PROCALCITONIN Evaluation & Use In Victoria, BC

PROCALCITONIN
Evaluation & Use
In Victoria, BC
J Penman, MD
30 th September 2010

CONTENTS
SIRS, SEPSIS, PCT HISTORY & PHYSIOLOGY
ASSAYS & INITIAL EVALUATION
RESULTS OF PCT VERSUS CRP
IMPLEMENTATION OF TESTING SERVICE
LESSONS OF THE FIRST 6 MONTHS
OTHER USES

SIRS & SEPSIS:
SIRS Systemic Inflammatory Reaction
Syndrome, Characterized by >2 of following
Fever or hypothermia >38 or 90 beats / min
Tachypnea >20 breaths / min or PaCO2 >32 torr
Leucocytosis or leucopenia >12 or

HISTORY OF PCT
Originally investigated as a marker for
medullary thyroid cancer in the 1970s
Relationship to sepsis found in the 1990s
Desired to distinguish Sepsis from SIRS
Advent of 1st automated assay (Brahms)
Other assays developed (Brahms patent)

PHYSIOLOGY-1
PCT is the precursor molecule of Calcitonin
Calcitonin only secreted by thyroid C-cells and acts
to increase blood calcium.
All body cells can transcribe the CALCA gene
Main triggers are G-ve lipopolysaccharides (LPS),
G+ve cell wall antigens & bacterial toxins that react
with Toll-like Receptors (TLRs) on cell surfaces.
These cells secrete Procalcitonin, not calcitonin

PCT STRUCTURE
PRODUCT OF THE CALCITONIN RELATED POLYPEPTIDE
ALPHA GENE (CALCA) ON CHROMOSOME 11 (p15.2)
PCT OF THYROID C-CELLS 116 AA LONG
PCT OF OTHER CELLS 114 AA LONG

THYROID C-CELL

OTHER BODY CELLS

PHYSIOLOGY-2
Stimulated by bacterial Products on TLRs
Part of innate immunity - uncertain function
Reports of added PCT worsening inflammation
Reports of removal of PCT decreasing inflammation
Increased levels detectable within 6h
Half life 30h
Without stimulus, drops 30-50% within 24h
Disposal – Internal degradation, renal clearance
is minor

PCT KINETICS

CONTENTS
SIRS, SEPSIS, PCT HISTORY & PHYSIOLOGY
ASSAYS & INITIAL EVALUATION
RESULTS OF PCT VERSUS CRP
IMPLEMENTATION OF TESTING SERVICE
LESSONS OF THE FIRST 6 MONTHS
OTHER USES

AUTOMATED ASSAYS
Brahms Kryptor CL immunoassays
All other assays under license from Brahms
Calibrated against Brahms standards
Licensed by Brahms; patent holder on PCT
Roche ECL immunoassay
BioMerieux Vidas CL immunoassay
Siemens Centaur CL immunoassay
Diasorin Liason CL immunoassay

INITIAL EVALUATION
Objectives:
Evaluate VIDAS & Roche assays
Compare PCT to CRP (our prev.marker)
Process:
Collected 22 suspect sepsis + 2 without SIRS
PCT (both assays) & CRP daily for 2-4 days
Results compared to culture & clinical
information from patients’ charts

COBAS ACCURACY
Apparatus: Roche Cobas e601
Analyte: PROCALCITONIN
Samples: PC PCT Level 1 & 2 (Roche QC)/VIDAS QC 1&2 Unit: ug/L
Operator: Jennifer Annand Accuracy tolerance limit : 10.0%
Level Sample Id Date Result 1 Result 2 Mean Result Assigned Deviation Accepted
Mean (%)
1 Vidas QC1 15-Jun-09 12.79 13.05 12.92 16.80 -23.1% NO
2 Vidas QC2 15-Jun-09 1.40 1.43 1.42 1.79 -20.9% NO
3
4 PC PCT 1 15-Jun-09 0.494 0.486 0.49 0.48 2.1% YES
5 PC PCT 2 15-Jun-09 9.80 9.88 9.84 9.69 1.5% YES
Level Sample Id Date Result 1 Result 2 Mean Result Assigned
Mean
Deviation
(%)
Accepted
1 Vidas QC1 16-Jun-09 12.85 12.88 12.87 16.80 -23.4% NO
2 Vidas QC2 16-Jun-09 1.45 1.40 1.43 1.79 -20.4% NO
3 FALSE
4 PC PCT 1 16-Jun-09 0.477 0.485 0.48 0.48 0.2% YES
5 PC PCT 2 16-Jun-09 9.71 9.82 9.77 9.69 0.8% YES

90
80
y = 0.8418x - 0.4055
R² = 0.9949
Roche e601 PCT (ug/L)
70
60
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90
BioMerieux VIDAS PCT (ug/L)
PCT Analytical-Systems Correlation between
the Roche e601 and the BioMerieux VIDAS

ANALYZER SYSTEM METHOD MATRIX
PCT
ug/L
Total
Imprecision
LLOQ
ug/L
BioMerieux VIDAS
Chemiluminescence
Monoclonal abs.
Sandwich assay
Vendor QC-1 15.28 2.91%
BioMerieux VIDAS Vendor QC-2 1.76 3.56%
0.09
Roche Cobas e601
Human Pl.-1 0.07 6.94%
Electro-Chemi-
Roche Cobas e601
Luminescence
Monoclonal abs.
Human Pl.-2 4.86 1.35%
Sandwich assay
0.05-0.07
Roche Cobas e601 Human Pl.-3 63.16 3.56%
Table 1: Technology, precision and lower limit of quantitation of analyzer-systems

CONTENTS
SIRS, SEPSIS, PCT HISTORY & PHYSIOLOGY
ASSAYS & INITIAL EVALUATION
RESULTS OF PCT VERSUS CRP
IMPLEMENTATION OF TESTING SERVICE
LESSONS OF THE FIRST 6 MONTHS
OTHER USES

12.00
LEGEND: VIDAS v CRP; ROCHE v CRP
10.00
8.00
PCT (ug/L)
6.00
4.00
y = 0.0148x + 0.7489
R² = 0.1824
y = 0.0148x + 0.1715
R² = 0.2746
2.00
0.00
0.00 50.00 100.00 150.00 200.00 250.00 300.00
CRPs (mg/L)
Correlation of PCTs with CRPs for PCT

INITIAL PCT AND CRP RESULTS
CULTURE RESULTS (N)
INTIAL PCT
RANGE (MEDIAN)
INITIAL CRP
RANGE (MEDIAN)
BLOOD CULT POS (7) 0.44->100 (63) 23-341 (87)
OTHER CULT POS (7) 0.13-45 (5.0) 136-253 (207)
CULTURE ND/NEG (10)

BLOOD CULTURE POSITIVE CASES
In 5/7 cases the CRP results do not correlate with PCT nor with clinical status or changes
CASES
VIDAS
CLIN CORREL
VIDAS
PCT
CRPs
ROCHE
PCT
ROCHE
CLIN CORREL
CULTURE RESULTS
CLINICAL
CORRELATION
SEPSIS
RANGES
BACTERIAL
INFECTION
A
C
H
I
L
O
R
1.25
1.48
1.01
0.93
>100
>100
>100
50.08
0.45
0.60
0.79
82.28
85.73
59.47
37
39
52
45
32
159
246
195
23
44
54
258
309
327
0.708
0.864
BL: MRSA
BL: MRSA
Improved with Rx
SEPTIC SHOCK >100 PRESENT
SHOCK LIKELY >50102100
BL:E.col
Recovered on Rx
POSSIBLE >0.50100 UNLIKELY 0.25 - 0.50 LIKELY
75.93 ABSENT 0.10 - 100
>100
341
353
87
118
62
62.97
28.47
>100
>100
>100
BL:Listeria
CSF:Listeria
SP/UR:NG
BL: E.coli
UR:NG
BL:MRSA
SPT:MRSA
BL:E.coli
BL:E.coli
BL:MSSA
Remained Infected. Antibiotic changed
after these results
Discharged 2 days
after last result
Improved clinically & on CXR over this time
Improved. Oral Rx subsequent
Died in septic shock

PCT v OTHER MKRS
SOFA = Sequential Organ Failure Assessment
Brahms’ data: www.procalcitonin.com

CONTENTS
SIRS, SEPSIS, PCT HISTORY & PHYSIOLOGY
ASSAYS & INITIAL EVALUATION
RESULTS OF PCT VERSUS CRP
IMPLEMENTATION OF TESTING SERVICE
LESSONS OF THE FIRST 6 MONTHS
OTHER USES

THE VALUE OF PCT
Decision to treat with antibiotics:
High negative predictive value (NPV) – ER Triage,
Culture & treat / admit or discharge
Wait 6-12h & repeat PCT / admit or discharge
Monitoring Treatment
PCT level tracks severity & progress – trend very useful
Dropping 30-50% /d = successful Rx – continue
Not dropping or increasing - change Rx, reculture
Decision to stop antibiotics
Unnecessary Rx is risky for patients and costly
>90% drop from peak or

PCT & ABIOTIC Rx
Brahms’ data: www.procalcitonin.com

OTHER POSSIBLE VALUE
Monitoring patients at high risk
Patients on immunosuppressive therapy
Neonates born after PROM, maternal GpB Strep+ve
Post Surgical & post trauma patients
Reduce need for CRP or Lactate in Sepsis
CRP and lactate are not sepsis specific
Many orders are based on monitoring sepsis
response to treatment which is better done with PCT
TAT for PCT better than CRP – not POC like Lactate

PCT CAVEATS
Not for guiding antibiotic treatment in :
Infections: endocarditis, osteomyelitis,
CNS infs, deep-infections, Pseudomonas
pneumonia.
Organisms: Listeria, Legionella, PCP,
Mycobacteria
Immunosuppressed patients

IMPLEMENTATION
3 month evaluation in SI - ICUs & ERs
Reference Interval Adults 0.25-0.50 – Bacterial infection likely – rpt 6-24h
>0.50-2.0 – Bacterial infection very likely . Moderate risk
for sepsis
>2.0 – Bacterial infection very likely. High risk for sepsis

CONTENTS
SIRS, SEPSIS, PCT HISTORY & PHYSIOLOGY
ASSAYS & INITIAL EVALUATION
RESULTS OF PCT VERSUS CRP
IMPLEMENTATION OF TESTING SERVICE
LESSONS OF THE FIRST 6 MONTHS
OTHER USES

ACCEPTANCE OF TEST
Generally good – some sceptics
Not a silver bullet – better than CRP
NPV and trend most useful of all
Rapid uptake & sustained interest from
ICU & ER
Interest from NICU, Surgery & from upisland

ALGORITHM COMPLIANCE
Criteria:
Stop Rx & discharge sooner than Std of Care
Order PCTs per algorithm
Poor compliance with algorithm because:
Decision levels too conservative (low)
Algorithm & comments often conflict
Cerner flags clear, comments not obvious

FALSE RESULTS
False negatives not significant. High NPV
False positives – i.e. not due to bact. inf.
Ac.Pancreatitis, ext. burns, ext. lung damage
Usually 80

NEXT STEPS
Obtain an extension of clinical evaluation
Revise the algorithm(s)
Separate algorithms for ICU and ER
Have regular case oriented discussions
with users
Evaluate the assay in other areas? NICU?

CONTENTS
SIRS, SEPSIS, PCT HISTORY & PHYSIOLOGY
ASSAYS & INITIAL EVALUATION
RESULTS OF PCT VERSUS CRP
IMPLEMENTATION OF TESTING SERVICE
LESSONS OF THE FIRST 6 MONTHS
OTHER USES

NEONATAL SEPSIS
Wealth of literature claims that PCT has
similar value in NICU as in adult ICU
Added value to monitor susceptible
neonates, e.g. low birth weight prems,
PROM cases, maternal GBS+ve
Reference intervals in first 24h a problem

PCT v HRS AFTER BIRTH
Brahms’ data: www.procalcitonin.com

NEONATAL PROJECT
Investigate physiological increase in PCT
Relation to delivery – C/S v Vaginal
Relation to GIT colonization
Look at LBWP infants (

OTHER USES FOR PCT
Prediction of renal disease (5)
parenchymal involvement in pediatric UTIs
Long-term morbidity in pediatric UTIs
In vesico-ureteric reflux
Severity of acute pancreatitis (2)
Diagnosis & monitoring of post Sx Infs. (9)
As an indicator of survival in the ICU

THANK YOU

KEY REFERENCES
1. Mirjam Christ-Crain et al: Effect of procalcitonin-guided treatment on
antibiotic use and outcome in lower respiratory tract infections:
cluster randomised, single-blinded intervention trial. Lancet; Feb 21,
2004, 363:600-607
2. Vandack Nobre et al: Use of Procalcitonin to Shorten Antibiotic
Treatment Duration in Septic Patients. Am J Respir Crit Care Med; 2008,
177:498-505
3. Philipp Schuetz et al: Effect of Procalcitonin-Based Guidelines vs
Standard Guidelines on Antibiotic Use in Lower Respiratory Tract
Infections (ProHOSP). JAMA; Sep 9, 2009, 302(10):1059-1066
4. Jamie N. Deis et al: Procalcitonin as a Marker of Severe Bacterial
Infection in Children in the Emergency Department. Ped Emerg Care;
Jan 2010, 26: 51-60