Download Inflammatory Markers in the 21st Century

INFLAMMATORY MARKERS IN THE
21ST CENTURY
Despina Demopoulos
Paediatric Intensivist
CH Baragwanath Hospital
OVERVIEW
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Introduction
Definitions
Ideal Biomarker
Biomarkers in Sepsis
PCT
CRP
sTREM
Cytokines
Biomarkers in fungal sepsis
Conclusion
INTRODUCTION
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Sepsis- leading cause of mortality
Hospital mortality of severe sepsis10.3% in US
Delay in diagnosis & initiation of antibiotics ↑mortality
But need for antimicrobial stewardship to combat
antibiotic resistance
• Need to distinguish between SIRS and severe sepsis
Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in
children in the United States. Am J Respir Crit Care Med 2003; 167:695
Kumar A, Roberts D, Wood K et al. Duration of hypotension before initiation of effective
antimicrobial therapy is the critical determinant of survival in human septic shock. Crit
care Med 2006; 34:1589-96
SIRS
• 2 or more of the following:
1. Body temperature <36 or >38.3 degrees
2. Tachycardia >90/min
3. Tachypnoea >20/min or PC02 <32mmHG
4. WCC <4000 or >12000 or >10% immature
forms
SEPSIS
SIRS
+
Culture proven infection
Or
Clinically suspected infection
DEFINITION OF BIOMARKER
• protein / lipid or other macromolecule
objectively measured that is associated with a
biological process, regulatory mechanism(s) or a
response to a therapeutic intervention.
Mueller C et al. Swiss Med wkly
2008;138(15-16):225-229
IDEAL BIOMARKER
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Easy to measure, use current specimens
Inexpensive
Highly sensitive & specific
Quantify severity in absence of clinical signs
Monitor disease course and response to therapy
BagshawSM, BellomoR.
CurrOpinCritCare 2007;13:638644
USES OF BIOMARKERS
BIOMARKERS IN SEPSIS
Stimulus(infection )
Inflammatory response(pro vs anti)
Mediator release
Direct effects
Indirect effects
Schuetzet al. Curr Opin Crit Care 2007;13:578-585
BIOMARKERS IN SEPSIS
• Over 178 biomarkers available
• Complexity & redundancy of host immune
response unlikely that single biomarker can
adequately describe and stratify the sepsis syndrome
• Shapiro et al Multimarker panel develop a
sepsis score
Carrigan SD, Scott G, Tabrizian M. Toward resolving the challenges of sepsis
diagnosis. Clin Chem 2004;50:1301.
Shapiro NI, Trzeciak S, Hollander JE, et al. A prospective, multicenter derivation
of a biomarker panel to assess risk of organ dysfunction, shock, and death in
emergency department patients with suspected sepsis. CCM 2009;37:96
Pierrakos and Vincent Critical Care 2010, 14:R15
.
SEPSIS BIOMARKERS
• Procalcitonin
• C-reactive protein
• Triggering receptor expressed
on myeloid cells 1 (TREM-1)
• Interleukins
• Eosinophil count
• Adrenomedullin (ADM) & proADM
• Atrial natriuretic peptide
(ANP) & pro-ANP
• Copeptin
• Interferon-γ
• Resistin
• Lipopolysaccharide-binding
protein
• Protein C
• Endocan
• Complement 3a
• Neopterin
• HLA-DR
J Antimicrob Chemother 2011; 66 Suppl 2: ii33–ii40
doi:10.1093/jac/dkq523
Crit Care Clin 22 (2006) 503-519
INFLAMMATORY HOST RESPONSE AFTER
ENDOTOXIN CHALLENGE
Crit Care Clin 22 (2006) 503-519
PROCALCITONIN
• 116-amino acid prohormone of calcitonin
• produced by parafollicular cells (C cells) of the
thyroid and by the neuroendocrine cells of the
lung and the intestine
• Normal <0.1 ng/ml
• ↑2 hrs, peak 24 hrs
Crit Care Clin 27 (2011) 253–263
NON INFECTIOUS CAUSES
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Major surgery and trauma
Severe burns
Cardiogenic shock
Birth stress in newborns
Heat shock
Different types of immune therapy
Some autoimmune diseases (Kawasaki disease, different types of
vasculitis) and paraneoplastic syndromes
• Induction of hypothermia after cardiac arrest
• Drug sensitivity reactions
Crit Care Clin 27 (2011) 253–263
Crit Care 2010; 14(6)
PCT IN SEPSIS
• PCT has the greatest sensitivity (85%) and
specificity (91%) for differentiating patients with
SIRS from those with sepsis, when compared
with IL-2, IL-6, IL-8, CRP and TNF-alpha.
BalcI C, Sungurtekin H, Gürses E, Sungurtekin U, Kaptanoglu B (February 2003). "Usefulness of
procalcitonin for diagnosis of sepsis in the intensive care unit". Crit Care 7 (1): 85–90.
META- ANALYSES 2004
Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and Creactive
protein levels as markers of bacterial infection: a systematic review and metaanalysis. Clin Infect Dis. 2004;39:
206-217.
META- ANALYSES 2007
Annals of Emergency Medicine
Volume 50, Issue 1, July 2007, Pages 34-41
META- ANALYSES 2007
Sensitivity and specificity plot of the procalcitonin test in the diagnosis
of bacteremia.
Annals of Emergency Medicine
Volume 50, Issue 1, July 2007, Pages 34-41
SEVERE SEPSIS
• Conflicting literature
• Tang et al (Meta-analyses) PCT cannot
differentiate SIRS from sepsis
• Uzzan et al (Meta-analyses)  PCT superior to
CRP; should be used to diagnose sepsis in ICU
Tang et al. Lancet Infect Dis 2007, 7:210-217
Uzzan et al. CCM 2006,34: 1996-2003
SEVERE SEPSIS
• Measured PCT 2x in adult patients, clinically
diagnosed sepsis
• Septic shock ↑PCT (p=0.02)
• Mortality lower if PCT decreased by >50% (by 72
hrs) (12.2% vs 29.8%, p=0.007)
Karlsson et al. Crit Care 2010; 14(6)
COMMUNITY-ACQUIRED PNEUMONIA
• ProRESP: 50% ↓antibiotics
• ProCAP: 65% ↓ antibiotics
• ProCOLD: sig ↓ antibiotics
• PRORATA: cessation of antibiotics
& monitoring response
Bouadma L et al. Lancet 2010;375:463-474
Mueller C et al. Swiss Med wkly 2008;138:225-229
ANTIBIOTIC STEWARDSHIP WITH PCT
• Recent review 11 RCTs on PCT-guided
antibiotic therapy (adults)
• Most higher-quality studies were performed in
patients pneumonia and LRTIs
Schuetz P, Albrich W, Christ-Crain M, et al. Procalcitonin for guidance of
antibiotic therapy. Expert Rev Anti Infect Ther 2010;8:575–87.
ANTIBIOTIC STEWARDSHIP WITH PCT
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PRORATA study critically ill
40% septic shock
two-thirds needed mechanical ventilation
23% relative reduction in antibiotic exposure
Bouadma et al.Lancet 2010; 375: 463–74
Recommendations for starting/stopping antibiotics based on the PRORATA
Kibe S et al. J. Antimicrob. Chemother. 2011;66:ii33-ii40
© The Author 2011. Published by Oxford University Press on behalf of the British Society for
Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
[email protected]
POTENTIAL BENEFITS
AIM OF THE STUDY
FINDINGS
REFERENCES
PCT levels in patients
with sepsis, severe sepsis,
and septic shock
PCT is significantly elevated
in patients with sepsis,
severe sepsis, and septic
shock.
Especially high
concentrations were found
in patients with severe
stages of the disease (severe
sepsis, septic shock)
Muller. CCM 2000
Ugarte. CCM 1999
Suprin. CCM 2000
Selberg. CCM 2000
Harbarth. Am J Respir Crit
Care 2001
Castelli. CCM 2004
Zeni. Clin Intens Care 1994
Al-Nawas. Eur J Med Res
1996
Crit Care Clin 27 (2011) 253–263
POTENTIAL BENEFITS
AIM OF THE STUDY
FINDINGS
REFERENCES
PCT in severe
bacterial infection
PCT levels were
significantly higher in
patients with bacterial
infection than in
those with viral and fungal
infections and sepsis
Uzzan. CCM 2006
Bohuon. Bull Acad Natl
Med 1998
Prat. Eur J Clin Microbiol
Infect Dis 2004
Mueller. Circulation 2004
Gras-le-Guen. Scand J
Infect Dis 2007
Crit Care Clin 27 (2011) 253–263
POTENTIAL BENEFITS
AIM OF THE STUDY
FINDINGS
REFERENCES
PCT as a marker for
effectiveness of
source control and
prognosis
PCT levels decline by
successful measures of
source control, and
sustained elevated PCT
levels are associated with
poor prognosis.
This finding was
demonstrated in adult
and paediatric patients with
sepsis, VAP, and CAP
Muller. CCM 2000
Wanner. CCM 200
Schroder. Langenbecks’
Arch Surg 1999
Seligman. Crit Care 2006
Luyt. Am J Respir Crit Care
2005
Chastre. Curr Opin Crit
Care 2006
Jensen. CCM 2006
Hatherill. CCM 2000
Crit Care Clin 27 (2011) 253–263
POTENTIAL BENEFITS
AIM OF THE STUDY
FINDINGS
REFERENCES
Usefulness of PCT
for antibiotic stewardship
PCT-guided antibiotic
therapy may result in a
20%–70% decrease in
antibiotic exposure without
a negative effect on patient
outcome
Christ-Crain. Lancet 2004
Briel. Arch Intern Med
2008
Stolz. Chest 2007
Schuetz. Jama 2009
Crit Care Clin 27 (2011) 253–263
PCT levels in patients with bacterial infection and different
severities of systemic inflammation
SIRS
Sepsis
Severe Sepsis Septic Shock Number of
Patients (n)
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2.4 ± 0.5 (mean, SD)
37 ± 16
45 ± 22
145
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0.6 ± 2.2
6.6 ± 22.5
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35 ± 68
337
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1.3 ± 0.2
2.0 ± 0
8.7 ± 2.5
39 ± 5.9
100
<0.5 ng/mL
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0.8 ng/mL
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4.3 ng/mL
190
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3.8 ± 6.9
1.3 ± 2.7
9.1 ± 18.2
38 ± 59
101
3.0 (0.7–29.5)
—
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19.1 (2.8–351)
16.8 (0.9–351)
All septic patients
33
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0.5 ± 0.2 (approx)
2.0 ± 2.0 (approx)
18.0 ± 10.0 (approx)
20 ± 10 (approx)
101
0.38 (0.16–0.93
quartiles)
—
3.0 (1.48–15)
5.58 (1.84–33)
13.1 (6.1–42)
101
0.6 (0–5.3)
—
3.5 (0.4–6.7)
6.2 (2.2–85)
21.3 (1.2–654)
78
Median (Range)
Mean (SD)
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Crit Care Clin 27 (2011) 253–263
Cutoff values for the differentiation between infectious and
noninfectious causes of inflammation
Diagnosis
Cutoff (PCT) Sensitivity/S PCT (ng/mL) Number of
pecificity (%)
Patients
Acute meningitis
>0.5 μg/L
Viral vs bacterial
infection (children)
94/100
(Mean, range)
41 vs 18
0.32 (0–1.7) vs 54.5
(4.8–110)
Autoimmune
>0.5 g/L
disorders
No infection vs
bacterial infection
Renal
>0.5 μg/L
transplantation
Diagnosis of acute
rejection vs
infection
Pneumonia
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Bacterial vs atypical
agents
100/84
(Mean, SD)
<0.5 vs 1.9 ± 1.19
42 vs 16
87/70
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13 vs 17
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(Median, range)
1.41 (0.05–65) vs
0.05 (0.05–7.5)
27 vs 9
Pneumonia
Bacterial vs viral
agents
Invasive vs local
infection in
children
Pancreatitis/edema
tous vs sterile
necrosis vs infected
necrosis
Patients in the ICU
No infection vs
infection
2 ng/mL
63/96
0.9 ng/mL
93/78
>1.8 μg/L
94/91
(Mean, range)
43 vs 29
2.7 (0.6–91) vs 0.63
(0.01–4.38)
(Mean, SD)
64 vs 27
27.5 ± 70 vs 0.32 ±
0.32
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18 vs 14 vs 18
>0.6 μg/L
67/61
0.5 (median) vs 2.5 79 vs 111
(median)
Crit Care Clin 27 (2011) 253–263
CRP
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C-reactive protein acute phase protein
↑4-6 hours after inflammatory trigger
Peaks 36-50hrs
Normal 0.8mg/L
Arch Dis Child Educ Pract Ed 2010
Vincent. Crit Care Clin 27(2011) 241-251
CRP
• Rheumatology ↑ RA, Ankylosing spondylitis,
psoriatic arthritis
• GIT ↑ Crohn disease, pancreatitis
• Resp COPD, severe asthma
• CVS identify pts who could benefit from
preventative therapy (eg statins)
Vincent. Crit Care Clin 27(2011) 241-251
CRP & INFECTION
• Most widely used biomarker of infection in
critically ill patients
• Absolute CRP values not helpful
Pulliam PN, Attia MW, Cronan KM. C-reactive protein in febrile children 1 to 36
months of age with clinically undetectable serious bacterial infection. Pediatrics
2001;108:1275–9.
Vincent. Crit Care Clin 27(2011) 241-251
CRP & INFECTION
• Sierra et al94.3% sensitivity, 87.3% specificity
using cutoff of 8mg/dL, ↑median CRP in sepsis
• Peres Bota et al combination of signs of sepsis
(HR, RR, WBC, SOFA score, CRP)  likelihood
of infection
Sierra R, Rello J, Bailen MA, et al. C-reactive protein used as an early indicator of
infection in patients with systemic inflammatory response syndrome. Intensive
Care Med 2004;30:2038–45.
Peres Bota D, Melot C, Lopes FF, et al. Infection probability score (IPS): a method
to help assess the probability of infection in critically ill patients. Crit Care Med
2003;31:2579–84
CRP & INFECTION
• Povoa et al CRP measured daily in ICU
patients
• maximum daily CRP variation > 4.1 mg/dL 
good marker for prediction of nosocomial
infection (sensitivity 92.1%, specificity 71.4%)
• combination with a CRP concentration > 8.7
sensitivity 92.1%, specificity 82.1%
Povoa P, Coelho L, Almeida E, et al. Early identification of intensive care unitacquired
infections with daily monitoring of C-reactive protein: a prospective
observational study. Crit Care 2006;10:R63
CRP & VIRAL INFECTION
• Attempts to distinguish type of infection
• CAP in children ↑CRP with bacterial infection
vs viral infection (median 9.6 vs 5.4 mg/dL,
P= 0 .008)
• BUT considerable overlapping of values in the 2
groups
Toikka P, Irjala K, Juven T, et al. Serum procalcitonin, C-reactive protein and
interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr
Infect Dis J 2000;19:598–602
CRP & FUNGAL INFECTION
• ↑ CRP in bacterial sepsis vs candidal sepsis
• 19.0 mg/dL vs 9.4 mg/dL ( P= 0 .002)
• Best cutoff value 10.0 mg/dL (sensitivity of
82%,specificity of 53%)
Martini A, Gottin L, Menestrina N, et al. Procalcitonin levels in surgical patients at
risk of candidemia. J Infect 2010;60:425–30.
CRP & INFECTION
• CRP>40-60mg/l weakly predictive of
bacterial pneumonia in children
• Child with a limp CRP>20mg/l suggests
septic arthritis (vs transient synovitis)
• Suspected NNS 2 CRP levels 24hrs apart
<10mg/l useful in excluding diagnosis
Arch Dis Child Educ Pract Ed 2010
CRP vs PCT
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PCT more reliable marker in sepsis
PCT predict severity of disease more reliably
PCT earlier predictor of infection
COPD CRP better
R72 (CRP)vs R399 (PCT)
Vincent. Crit Care Clin 27(2011) 241-251
sTREM
• soluble triggering receptor expressed on myeloid
cells
• Immunoglobulin family
• PMN & monocyte expression
• Triggers secretions of proinflammatory mediators
(IL-8, tumor necrosis factor-a & IL-1b)
• Helpful in BAL fluid
GibotS et al. NEJM 2004;350:451-458
Crit Care Clin 22 (2006) 503–519
CYTOKINES
• Tumor necrosis factor-a, IL-1, IL-6, IL-8 & IL-10
most associated with sepsis
• NNS IL-6 & IL-8 plasma levels predicted early
onset of sepsis
• ↑ major surgery, severe trauma, autoimmune
disorders, viral infection & after graft rejection
Crit Care Clin 22 (2006) 503–519
MARKERS OF FUNGAL INFECTION ?
DETECTING FUNGAL INFECTIONS
• 1,3 B-d-glucan
◦Detects Candida and Aspergillus
◦Unable to differentiate
◦Affected by previous anti-fungals
• Mannans
◦Candida mannan or antimannan
◦Aspergillus mannan
• Low sensitivity & specificity
HerbrechtR, BerceanuA. ClinInfect Dis2008;46:886-889
PasqualottoAC, SukiennikTC. ClinInfect Dis2008;47:288
1,3 BETA-D-GLUCAN
• Fungal cell wall
• Antigen
◦Expressed
◦1-2d(pre-signs or micro +)
◦Best > 2 consec. samples
◦High false + on 1 sample
◦Cut-off: >7pg/ml
SennL et al.ClinInfect Dis2008;46:878-885
GALACTOMANNAN
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Fungus release
Antigen detected
Ratio vs control= Galactomannan Index
Uses
•Diagnosis invasive aspergillosis
•Immune suppression & neutropaenia
•Fungal endocarditis
•No use for endovascular disease
• Poor sensitivity for immunocompetent
• Scanty evidence in literature
Garcia-Rodriguez J et al. ClinInfect Dis2008; 47:e90-92
SUMMARY
CONCLUSION
• Biomarkers useful adjuncts to the clinician
• More useful to ―rule out‖ than ―rule in‖ sepsis
• Serve as targets in large, randomized, controlled
trials for new therapeutic agents and
management strategies
CONCLUSION
• PCT & CRP best studied biomarkers
• PCT potential usefulness to guide antibiotic
therapy
• Need better techniques to diagnose sepsis
Thank you