"Biomarkers in sepsis and septic shock" by Prof. Jérôme Pugin

Use of of Biomarkers in the Care of Patients with sepsis
Prof. Jérôme Pugin, MD
Intensive Care
University Hospitals
Geneva, Switzerland
October 21st, 2014
Seminar VHIR
Vall 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/siqnature
Bauer, 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 severe
infections 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 study
Standard cultures vs. molecular determination
609 suspicions of severe infectiosns in ICU patients
Blood cultures, cultures of TA, BALs, ascites, etc.

Combining clinical data and biomarkers (ALI)
Crit Care Med 2011

γINF
IL-18
IL-1ra
sTNFR2
sTNFR1
IL-10
IL-4
IL-12
Endothelin Nitrites
NO
iNOS
Lymphotoxin
IL-8 IL-6
IL-1ß
PCT
C3a
sVCAM-1
sE-selectin
sICAM-1
LBP
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 patients
admitted 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): Fever
Leucocytosis
Tachypnea
Tachycardia
Sepsis: SIRS + bacterial infection
Severe sepsis: Sepsis + organ failure
Septic shock: Severe sepsis + refractory
shock
ACCP/SCCM consensus conference 1992

.01
.1
1
10
100
1000
PCT(ng/mL)
Septic
shock
Severe
sepsis
SepsisSIRS
Harbarth et al. Am J Respir Crit Care Med 2001
Diagnostic yield of PCT in sepsis
1.1 ng/mL
Sensitivity 97%
Specificity 78%

1 - specificity
sensitivity
1.00
0.75
0.50
0.25
0.00
0.00 0.25 0.50 0.75 1.00
Clinical model with PCT
Clinical model without PCT
PCT adds to a clinical prediction model
for the diagnosis of sepsis

.01
.1
1
10
100
1000
PCT(ng/mL)
Septic
shock
Severe
sepsis
SepsisSIRS
Procalcitonin
1
10
100
1000
10000
100000
IL-6(pg/mL)
Septic
shock
Severe
sepsis
SepsisSIRS
Interleukin-6
Only PCT discriminates sepsis from SIRS

0.1
1
10
100
Survived
Sepsis-
related
death
PCT (ng/ml) IL-6 (pg/ml)
At the time of admission to the ICU,
IL-6 is a better prognostic marker than PCT
1
10
100
1000
10000
100000
Survived
Sepsis-
related
death

Antibiotic guidance: who needs guidance?

Duration of antibiotic therapy in the ICU.
Who cares?
Bacterial
resistance $$$
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
PCT(ng/mL)
0 2 4 6 8 10 12 14 16
Days
0.1
1
10
100
1000
PCT(ng/mL)
0 2 4 6 8 10 12 14 16
Days
Survived Died
Decrease of plasma procalcitonin levels with time
in survivors vs. non-survivors
Would PCT help clinicians to stop antibiotics earlier ?

Christ-Crain et al. Am J Resp Crit Care Med 2006
Schuetz 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 : NO
antibiotic 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 sepsis
and 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 or
septic shock*
Suspicion of severe sepsis or
septic 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

%patientswithoutantibiotics
n=68
HR: 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 treatment
duration does not affect outcome

1315 patients assessed for eligibility
685 ineligible
158 had expected ICU stay <3 days
138 had SAPS II >65
104 had received AB for >24 hours
99 required prolonged therapy
63 not enrolled for logistic reasons
46 had do-not-resuscitate orders
31 were neutropenic
15 had no medical insurance
12 had been enrolled in other studies
10 refused consent
9 excluded for other reasons
630 randomized
311 assigned to
Procalcitonin Group
319 assigned to
Control Group
307 Included in
analysis
(1 lost to follow-up
on day 15)
314 Included in
analysis
(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

All
patients
VAP abdominal
infection
UTI (+) Blood
cultures
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
Durationoftreatment(days)
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

Use of procalcitonin to shorten antibiotic exposure
in ICU patients : the ProRata trial
Probabilityofsurvival,%
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
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 the
potential for harm remains a concern.
Intensive Care Med Feb 2013
Crit 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
mortality
Increased LOS
Increased MOF

Days on antibiotics
PCT-guided antibiotic therapy in critically ill patients.
Days on antibiotics
Nobre et al. AJRCCM 2008
Christ-Crain et al. AJRCCM 2006
(n=630)
(n=302)
(n=79)

0 5 10 15 20 25 30 35
10
100
1000
10000
100000
D a y
0 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
GC
GC

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"Biomarkers in sepsis and septic shock" by Prof. Jérôme Pugin