive agents •Endoscopic tx •Antibiotic prophylaxis

Predictors of survival

•

Type of therapy

•

Antibiotic prophylaxis

Carbonell, Hepatology 2004; 40:652-659

Altre infezioni

Tubercolosi Stessi fattori di rischio dei pazienti non cirrotici Micosi sistemiche Criptococcosi e Aspergillosi: rischio più elevato nella cirrosi Leishmaniosi Descritta in Italia nelle aree di endemia. Rischio più elevato nella cirrosi