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:
404 ricoveri in 361 pazienti
Pazienti con cirrosi: 536
%
%
Urinary tract
26.1
Urinary tract
41
SBP
23.9
Ascites
23
Bacteremia
18.5
Bacteremia
21
Pneumonia
16.3
Pneumonia
17
Soft tissue
4.3
Soft tissue
-
Other
-
Other
10.9
Multicenter Italian Database, unpublished
Borzio et al, 2001
Some outcome measures
499 in-hospital patients with cirrhosis
Length of hospitalization (days):
With bacterial infection
15.5 ± 9.9
Without bacterial infection 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
N° of studies
N° of pataients
Median Mortality
Total mortality
178
11.987
38 %
- 1 mo
51
2449
30.3%
- 3 mo
27
1439
44 %
- 12 mo
40
2154
63 %
1978-1999 total mortality
89
4890
47.4 %
- 1 mo
21
737
37.3 %
- 3 mo
18
578
43 %
- 12 mo
25
758
69.7%
2000-2009 total mortality
89
7132
32.3%
- 1 mo
29
1621
26 %
- 3 mo
9
681
44%
- 12 mo
14
634
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
3.5 mg/dL
Ascites
mild
Case discussion
On admission
3 months before
Tot. Bilirubin
Ascites
2.08 mg/dL
NO
Tot. Bilirubin
3.5 mg/dL
Ascites
mild
WBC
4900/µL
WBC
8400/ µL
Neutrophils
3050/µL
Neutrophils
5300/ µL
Il paziente con cirrosi è immunocompromesso
Bonnel, Clinical Gastroenterol Hepatol 2011
Infections occurring during Peg IFN+RBV treatment
Ref.
Pts
n.
Type of Pts
1
255
F3-F4 Metavir
17%
12%
(24 / 100 pts / yr)
Neutropenia only in
respiratory infection
2
319
F3-F4 Metavir
34%
23%
(41/100 pts / yr)
Age> 60
(not neutropenia)
3
119
Cirrhosis
15%
18%
None with neutropenia
4
30
OLT listed
(50% CTP A)
13%
n.a.
5
66
Decompensated
cirrhosis
28%
0.45 / 1000pts / mo.
OR = 2.95 (0.93-9.3)
casecontrol
Infections
Factors associated
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
On admission
3 months before
Tot. Bilirubin
Ascites
2.08 mg/dL
NO
Tot. Bilirubin
3.5 mg/dL
Ascites
mild
WBC
4900/µL
WBC
8400/ µL
Neutrophils
3050/µL
Neutrophils
5300/ µL
Creatinine
1.3 mg/dL
Creatinine
2.5 mg/dL
Cr Clearance
39.26 mL/min
Cr clearance
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
On admission
3 months before
Tot. Bilirubin
Ascites
2.08 mg/dL
NO
Tot. Bilirubin
3.5 mg/dL
Ascites
mild
WBC
4900/µL
WBC
8400/ µL
Neutrophils
3050/µL
Neutrophils
5300/ µL
Creatinine
1.3 mg/dL
Creatinine
2.5 mg/dL
Cr Clearance
39.26 mL/min
Cr clearance
20.6 mL/min
CRP
0.25 mg/dL
CRP
5 mg/dL
Other sources
Enteric bacteria
overgrowth
Increased intestinal
permeability
Portal vein
Cirrhosis-associated
immune dysfunction
Bacteremia
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
(TNFα, 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
TNFα 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 peritonitisare 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
On admission
3 months before
Tot. Bilirubin
Ascites
2.08 mg/dL
NO
Tot. Bilirubin
3.5 mg/dL
Ascites
mild
WBC
4900/µL
WBC
8400/ µL
Neutrophils
3050/µL
Neutrophils
5300/ µL
Creatinine
1.3 mg/dL
Creatinine
2.5 mg/dL
Cr Clearance
39.26 mL/min
Cr clearance
20.6 mL/min
CRP
0.25 mg/dL
CRP
5 mg/dL
Body temp
37.5 °C
Caratteristiche cliniche delle
infezioni batteriche nel cirrotico
Deterioramento
della funzione
epatica
Segni e sintomi tipici di
infezione
Febbre
Ittero
(assente nel 30-50%)
Creat. clearance
Leucocitosi neutrofila
Encefalopatia
(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)
(53)
T° < 37 26
14
(32,9%)
(26,4%)
T° > 37 53
39
(67,1%)
(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%)
Modify tx
NEG (60%)
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 +
Norfloxacin -
tot
Novella 1997
9/10 (90%)
4/11 (36%)
13/21
Campillo 1998
3/23 (13%)
8/42 (19 %)
11/65
Fernandez 2002
24/37 (65%)
39/135 (29%)
63/172
Cereto 2003
9/13 (69 %)
3/34 (31 %)
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
7 – 33%
Health care associated
21 – 50%
Hospital acquired
40 – 80%
Merli, 2012; Ariza 2012
Prevalence of resistance to ESBL among E. coli isolates
bacteremias (EARSS 2005)
No data
< 1%
1-5%
5-10%
10-25%
>25%
from
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
Gram neg
Gram pos
30
20
10
0
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
Norfloxacin
0
100
200
300
400
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824.
days
Improved survival after variceal bleeding
80%
Child A
Child B
Child C
70%
mortality (%)
60%
Predictors of
survival
50%
40%
•Type of therapy
30%
•Antibiotic
prophylaxis
20%
10%
0%
year:
Tx:
1980
•Ballon
tamponade
2000
•Vasoactive agents
•Endoscopic tx
•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