The contribution of a Procalcitonin test in patients with suspicion of infection 1
Clinical questions: Patient presenting with clinical signs of potential infection: Is that of infectious origin? Is there an obvious source of infection? Is this from viral or bacterial origin? Is Antibiotic therapy necessary? Are there severity signs and risk of severe sepsis? 2
Why Do We Need a Marker of Severe Bacterial Infection? Because 1. The diagnosis of bacterial infection is sometimes difficult due to Atypical signs, e.g. no fever Etiologic diagnosis (microbiology) often delayed or impossible 2. Need to make rapid diagnosis since appropriate intervention reduces mortality rate in patients with sepsis. 3. Empirical use of antibiotics leads to bacterial resistance 3
When clinical symptoms are not clear enough Atypical symptoms of severe infection: Isolated fever or hypothermia isolated moderate fever in elderly people patient with previous corticoids Altered state of consciousness (confusion,..) myocardial damage (elevated troponin) shock syndrome (low Blood Pressure) Etc Non obvious source of infection Non documented infection (very often in ER) 4
What Is Procalcitonin? 5 A pro-hormone of calcitonin < 0.1 ng/ml in healthy patient s blood PCT increased during relevant bacterial infection Specific to bacterial challenge, increasing rapidly in 3-4 hrs with a peak after 6-12 hrs, Short half-life time (~ 24 hrs) Rapidly decreases with effective therapy (source control & antibiotics) High dynamic range (0,05-1.000ng/ml) To measure in serum and plasma Meisner M. Clin Chim Acta 2002;323:17 Gendrel D. Pedtriar Infect Dis J 2000;19:679 PCT is considered as the best marker of bacterial infection/sepsis
PCT vs CRP Best Current Marker for bacterial infections Why PCT is better than CRP Faster kinetics - Better sensitivity Better specificity for bacterial infection High negative predictive value to exclude bacterial infection Tool to monitore AB treatment 6
VIDAS Brahms Indirect PCT Competitions by the Marketing II CRP is often unspecifically increased CRP -> high sensitivity, but low(er) specificity 7
ROC plot PCT has highest sensitivity and specificity for the diagnosis of severe sepsis 1 PCT CRP Sensitivity IL-6 Lactate 0 1 0 1-Specifity 8 Müller B, et al. Crit Care Med (2000) 28:977-983
The ProCAP Study: Guidelines say AB Duration should depend of Pathogen Antibiotic Duration (days) 20 16 12 8 4 0 Standard Group Procalcitonin Group p = 0.25 P<0.001 Negative Positive Negative Positive Blood Cultures Lower AB duration in BC neg. patients In PCT group 90% of blood cultures remain negative in presumed bacterial Pneumonias! 9 Christ-Crain M et al, Am J Respir Crit Care Med 2006
Decrease in serum procalcitonin levels over time during treatment of acute bacterial meningitis 10 Viallon A, Critical Care 2005, 9:R344-R350
PCT concentrations increase with extension of infection severity of disease 11 Illustration from Brahms, based on literature
How can a PCT test result aid in your Clinical Practice? 1. Support in diagnosis Bacterial / non bacterial Localized vs systemic infection 2. Support in prognosis If systemic bacterial infection may worsen 3. Support in antibiotic stewardship Decision to start antibiotics Decision to stop antibiotics PCT test results must be associated with clinical findings. Result interpretation depends on the pre-test probability assessment. 12
Impact of PCT test on clinical use PCT aids in diagnosis of bacterial infection especially in patients with atypical signs «Diagnostic tool» PCT helps in assessing prognosis / or monitoring antibiotic treatments «Prognostic/ monitoring tool» Emergency Departments, ICU, others Emergency Departments, ICU, others 13
How Can a PCT Test Result Aid in Your Clinical Practice? 1. Support in diagnosis Bacterial / non bacterial Localized vs systemic infection Does the patient needs AB therapy? 14
Clinical Case 1 Female 62 years old, presenting in ED with: Fever, Headaches, cough, myalgia Underlying disease: Parkinson disease On admission, the triage nurse reports: Blood pressure = 140/75, Temperature = 39.2 C Heart rate = 120/mn 15 Paris Emergency Dept CASE STUDY The clinical findings are normal The chest X-ray is normal WBC: 6200 CRP: 100 mg/l
Clinical Case 1 This patient is hospitalized in the observation unit because of: Fever: 39.2 C Parkinson s disease HR: 120/mn No identified cause of infection The clinician suspects Flu PCT: 0.17 ng/ml - confirms the probability of non bacterial infection After 24 hrs that patient is discharged without antibiotic treatment. Only with paracetamol. Final Diagnosis: non complicated Flu Paris Emergency Dept CASE STUDY 16 Together with clinical suspicion Procalcitonin can aid to differentiate bacterial from viral infection
Integration of PCT into the Diagnostic Algorithm improves the accuracy of sepsis diagnosis significantly AUC=0.94 AUC=0.77 17 Harbarth S. Am J Respir Crit Care Med 2001
How Can a PCT Test Result Aid in Your Clinical Practice? 1. Support in diagnosis Differential diagnosis from viral to bacteria Localised vs. systemic bacterial infection 2. Support in prognosis If systemic bacterial infection may worsen 3. Support in antibiotic stewardship Decision to start antibiotics Decision to stop antibiotics PCT test results must be associated with clinical findings. Result interpretation depends on the pre-test probability assessment. 18
Clinical Case 2 Male 18 years old, return from visit to Mali No underlying diseases Presenting to the ED with: Fever, headaches, abdominal pain, no diarrhoae On admission, the triage nurse reports: Blood pressure = 115/70, Heart rate = 70/mn temp = 40 C Paris Emergency Dept CASE STUDY Clinical examination: Cutaneous Excoriations (Cuts and scratches from insect bites) 19
Clinical Case 2 First results of investigations WBC: 15,500 x 103/ microl Malaria test: negative Chest X-ray: normal Urinalysis: negative Abdominal echography: normal Lumbar puncture: normal Paris Emergency Dept CASE STUDY PCT: 168 ng/ml It is decided to start Antibiotic treatment, This patient is hospitalized for observation The plan is to transfer the patient the next day to Infectious Diseases Dept. 20
Clinical Case 2 The Next Day Vital signs are checked before leaving the ED: BP: 85/60 mmhg HR: 80/mn Paris Emergency Dept CASE STUDY Transfer to ID dept is cancelled and urgent treatment is undertaken Start fluid resuscitation & antibiotic therapy for suspected typhoid fever. Transfer to ICU for severe sepsis After 3 days, blood cultures are positive: S.pyogenes The final diagnosis: severe sepsis from cutaneous origin PCT as a good marker of sepsis prognosis, as well as 21 a good indicator of bacterial infection
How Can a PCT Test Result Aid in Your Clinical Practice? 1. Support in diagnosis Differential diagnosis from viral to bacteria Localised vs. systemic bacterial infection 2. Support in prognosis If systemic bacterial infection will worsen 3. Support in antibiotic stewardship Decision to start antibiotics Decision to stop antibiotics PCT test results must be associated with clinical findings. Result interpretation depends on the pre-test probability assessment. 22
Response to successful antibiotic therapy reflected in decreasing PCT values Typical course of PCT serum level according to patient s response to antibiotic treatment (n=109) Review: LRTI ATB monitoring Christ-Crain Lancet 2004, American Journal of Respiratory 2006 S. Harbarth: ICU antibiotic Monitoring Sunday workshop 23 Source: F. Stüber, University Bonn, Lecture at ISICEM, Brussels 2001
Prospective randomized studies on PCT-based therapeutic decisions in LRTI (Müller, Christ-Crain) demonstrating the impact on antibiotic use PCT Cut-Off Ranges Used in these studies: If PCT result is <0.1 ng/ml then starting antibiotics is discouraged. If PCT result is 0.1 to 0.25ng/mL then antibiotic treatment is more or less discouraged. If PCT result is >0.25 ng/ml then antibiotic usage is encouraged. If PCT result is >0.5 ng/ml then antibiotic usage is strongly encouraged. Study by Christ-Crain, Muller - Lancet 24
Study 1: PCT-Guided Antibiotic Therapy in Lower Respiratory Tract Infections (LRTI) ProRESP: interventional study in Emergency Department Standard group ProCT group 100 80 60 40 20 0 CAP AECOPD Bronchitis Asthma Others Christ-Crain et al., Lancet 2004; 25 PCT guidance reduces antibiotic prescription in 243 patients with LRTI by almost 50% With similar outcome compared to the standard group
Study 2: PCT-Guided Antibiotic Duration for Patients with Community Acquired Pneumonia ProCAP: interventional study in Basel hospital, 302 patients Christ-Crain et al., Am J Resp C.Care Med 2006 26 PCT guided Antibiotic duration was shortened by 65 % from 12.9 to 5.8 days With similar outcome in patients with all severity levels of CAP
Study 3: PCT-Guided Antibiotic Initiation for Patients With Exacerbation of Chronic Obstructive Pulmonary Disease ProCOLD: interventional study in Emergency Department. 226 patients Stolz et al.,chest 2007 27 Reduction of Antibiotic prescription 40% in PCT group vs 72 % in standard group Long-term safety with similar readmission rate over 6 months
Limitations of PCT Test Unspecific PCT inducers potential false positive results include: Surgical Trauma, poly trauma: in the first 2 post-operative days Neonates less than 48 hrs of age Immune-stimulatory drugs (OKT3,TNFa,IL-2.) Severe Burns Hemodialysis Heatstroke Weak increase in PCT Early course of infection ( re-measure 6-12 hours later!) Previous efficient antibiotic therapy Atypical pneumonia (M.pneumoniae, C.pneumoniae) Localized infections (nephritis) 28
Summary PCT is today the best marker for systemic bacterial infection: Improves accuracy of clinical diagnosis Allows assessment of severity of disease and prognosis Reduces antibiotic usage, resistance Reduces unnecessary hospitalization Using PCT as an additional piece of information for a clearer picture adding valuable information to the clinical assessment... 29
Clinical evidence Use of PCT has been described in many clinical situations - LRTI, Meningitis, peritonitis, pyelonephritis, neonatal infections, etc.. more than 1300 publications But only the recent studies have been performed with sensitive PCT assays: 30 Prospective randomized interventional studies on PCT-based therapeutic decisions in LRTI (Müller, Christ-Crain) demonstrating the impact on antibiotic use.
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Indications Diagnosis ProCT (μg/l) 100 Antibiotic (AB) use? ICU Co-Morb. RTI Trauma COPD Assay? Septic Shock Severe Sepsis Sepsis Pneumonia Bronchitis COLD 10 2 1 0.5 0.25 0.1 YES! Yes No NO! YES! Yes No NO! YES! Yes No PCT KRYPTOR / VIDAS LUMItest PCT LIA PCT-Q Healthy 0.01 NO! Muller B, Swiss Med Wkly, 2005 32
DEVELOPMENT and VERIFICATION Comparison studies VIDAS - PCT (ng/ml) 200 150 100 50 Identity line Identity line Y = X 200 Y = X 200 y = 1,1153x - 0,106 0 0 50 100 150 200 PCT LIA - PCT (ng/ml) VIDAS - PCT (ng/ml) 150 100 50 y = 1,1355x - 0,0472 0 0 50 100 150 200 KRYPTOR - PCT (ng/ml) KRYPTOR - PCT (ng/ml) 150 100 50 Identity line Y = X y = 0,9774x - 0,0707 0 0 50 100 150 200 PCT LIA - PCT (ng/ml) Comparison : VIDAS B.R.A.H.M.S PCT = 1.12 B.R.A.H.M.S PCT LIA 0.12 33
DEVELOPMENT and VERIFICATION Comparison between serum and plasma External verification (Pitié-Salpétrière hosp./paris) N = 30 samples (dry tubes-serum and heparin-tubes) Passing & Bablok regression 40 Identity line Y = X PCT-Plasma (ng/ml) 35 30 25 20 15 10 5 y = 1.0181x - 0.0114 PCT-Plasma = 1.018 PCT-Serum - 0.011 r = 0.999 slope : [0.998-1.053] 95 % intercept : [-0.035-0.000] 95 % 0 0 10 20 30 40 PCT-Serum (ng/ml) 34
ASSAY FEATURES ITEM DESCRIPTION Code PCT Reference 30450 Tests/Kit 60 Sample type Plasma (Heparin) or serum Sample volume 200 µl Stability of the reagent Until expiration date Shelf life 9 months Calibration stability 28 days Calibrators (iuncluded in the kit) 2 bottles of S1 and S2 (2mL each) Controls (included in the kit) 2 bottles of C1 and C2 (2mL each) Diluant in the kit No Measuring range 0.05-200 ng/ml Traceability BRAHMS PCT LIA Time to result 20 minutes Protocol compatibility NT-proBNP, Troponin I Ultra 99th percentile of asymptomatic population 0.09 ng/ml Functional sensitivity at 20%CV 0.09 ng/ml 35
ASSAY FEATURES 1/ The VIDAS/miniVIDAS systems Robust / compact system (MTBF) Rapid results 24/7 hour available Single dose test, all inclusive kits Ease of use Random access Cost effective Every 28 days calibration 2/ Complete Emergency panel Cardiac markers: Myoglobin CK MB Troponin I Ultra NT-proBNP Thrombosis Marker D Dimer Exclusion Sepsis and bacterial infection Procalcitonin Others Digoxin hcg 36
biomérieux Emergency offer Major symptoms in patients presenting to the ED cough, dyspnea/sob, fever, chest pain Respiratory VIDAS - ctni -D-dimer - NT-proBNP -PCT Cardiac Infectious Non-infectious CHF ACS NT-proBNP ctni Bacterial Viral PE Other - Acute asthma/bronchitis PCT D-dimer - Acute exarcerbation of COPD 37 SOB: shortness of breath CHF: congestive heart failure ACS: acute coronary syndromes PE: pulmonary embolism COPD: chronic obstructive pulmonary disease
38 Web site: www.procalcitonin.com in which VIDAS B.R.A.H.M.S. Procalcitonin will be described