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The research interest of the investigator has focused on the molecular and cellular pathogenesis of sepsis. In particular, he has worked on soluble proteins involved in the innate recognition of bacteria such as soluble CD14 and MD-2, as well as in the Toll-like receptors activated by Gram-negative and Gram-positive bacteria. Another area of study is the molecular pathogenesis and cell signaling of ventilator-induced lung injury, and lung inflammation in the context of acute respiratory distress syndrome. He has also identified and tested biomarkers in the field of clinical sepsis. Watch the presentation on Youtube: https://www.youtube.com/watch?v=CyWN7JlhlmI&
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Use of of Biomarkers in the Care of Patients with sepsis
Prof. Jérôme Pugin, MD
Intensive CareUniversity HospitalsGeneva, Switzerland
October 21st, 2014Seminar VHIRVall d’Hebron
Why do I want a biomarker and what for?
• To make a diagnosis?
• To make a decision?- antibiotic therapy?- ICU admission, stratification?- diagnostic procedure? - to start specific therapy (steroids, …)?
• To monitor?
• To predict outcome?
• To enroll patients into studies?
• To perform epidemiological studies?
• To understand the disease?
PCT
PCT??cortisol
PCT, CRP, lactate
IL-6, PCT
IL-6, PCT?
Genetics
Many
Adapted from Samraj et al. Shock 2013
Diagnosis of sepsis
The ideal marker:
• Excellent diagnostic yield
sensitive discriminative with other sepsis-like situations
• Cross-validated
• Easy & rapid to measure
• Cheap
• Impact on the care of the sepsis patient
1. Sepsis is a continuum between colonization, infection and systemic infection with various levels of severity
2. Sepsis is a heterogeneous syndrome
3. Consequences (organ dysfunction) of sepsis vary
4. Clinical definition of sepsis is vague
5. Bacterial pathogens triggering sepsis are numerous
It is unlikely that a single biomarker will yield perfect diagnosis in the context of sepsis
• Single biomarker: simple, rapid, cheap, sensitive, usually not very specific
• Single biomarker associated with clinical signs: probably better, introduces the clinical context
• Multiple biomarkers: technology? Less rapid, more expensive, increased specificity, lack of sensitivity?
Single vs. multiple biomarkers
Am J Respir Crit Care Med 2012
The challenges:
1. Find specificity in host response to severe bacterial infection as compared with systemic response due to other SIRS conditions (immense overlap!)
2. Combining infection and host response markers
3. Timing issue (sepsis is an ongoing process)
Host response to severe bacterial infection
Molecular signature of sepsis (host)
Siqnature® (SIRS-Lab)
http://www.sirs-lab.com/siqnatureBauer, Möller, Rußwurm,and Reinhart, ISF meeting 2008
Siqnature® score discriminates sepsis from SIRS better than PCT and CRP
Molecular signature of the pathogen
• SeptiFastTM (Roche), VYOOTM (SIRS-lab), Plex ID (Abbott)
• PCR-based methods or oligoarray
• Detect a wide variety of pathogens causing severeinfections and sepsis in critically ill patients
• Performed on whole blood (and other body fluids)
• Take ~6 hrs
• Sensitivity/Specificity in the clinical arena?
Vincent el al. In preparation
Results of RADICAL studyStandard cultures vs. molecular determination
609 suspicions of severe infectiosns in ICU patientsBlood cultures, cultures of TA, BALs, ascites, etc.
Combining clinical data and biomarkers (ALI)
Crit Care Med 2011
γINF
IL-18
IL-1ra sTNFR2
sTNFR1IL-10
IL-4
IL-12
Endothelin Nitrites
NOiNOS
Lymphotoxin
IL-8 IL-6IL-1ß
PCT
C3a
sVCAM-1
sE-selectin
sICAM-1LBP
cortisol
Neopterin
CRP
HMGB-1
MIF
C5a
D-dimers
APC
TNF
ATIII
PGE2
PGI2
TxA2
LPS
LTB4
sCD14
ESM-1
albumin
HLA-DR
Sepsis
γINF
IL-18
IL-1ra sTNFR2
sTNFR1IL-10
IL-4
IL-12
Endothelin Nitrites
NOiNOS
Lymphotoxin
IL-8 IL-6IL-1ß
PCT
C3a
sVCAM-1
sE-selectin
sICAM-1LBP
cortisol
Neopterin
CRP
HMGB-1
MIF
C5a
D-dimers
APC
TNF
ATIII
PGE2
PGI2
TxA2
LPS
LTB4
sCD14
ESM-1
albumin
HLA-DR
Sepsis
• Recognized by Assicot et al. as a marker of severe bacterial infection in children (Lancet 1993)
• Serum PCT levels increase 4-8 hrs after experimental sepsis or LPS injection to humans, and peak after 12-24 hrs
• Serum PCT levels are slightly elevated in severe parasite et fungal infections
• Serum PCT levels are low in any viral diseases
• “False positives”: 2 first days of life, heat stroke, multiple trauma, some surgical patients, medullar thyroid cancer
Procalcitonin: FAQs
Müller et al., J Clin Endocrinol Metabol, 2000, 86: 396-404
Procalcitonin gene induction during experimental sepsis
• Pulmonary sepsis vs. ARDS?
• Abdominal sepsis vs. uninfected severe pancreatitis?
• Bacterial vs. viral meningitis?
• Bacterial vs. inflammatory arthritis?
• Organ Tx rejection vs. bacterial sepsis?
• Bacterial vs. nonbacterial origin in FUO?
• Bacterial vs. nonbacterial origin in respiratory tract infection?
Suprin E. ICM 2000, van Langevelde P. CID 2000, Viallon A. CID 1999, Schwarz S. CCM 2000, Hedlund J. Infection 2000, Boeken U. ICM 2000, Hammer. Ann Transpl 1999, Kuse ER. CCM 2000, Aouifi A. CCM 2000, Wanner GA. CCM 2000, Mimoz O. ICM 1998, Rau B. Gut 1997, Muller CA. Gut 2000, Brunkhorst FM. CCM 2000, Christ-Crain. Lancet 2004.
Usefulness of PCT as a diagnostic test (> 600 studies)
PCT algorithm for patients with respiratory tract infection
Schuetz P BMC Med 20111
PCT algorithm for patients with sepsis
Schuetz P BMC Med 20111
PCT is not a sepsis screening tool for patientsadmitted to the ICU
Plasma PCT levels in 100 patients admitted to the ICU(sepsis prevalence: <15%)
Ugarte et al. Crit Care Med 1999
The highest the prevalence (pre-test probability), the greatest the performance for a diagnostic test
Sepsis: definitions
SIRS (≥ 2 criteria): FeverLeucocytosisTachypneaTachycardia
Sepsis: SIRS + bacterial infection
Severe sepsis: Sepsis + organ failure
Septic shock: Severe sepsis + refractoryshock
ACCP/SCCM consensus conference 1992
.01
.1
1
10
100
1000
PC
T (
ng
/mL
)
Septic shock
Severesepsis
SepsisSIRS
Harbarth et al. Am J Respir Crit Care Med 2001
Diagnostic yield of PCT in sepsis
1.1 ng/mLSensitivity 97%
Specificity 78%
1 - specificity
sen
siti
vity
1.00
0.75
0.50
0.25
0.00
0.00 0.25 0.50 0.75 1.00
Clinical model with PCTClinical model without PCT
PCT adds to a clinical prediction modelfor the diagnosis of sepsis
Harbarth et al. Am J Respir Crit Care Med 2001
.01
.1
1
10
100
1000
PC
T (
ng
/mL
)
Septic shock
Severesepsis
SepsisSIRS
Procalcitonin
1
10
100
1000
10000
100000
IL-6
(p
g/m
L)
Septic shock
Severesepsis
SepsisSIRS
Interleukin-6
Harbarth et al. Am J Respir Crit Care Med 2001
Only PCT discriminates sepsis from SIRS
0.1
1
10
100
SurvivedSepsis-relateddeath
PCT (ng/ml) IL-6 (pg/ml)
At the time of admission to the ICU, IL-6 is a better prognostic marker than PCT
Harbarth et al. Am J Respir Crit Care Med 2001
1
10
100
1000
10000
100000
SurvivedSepsis-relateddeath
Antibiotic guidance: who needs guidance?
Duration of antibiotic therapy in the ICU.Who cares?
Bacterialresistance $$$
Toxicity -interactions
When to stop the antibiotic therapy?
“We said 8 days”“Patient is stable”“Patient is transferred to the ward”“Patient develops a rash”“Renal function is deteriorating”“The fellow (attending) is changing”“Cultures came back negative”…
Strategies to reduce antibiotics in ICU
1. Decrease empirical time!
Lancet 2010
2. Use procalcitonin!
Chastre et al. JAMA 2003
AJRCCM 2008
1. Decrease empirical time!
VAP: 8 vs. 15 days antibiotic therapy
Chastre et al. JAMA 2003
Cave: increased relapse of nonfermentative GNB!Cave: increased relapse of nonfermentative GNB!
0.1
1
10
100
1000
PC
T (
ng
/mL
)
0 2 4 6 8 10 12 14 16
Days
0.1
1
10
100
1000
PC
T (
ng
/mL
)
0 2 4 6 8 10 12 14 16
Days
Survived Died
Decrease of plasma procalcitonin levels with timein survivors vs. non-survivors
Harbarth et al. Am J Respir Crit Care Med 2001
Would PCT help clinicians to stop antibiotics earlier ?
Christ-Crain et al. Am J Resp Crit Care Med 2006Schuetz et al. BMC Health Services Research 2007
Concept :To guide antibiotic therapy initiation and
duration on PCT values in CAP patients
Initiate or continue < 0.1 µg/L : NOantibiotic therapy: > 0.1 < 0.25 : no
> 0.25 < 0.5 : yes> 0.5 µg/L : YES
PCT
Christ-Crain et al. Am J Resp Crit Care Med 2006
PCT guidance in CAP: 6 days less antibiotic therapy,identical outcome!
PCT Control
Cure 85% 85%
Mortality 12% 13%
Duration of antibiotic therapy in the ICU:
• Mostly empiric
• Rarely tailored for a given patient
• Rarely customized for a given bacterium or infection
Does one size fit all?
PCT guidance in patients with severe sepsisand septic shock?
Inclusion criteria
• Patient suspected of severe sepsis or septic shock
• Initiation of antibiotic therapy < 48hr
Exclusion criteria
• High-risk bacteria (P.aeruginosa, A.baumanii)
• Infection known to require prolonged antibiotic therapy
(e.g. endocarditis, deep abcesses, osteomyelitis)
• Severe immune suppression/neutropenia
Nobre et al. Am J Respir Crit Care Med 2008
Suspicion of severe sepsis orseptic shock*
Suspicion of severe sepsis orseptic shock*
Antibiotic therapyAntibiotic therapy
PCT D1PCT D1
PCT D5PCT D5
• in non-complicated infections** and patient stable
antibiotics
PCT DxPCT DxPCT decrease > 90% on Dx**
antibiotics
Cultures
Stopping rules
Daily PCT measurement
PCT decrease > 90% on D5** PCT decrease < 90% on D5
% p
atie
nts
without
antibio
tics
n=68HR: 1.9 (1.2-3.1)p=0.009
Probability to have antibiotics stopped
Time to antibiotic discontinuation (days)
PCT
controls
0 5 10 15 20
0.00
0.25
0.50
0.75
1.00
Nobre et al. Am J Respir Crit Care Med 2008
Control(n=37)
PCT (n=31)
p value
28-day mortality 16.2% 16.1% 0.74
Clinical cure 83.8% 90.3% 0.33
Nosocomial infection 29.7% 22.6% 0.20
Infection replase, % 2.7% 3.2% 0.70
PCT-guided shortening of antibiotic treatmentduration does not affect outcome
1315 patients assessed for eligibility
685 ineligible158 had expected ICU stay <3 days138 had SAPS II >65104 had received AB for >24 hours99 required prolonged therapy63 not enrolled for logistic reasons46 had do-not-resuscitate orders31 were neutropenic15 had no medical insurance12 had been enrolled in other studies10 refused consent9 excluded for other reasons
630 randomized
311 assigned toProcalcitonin Group
319 assigned toControl Group
307 Included inanalysis
(1 lost to follow-up on day 15)
314 Included inanalysis
(1 lost to follow-up on day 22)
4 withdrew consent 1 randomized twice
The ProRata Trial
4 withdrew consent
Bouadma et al. Lancet 2010
Allpatients
VAP abdominalinfection
UTI (+) Bloodcultures
N
CAP
20 14
9.9
6.1
10.6
5.6
9.4
7.3
10.8
8.1
14.5
7.4
12.8
9.8
0
2
4
6
8
10
12
14
16
Du
rati
on
of
trea
tmen
t (d
ays)
314 307 101 79 66 75 18 24 53 55
PCT-guided
Control
Use of procalcitonin to shorten antibiotic exposure in ICU patients : the ProRata trial
Bouadma et al. Lancet 2010
Use of procalcitonin to shorten antibiotic exposure in ICU patients : the ProRata trial
Pro
bab
ilit
y o
f su
rviv
al,
%
Days after inclusion
Procalcitonin (n=311)
Control group (n=319)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60
Bouadma et al. Lancet 2010
p = n.s.
Matthaiou et al. Intensive Care Med 2012
PCT guidance: duration of antibiotic therapy
Matthaiou et al. Intensive Care Med 2012
28-day mortality, PCT guidance vs. control
Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C).
… no evidence demonstrates that this practice reduces the prevalence of antimicrobial resistance.
… clinical experience with this strategy is limited and thepotential for harm remains a concern.
Intensive Care Med Feb 2013Crit Care Med Feb 2013
Conclusions
1. It is unlikely that a single biomarker will be sufficient to diagnose & manage sepsis
2. The ideal marker(s) will associate marker(s) of infection and host response
3. Procalcitonin remain the best sepsis marker, so far
4. Shortening the duration of antibiotic therapy should be a priority in our ICUs
5. Empirical rules should be replaced by rules tailored for a given patient
6. PCT guidance allows:
- to decrease the overall duration of antibiotic therapy
- a customization of antibiotic therapy
…without apparent harm!
- It remains to be shown if PCT guidance is cost-efficient!
PASS study. Jensen et al. Crit Care Med 2011
Antibiotic escalation therapy based on PCT !
No effect on mortalityIncreased LOSIncreased MOF
Days on antibiotics
PCT-guided antibiotic therapy in critically ill patients. Days on antibiotics
Bouadma et al. Lancet 2010Nobre et al. AJRCCM 2008Christ-Crain et al. AJRCCM 2006
(n=630)
(n=302)
(n=79)
0 5 10 15 20 25 30 3510
100
1000
10000
100000
D a y0 5 10 15 20 25 30 35
0.01
0.1
1
10
100
1,000
D a y
75 yr old, diabetic, COPD, hospitalized for a severe community acquired pneumonia.Treated by ceftriaxone for 9 days, difficult weaning from the ventilator. Tracheostomized on day 14. Treatment with glucocorticoids starting Day 14. Bowel obstruction (feces +++), with colonic perforation on Day 20 with fecal peritonitis and septic shock. E.coli and E.feacium in blood cultures. Died on Day 31 in persistent multiple organ failure.
SCAP Peritonitis SCAP Peritonitis
Procalcitonin IL-6
GCGC
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