The Basics. Editorial Team. Editorial Team 10/17/2016

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1 Title of Program: Estimation of procalcitonin levels for the diagnosis of sepsis in infants: Evidence from diagnostic test accuracy reviews Speakers/Moderators: Gautham Suresh, MD, Miriam Stewart, MD Roger F. Soll, MD Planning Committee: Jeffery D. Horbar, MD, Madge E. Buus-Frank, RN, MS, APRN-BC, FAAN, Roger F. Soll, MD Date: October 17, 2016 Learning Objectives: Participants will be presented with evidence from clinical trials and systematic reviews and will be able to evaluate and translate the evidence in the field of neonatology to better serve their practices. Specifically, evidence for the diagnostic test accuracy of procalcitonin for sepsis will be presented and critiqued. DISCLOSURE: Is there anything to disclose? No financial interests to disclose Estimation of procalcitonin levels for the diagnosis of sepsis in infants: Evidence from diagnostic test accuracy reviews Conference begins at 12 Noon EST October 17, 2016 COMMERCIAL SUPPORT ORGANIZATIONS (if applicable): No Commercial Support The University of Vermont College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The University of Vermont designates this live activity for a maximum of 1 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. PowerPoint Slide presented at start of program Supported by: The National Institute of Child Health and Human Development and Vermont Oxford Network Trusted evidence. Informed decisions. Better health. The Basics Follow the slides on your screen. Listen to the Audio Broadcast via your computer speakers. If the computer audio is not working well, click and follow the prompts to call in on the telephone. Send questions and comments via Chat to All Panelists. Cochrane Preparing, maintaining and promoting the accessibility of systematic reviews of the effects of health care interventions Cochrane Neonatal Prepares and disseminates evidence-based reviews of the effects of therapies in the field of neonatal medicine Editorial Team Editorial Team Roger F. Soll Coordinating Editor Colleen Ovelman Managing Editor Yolanda Brosseau Information Specialist Michael Bracken Yale University Jeffrey Horbar University of Vermont Arne Ohlsson Gautham Suresh University of Toronto Texas Children s Hospital Baylor College of Medicine 1

2 Guest Discussants Support Gautham Suresh, MD Texas Children s Hospital Baylor College of Medicine Miriam Stewart, MD Children s Hospital of Philadelphia Disclosure Roger F. Soll and Gautham Suresh are editors of Cochrane Neonatal supported by a contract from the NICHD Why These Webinars? Estimation of procalcitonin levels for the diagnosis of sepsis in infants: Evidence from diagnostic test accuracy reviews Learning Objectives: Participants will be presented with evidence from clinical trials and systematic reviews and will be able to evaluate and translate the evidence in the field of neonatology to better serve their practices. Specifically, evidence for the diagnostic test accuracy of procalcitonin for sepsis will be presented and critiqued. Ultimate Question DIAGNOSTIC TESTING: GENERAL CONCEPTS How will doing the test change your management? 2

3 Why Perform Diagnostic Tests? To help physicians become better stewards of finite health care resources by developing lists of testing and treatment practices that are not evidence-based and whose necessity should be questioned and discussed Why Perform Diagnostic Tests? Assign patient: disease vs. non-disease state Classify severity of disease Classify according to prognosis Predict response to therapy Predict future course of illness Sackett. Clinical Epidemiology, 2 nd Edn Why Perform Diagnostic Tests? Because that s the way it is done Psychological effects Reassurance from normal results Feeling of doing something Patients feel better doctors do more tests It s useful to know what s in the neighborhood (for tracheal aspirates) Incentives Profits Medico-legal concerns Bayesian Approach 100% Bayesian Approach 100% Treatment threshold Post-test probability Treatment threshold Likelihood of Sepsis Likelihood of disease Pre-test probability Test threshold Test threshold 0 % 0 % How useful is the CBC in moving you up or down this line? A test is useful only if its result moves you across test or treatment threshold 3

4 Positive Likelihood Ratio Likelihood Ratio Nomogram Probability of person with disease having a positive test Probability of person without disease having a positive test Negative Likelihood Ratio Probability of person with disease having a negative test Probability of person without disease having a negative test SINGLE STUDIES OF DIAGNOSTIC TESTS 1. Are the results of the paper valid? 2. Can the test accurately distinguish patients who do and do not have disease? 3. How can I apply this valid, accurate diagnostic test to a specific patient? Sackett. Evidence Based Medicine Study considered good quality if it had: Prospective consecutive recruitment Adequate description of population Test and reference standard Masking Full verification of the test with reference standard More than 90% follow-up Ann Intern Med. 2011;155:

5 Risk of Bias Patient selection Index test Reference standard Patient flow and timing Patient (Participant) Selection Was a consecutive or random sample of patients enrolled? Was a case control design avoided? Did the study avoid inappropriate exclusions? Yes / No / Unclear Index Test Were the index test results interpreted without knowledge of the results of the reference standard? If a threshold was used, was it prespecified? Reference Standard Was an independent gold-standard test used? Is the reference standard likely to correctly classify the target condition? Were the reference standard results interpreted without knowledge of the results of the index test (blinded)? Yes / No / Unclear Yes / No / Unclear Patient Flow and Timing Was there an appropriate interval between index tests and reference standard? Did all patients receive a reference standard (Was it applied to all patients, irrespective of the results of the diagnostic test)? Did all patients receive the same reference standard? Were all patients included in the analysis? Applicability Are there concerns that the following do not match the review question? Included patients - was the diagnostic test evaluated in an appropriate spectrum of patients (not just florid or asymptomatic patients)? Index test, its conduct, or interpretation Reference standard Yes / No / Unclear High / Low / Unclear 5

6 What is an Abnormal Test? Ideal Test (Continuous Measures) Outside 2 SD, or outside percentile Level at which risk of disease is increased Range where target disease highly probable Range in which Rx does > good than harm No Disease Disease Modified from Sackett: Evidence Based Medicine Test Results Actual Tests Actual Tests Varying Thresholds Varying thresholds results in trade-offs between false positives and false negatives No Sepsis Sepsis No Sepsis Sepsis Increasing IT Ratio Increasing IT Ratio Accuracy of Test Accuracy of Test Diagnostic Test Positive Diagnostic Test Negative Disease Present (True Pos) (False Neg) Disease Absent (False Pos) (True Neg) Diagnostic Test Positive Diagnostic Test Negative Disease Present 6 (60%) (True Pos) 4 (40%) (False Neg) Disease Absent 300 (30%) (False Pos) 700 (70%) (True Neg)

7 Receiver Operating Characteristic Curve Mnemonics SENSITIVITY PID positive in disease SnOut: Tests with a high sensitivity rule OUT the disease SPECIFICITY NIH Negative in health SpIn: Tests with a high specificity rule IN the disease 38 Systematic Reviews of Diagnostic Test Accuracy SYSTEMATIC REVIEWS OF DIAGNOSTIC TEST ACCURACY Identify all available evidence Evaluate the quality of published studies Produce estimates of test performance and impact based on all available evidence Account for variation in findings between studies Results Quality Assessment of Studies Systematic Reviews of Diagnostic Test Accuracy Each study reports a pair of related summary statistics (e.g., sensitivity and specificity) rather than a single statistic (such as a risk ratio) Hence requires different statistical methods to pool the results of the studies. 7

8 Guest Discussant Estimation of procalcitonin levels for the diagnosis of sepsis in infants: Evidence from diagnostic test accuracy reviews Estimation of procalcitonin levels for the diagnosis of sepsis in infants: Evidence from diagnostic test accuracy reviews Miriam Stewart, MD Children s Hospital of Philadelphia Trusted evidence. Informed decisions. Better health. Estimation of procalcitonin levels for the diagnosis of sepsis in infants: Evidence from diagnostic test accuracy reviews Miriam Stewart Thank you to my co-authors: Elliott Weiss Gautham Suresh Kevin Dysart Roger Soll Haresh Kirpilani Trusted evidence. Informed decisions. Better health. Learning objectives 1. Name theorized advantages of procalcitonin over existing neonatal sepsis screening tests 2. Define the diagnostic test accuracy of procalcitonin for the diagnosis of the following conditions: Blood culture proven neonatal sepsis Blood culture proven or clinically diagnosed neonatal sepsis 3. Describe the limitations inherent in this meta-analysis Background: Rationale for Current Review Bacterial sepsis is an important cause of neonatal morbidity and mortality. Positive culture is the only widely accepted means of diagnosis. A rapid biomarker that distinguishes septic infants from ill nonseptic infants would allow timely treatment of neonatal sepsis while reducing unnecessary antibiotic exposure. Serum procalcitonin (PCT) has been proposed as an improved marker of sepsis. Commonly used sepsis screening tests: CBC In 1972, Marietta Xanthou performed serial leukocyte counts on 24 ill infants and 11 well infants and found that the following changes were associated with infection: Increased absolute neutrophil count Increased immature neutrophil count Fall in neutrophils below 1000/mm 3 Fall in eosinophils Toxic granulation of neutrophils Since that time, the CBC has become a very common sepsis screening test. 8

9 Limitations of CBC indices Hornik et al (2012) studied infants with CBC obtained concurrently with a blood culture to assess for sepsis 166,092 infants evaluated for early-onset sepsis 37,825 infants evaluated for late-onset sepsis Indices studied included WBC count, I/T ratio, ANC, and platelet count Odds ratios for all the studied indices became significant only at the extremes of high and low values for each index Areas under the ROC curves demonstrated poor performance for all indices studied Diagnostic Accuracy of CBC Indices for EOS WBC Odds ratios of infection for ascending values of CBC indices ANC Diagnostic Accuracy of CBC Indices for EOS Diagnostic Accuracy of CBC Indices for LOS I/T ratio Platelet count I/T ratio Platelet count WBC <15K ANC Odds ratios of infection for ascending values of CBC indices WBC >15K Receiver operating characteristic curves for CBC indices Commonly used sepsis screening tests: CRP Limitations of CRP Acute phase reactant synthesized mainly in the liver Synthesis is upregulated in response to the release of inflammatory cytokines CRP has been investigated as a screening for neonatal sepsis since the 1970s Sabel and Wadworth reported an association between elevated CRP and bacteremia in 1979 Wide variability exists in reported diagnostic accuracy of CRP In a systematic review by Fowlie (1998): Positive likelihood ratios ranged from 0.82 to Negative likelihood ratio ranged from 0.12 to

10 Limitations of CRP Procalcitonin (PCT) Sensitivity is low at the time of initial testing (Benitz 1998) 35% (30.2 to 40.6%) for EOS 61.5% (48.3 to 74.8%) for LOS Sensitivity improves over the next 48 hours, but in this time frame, cultures also result and the infant s clinical condition typically declares itself For early-onset sepsis specificity declines over this same 48 hours time frame (Benitz 1998) 90% (88.1 to 91.9%) at initial testing 73.8% (71.1 to 76.6%) A 116-amino acid protein prohormone precursor to calcitonin, which is involved in skeletal homeostasis Synthesized predominantly in the C cells of the thyroid gland in uninfected people Found in low levels in the blood of uninfected persons Synthesized at sites throughout the body during sepsis Blood levels can rise to thousands-fold the normal level Physiologic role of procalcitonin rise during infection is not well understood Whang 1998, Becker 2004 Potential advantages of PCT over CRP More rapid rise in response to bacterial endotoxin Potential advantages of PCT over CRP More specific for bacterial infection vs other inflammatory triggers Detectable CRP 4-6 hours after stimulus PCT 4 hours after stimulus Brunkhorst et al (1999) studied 27 adult patients with septic and non-septic ARDS Peaks Duration 36 hours after stimulus Can remain elevated 48 hours after stimulus 6-12 hours after stimulus Begins to fall 24 hours after stimulus Significant differences were found between septic and non-septic patients in levels of PCT, neopterin, and IL- 6 but NOT CRP Dandona 1994, Povoa 2002 Potential advantages of PCT over CRP Potential advantages of PCT over CRP More specific for bacterial infection vs other inflammatory triggers Simon et al, 2004 Systematic review and meta-analysis of studies comparing PCT and CRP for differentiating between bacterial and non-bacterial causes of inflammation Literature search yielded 351 studies, of which 12 were ultimately included in the meta-analysis 10 studies (905 patients) compared patients with bacterial infection to those with a non-infective source of inflammation 3 studies (592 patients) compared patients with bacterial infection to those with viral infection PCT more sensitive and specific SROC curves for bacterial vs non-infectious causes of inflammation PCT more sensitive but not more specific SROC curves for bacterial vs viral causes of inflammation 10

11 Objectives of procalcitonin review Methods: Literature Search Primary Objectives To evaluate the performance of procalcitonin as a marker for culture-proven neonatal sepsis in the following populations: Early-onset sepsis Late-onset sepsis Early- or late-onset sepsis Secondary Objectives To evaluate the performance of procalcitonin as a marker for culture-proven or culture-negative neonatal sepsis in the following populations: Early-onset sepsis Late-onset neonatal sepsis Early- or late-onset sepsis Medline, EMBASE, Scopus, and CENTRAL searched from inception through July 2014 Inclusion criteria Prospective cohort and retrospective studies Infants hospitalized within the first 28 days of life PCT obtained during a sepsis evaluation Reference standard either positive blood or CSF culture or a clinical diagnosis of sepsis based on clearly defined criteria that included at least one laboratory abnormality Methods: Literature Search Review: Measures of Quality in DTA Studies Medline, EMBASE, Scopus, and CENTRAL searched from inception through July 2014 Exclusion criteria Studies in which healthy infants were the only control group Semi-quantitative PCT test Non-English articles 1) Did participating patients present a diagnostic dilemma? Healthy controls do not represent a diagnostic dilemma Studies that compare test performance in sick patients with test performance in healthy patients do not resemble the clinical situation 2) Did the investigators compare the test to an appropriate, independent reference standard? The reference standard should accurately and consistently be able to diagnose the disease Guyatt 2008 Meeting Guyatt s Standards of Quality in DTA Studies Meeting Guyatt s Standards of Quality in DTA Studies 1) Did participating patients present a diagnostic dilemma? By excluding healthy controls never suspected of sepsis, we are trying to more closely approximate the clinical situation 1) Did the investigators compare the test to an appropriate, independent reference standard? Positive blood culture is the only true gold standard for the diagnosis of sepsis. Our primary analysis will use only gold standard as the reference standard The clinical diagnosis of sepsis is not standardized and thus less reliable. We will limit our secondary analysis to studies that use clearly articulated criteria for the clinical diagnosis of sepsis including at least one laboratory parameter. 11

12 Methods: Meta-analysis Results: Literature Search Flow Diagram Data extracted independently by two researchers Study quality assessed using the QUADAS-2 tool modified to address issues specific to the review 2x2 tables generated and used to calculate summary sensitivities and specificities in STATA In cases where 2x2 tables could not be generated or additional questions existed about study methodology, attempts were made to contact study authors 1968 unique papers identified 116 studies underwent full joint review 15 studies included in meta-analysis 1852 papers excluded Did not meet inclusion criteria, n=1816 Foreign language, n=35 Unable to obtain paper, n=1 101 studies excluded after full review Age, n=13 Healthy controls, n=27 Inadequate definition of sepsis, n=12 Inconsistent data, n=1 No data on diagnostic test accuracy, n=13 Not enough information provided, n=21 PCT not studied, n=1 Semi-quantitative PCT test, n=2 Wrong population, n=3 Unable to reconstruct 2x2 tables, n=6 Data previously published, n=2 Article Auriti, 2012 Bender, 2008 Characteristics of Included Studies EOS, LOS, or both Cord blood studied? PCT threshold (ng/ml) N Population (GA) Incidence of sepsis 762 Not descried LOS No % Bcx positive + (27% VLBW) clinical sepsis weeks EOS No % Bcx positive 23.7% Bcx positive + clinical sepsis Blommendahl, % preterm Both No 1 7.7% Bcx positive 2002 Boraey, Term Both No % Bcx positive Canpolat, Preterm EOS Yes % Bcx positive Cetinkaya, Preterm Both No % Bcx positive Gomez, Not described Both No % Bcx positive Grosselj-Grenc, weeks Both No % Bcx positive 2009 Jacquot, % preterm LOS No % Bcx positive Joram, % preterm EOS Yes % Bcx positive Koksal, Majority preterm Both No % Bcx positive Koskenvuo, Not described EOS No % Bcx positive Sakha, > 34 weeks GA Both No % Bcx positive Sucilgatham, % preterm Both No % Bcx positive Zahedpasha, Not described Both No % Bcx positive Totals 4129 Weighted average sepsis incidence 8.9% Article Study Quality Assessment Using QUADAS-2 Tool Risk of bias Patient Selection Index Test Reference Standard Flow and Timing Concern for applicability to review question Patient population Index test Reference Standard Auriti, 2012 Unclear Low Unclear Low Low Low Low Bender, 2008 Low High Low Low Low Low Low Blommendahl, 2002 Low High Low Low Low Low Low Boraey, 2012 Unclear High Low Low Low Low Low Canpolat, 2011 Unclear High Low Low Low Low High Cetinkaya, 2009 High Low Low Low Unclear Low Low Gomez, 2012 Low Low Low Low Low Low Low Groselj-Grenc, 2009 Low High High Low Low High Low Jacquot, 2009 Low High Unclear Low Low Low Low Joram, 2011 Low High Low High Low Low Low Koksal, 2001 High Low Low Low Low Low Low Koskenvuo, 2003 Unclear Low Low Unclear Low Low Low Sakha, 2008 Unclear Low Low Low Low Low Low Sucilgatham, 2012 Low Low High Low Low Low Low Zahedpasha, 2009 Unclear Low High Low Low Low High Forest plots of sensitivity Forest plots of specificity 12

13 Objectives of procalcitonin review Results of Meta-analysis Primary Objectives To evaluate the performance of procalcitonin as a marker for culture-proven neonatal sepsis in the following populations: Early-onset sepsis not enough studies to complete a meta-analysis Late-onset sepsis not enough studies to complete a meta-analysis Early- or late-onset sepsis meta-analysis completed Secondary Objectives To evaluate the performance of procalcitonin as a marker for culture-proven or clinical neonatal sepsis in the following populations: Early-onset sepsis not enough studies to complete a meta-analysis Late-onset neonatal sepsis not enough studies to complete a meta-analysis Early- or late-onset sepsis meta-analysis completed Positive culture as reference standard Positive culture or clinical diagnosis as reference standard # of subjects Sensitivity (95% CI) 89.3% (80.2% %) 86.7% (78.1% %) Specificity (95% CI) 55.7% (43.3% %) 62.1% ( %) + LR (95% CI) 2.0 ( ) 2.3 ( ) - LR (95% CI) 0.19 ( ) 0.21 ( ) HSROC Curves Blood culture only reference standard Blood culture + clinical diagnosis Interpreting the data using the Fagan nomogram Blood culture only as reference standard: Assuming a 9% pre-test probability of sepsis, using likelihood ratios and their confidence intervals Positive result increases probability from 9% to 16% (95% CI 13% to 21%) Negative result reduces the probability from 9% to 2% (95% CI 1% to 4%) Interpreting the data using the Fagan nomogram Blood culture or clinical diagnosis as reference standard: Assuming a 9% pre-test probability of sepsis, using likelihood ratios and their confidence intervals Positive result increases probability from 9% to 18% (95% CI 13% to 26%) Negative result reduces the probability from 9% to 2% (95% CI 1% to 4%) Article Auriti, 2012 Bender, 2008 Blommendahl, 2002 Boraey, 2012 Canpolat, 2011 Cetinkaya, 2009 Gomez, 2012 Grosselj-Grenc, 2009 Jacquot, 2009 Joram, 2011 Koksal, 2001 Koskenvuo, 2003 Sakha, 2008 Sucilgatham, 2012 Zahedpasha, 2009 Population (GA) Not descried (27% VLBW) weeks 46% preterm Term Preterm Preterm Not described weeks 89% preterm 37.7% preterm Majority preterm Not described > 34 weeks GA 44% preterm Not described Limitations: Heterogeneity Study populations differ: Gestational age Setting (NICU vs ED) Birth weight Some studies do not describe their study population with respect to these variables 13

14 Limitations: Heterogeneity Limitations: Heterogeneity Article Auriti, 2012 Bender, 2008 Blommendahl, 2002 Boraey, 2012 Canpolat, 2011 Cetinkaya, 2009 Gomez, 2012 Grosselj-Grenc, 2009 Jacquot, 2009 Joram, 2011 Koksal, 2001 Incidence of sepsis 8.5% Bcx positive + clinical sepsis 3.4% Bcx positive 23.7% Bcx positive + clinical sepsis 7.7% Bcx positive 70% Bcx positive 20.3% Bcx positive 80.5% Bcx positive 3.6% Bcx positive 17.4% Bcx positive 39.7% Bcx positive 1.2% Bcx positive 8.2% Bcx positive Koskenvuo, % Bcx positive Sakha, % Bcx positive Sucilgatham, % Bcx positive Zahedpasha, % Bcx positive Totals 8.9% Incidence of sepsis varies widely between studies, from 1.2% to 80.5% High sepsis incidence in some studies may reflect underlying population (increased risk) or local practices (poor aseptic technique in obtaining blood cultures) Article Auriti, 2012 Bender, 2008 PCT threshold (ng/ml) Blommendahl, Boraey, Canpolat, Cetinkaya, Gomez, Grosselj-Grenc, Jacquot, Joram, Koksal, Koskenvuo, Sakha, Sucilgatham, Zahedpasha, Some authors used a predetermined threshold for positivity, others derived the threshold from their data set Data from previous studies suggests that there is a natural physiologic rise in procalcitonin in infants in the first 24 hours, so findings in studies of early-onset sepsis may not be generalizable to older infants Franz 1999, Chiesa 2003 Limitations: Clinical pathway Conclusions This review does not compare procalcitonin to existing sepsis screening tests (CBC or CRP) or assess its utility in combination with existing tests. Analysis of procalcitonin compared to or in addition to existing sepsis screens would be necessary to determine if substituting or adding procalcitonin in the clinical pathway would be safe, beneficial, or cost-effective. Negative PCT may indicate low probability of sepsis but a positive test only modestly increases the probability of sepsis. Methodological heterogeneity and poor quality among included studies of PCT precludes firm conclusions about its clinical utility and limit the generalizability of the meta-analysis findings. It is premature to routinely use procalcitonin in neonatal practice. References Review next steps We are still eliciting data from study authors with hopes that additional information will allow us to include more studies in the final meta-analysis. The literature search will be updated through 2016 prior to publication of the review. 1. Becker KL, Nylén ES, White JC, Müller B, Snider RH Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab Apr;89(4): Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics Oct;102(4):E Brunkhorst, F.M., Heinz, U. & Forycki, Z.F. Intensive Care Med (1998) 24: Chiesa C, Pellegrini G, Panero A, Osborn JF, Signore F, Assumma M, Pacifico L.C-reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complications, and infection. Clin Chem Jan;49(1): Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M, Bohuon C. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab Dec;79(6): Guyatt G, Rennie D, Meade MO, Cook DJ. Part D: Diagnosis in User s Guide to the Medical Literature. McGraw Hill Fowlie PW, Schmidt B. Diagnostic tests for bacterial infection from birth to 90 days--a systematic review. Arch Dis Child Fetal Neonatal Ed Mar;78(2):F Franz AR, Kron M, Pohlandt F, Steinbach G. Comparison of procalcitonin with interleukin 8, C-reactive protein and differential white blood cell count for the early diagnosis of bacterial infections in newborn infants. Pediatr Infect Dis J Aug;18(8):

15 References Questions/Discussion? 9. Hornik CP, Benjamin DK, Becker KC, Benjamin DK Jr, Li J, Clark RH, Cohen-Wolkowiez M, Smith PB. Use of the complete blood cell count in late-onset neonatal sepsis. Pediatr Infect Dis J Aug;31(8): Hornik CP, Benjamin DK, Becker KC, Benjamin DK Jr, Li J, Clark RH, Cohen-Wolkowiez M, Smith PB. Use of the complete blood cell count in early-onset neonatal sepsis. Pediatr Infect Dis J Aug;31(8): Póvoa P. C-reactive protein: a valuable marker of sepsis. Intensive Care Med Mar;28(3): Sabel KG, Wadsworth C. C-reactive protein (CRP) in early diagnosis of neonatal septicemia. Acta Paediatr Scand Nov;68(6): Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis Jul 15;39(2): Whang KT, Steinwald PM, White JC, Nylen ES, Snider RH, Simon GL, Goldberg RL, Becker KL. Serum calcitonin precursors in sepsis and systemic inflammation. J Clin Endocrinol Metab Sep;83(9): PubMed PMID: Xanthou M. Leucocyte blood picture in ill newborn babies. Arch Dis Child Oct;47(255): Next Web Seminars? Thank you for participating Please complete the survey for CME credit Webinar and slides will be distributed via For questions or more information please contact: Yolanda Brosseau (Yolanda.brosseau@med.uvm.edu) Please watch for s regarding our Winter 2017 Web Seminar 15