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INFLAMMATORY MARKERS IN THE 21ST CENTURY Despina Demopoulos Paediatric Intensivist CH Baragwanath Hospital OVERVIEW • • • • • • • • • • Introduction Definitions Ideal Biomarker Biomarkers in Sepsis PCT CRP sTREM Cytokines Biomarkers in fungal sepsis Conclusion INTRODUCTION • • • • Sepsis- leading cause of mortality Hospital mortality of severe sepsis10.3% 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 • • • • • 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 • • • • • • • 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 • • • • 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) — 2.4 ± 0.5 (mean, SD) 37 ± 16 45 ± 22 145 — 0.6 ± 2.2 6.6 ± 22.5 — 35 ± 68 337 — 1.3 ± 0.2 2.0 ± 0 8.7 ± 2.5 39 ± 5.9 100 <0.5 ng/mL — 0.8 ng/mL — 4.3 ng/mL 190 — 3.8 ± 6.9 1.3 ± 2.7 9.1 ± 18.2 38 ± 59 101 3.0 (0.7–29.5) — — 19.1 (2.8–351) 16.8 (0.9–351) All septic patients 33 — 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) — 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 — Bacterial vs atypical agents 100/84 (Mean, SD) <0.5 vs 1.9 ± 1.19 42 vs 16 87/70 — 13 vs 17 — (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 — 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 • • • • 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 al94.3% 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 • • • • • 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 • • • • 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