Procalcitonin and CRP in Lower

Respiratory Tract Infections

Doç. Dr. Aykut Çilli

Akdeniz Üniversitesi Tıp Fakültesi Göğüs
Hastalıkları Anabilim Dalı, Antalya
 Studies related with CRP and PCT

• Fungal infections
• HIV
• Transplantation
• Febril neutropenia
• Sepsis
• VAP
• TB
• SARS
• Children
 Plan

• Introduction
• Usefulness of PCT and CRP as a diagnostic tool
in LRTI
• CRP and PCT as a predictor of etiology and
prognosis in CAP
• PCT in severe CAP
• Procalcitonin-guided treatments
• Limitations
• Conclusions
CRP
•Acute phase protein
produced in the liver.

•Increased production is
triggered by cytokines
released by infection or
tissue damage.

•Serum concentration is
usually <3 mg/L, but can
increase to 500 mg/L.
 Procalcitonin (PCT)
• Precursor peptide of the hormone procalcitonin.
• PCT is a small (13 kd) protein that is normally
undetectable in plasma.
• PCT increases markedly in bacterial infections.

NH3 COOH

Sinyal dizisi Aminokalsitonin Kalsitonin Katakalsin

PROCALCİTONİN
For the diagnosis of infections, the diagnostic accuracy of PCT and its optimum
cut-offs are completely dependent on the use of a sensitive assay.
The usefulness of PCT and CRP as
a diagnostic tool in LRTI
• Aim: To evaluate the diagnostic and
prognostic accuracy of clinical signs,
symptoms and biomarkers for CAP

373 CAP

545 patients with

suspected LRTI 132 other RTI

40 other diagnosis

Müller B et al, BMC Infect Dis 2007

 ROC of different parameters for the diagnosis of pneumonia

A. Diagnostic accuracy to predict CAP without XR B. Diagnostic accuracy to predict radiographically

defined CAP

PCT > CRP, p=0.36 PCT > CRP, p=0.04

PCT, CRP > temp,WBC,chest ausc,sputum p<0.001 PCT > temp,WBC,chest ausc,sputum p<0.001

Müller B et al, BMC Infect Dis 2007

 ROC of different parameters for the diagnosis of pneumonia

C. Diagnostic accuracy to predict radiographically D. Diagnostic accuracy to predict bacteremic CAP

suspected CAP (included non-infectious origin)

PCT>CRP, p<0.001 PCT>CRP, p=0.01

Müller B et al, BMC Infect Dis 2007

Müller B et al, BMC Infect Dis 2007
Diagnostic accuracy of C reactive protein in
detecting radiologically proved pneumonia

Systematic review:
6 studies, N=1178
Sensitivities: 10% to 98%
Specificities: 44% to 99%

Testing for C reactive protein is neither

sufficiently sensitive to rule out nor sufficiently
specific to rule in an infiltrate on chest
radiograph and bacterial aetiology of lower
respiratory tract infection.

van der Meer V, et al. BMJ 2005

CRP and PCT as a predictor of
etiology and prognosis in CAP
• One-year, population-based, prospective
study
• 185 adult patients with CAP
• Patients were classified according to
microbial diagnosis, PSI and PCT levels

Masia M et al, Chest 2005

Masia M et al, Chest 2005
 Low PSI risk classes (I-II) Higher PSI risk classes (III-V)

p=0.08

Masia M et al, Chest 2005

• Aim: Diagnostic value of admission serum levels of PCT
and CRP as indicators of etiology and prognosis

• 96 patients with CAP

• All patients had elevated CRP levels (>10 mg/l)
• Only 60 patients had elevated PCT levels (>0.1 µg/l)
• APACHE II score was strongly associated with PCT
(p=0.006), but not with CRP

Hedlund J et al, Infection 2000

 p<0.03

Hedlund J et al, Infection 2000

•116 patients with mild CAP
•Aetiology was established P<0.0001

for 62 patients
•PCT levels seems to be a
useful tool to rule out an
atypical aetiology. P=0.021

Beovic et al, CMI 2005

• Objective: To assess the usefulness of
serum CRP in patients with CAP, identify
etiologic diagnosis and to predict severity
outcome

• Population-based case-control study

• 201 patients with CAP and 84 controls

Almirall J et al, Chest 2004

Table 1. Serum CRP values in 89 patients with CAP according to
causative pathogen

Pathogen Cases (n) Median p value

S pneumoniae 25 166.0 0.0002

C pneumoniae 21 137.7 NS
M pneumoniae 8 115.6 NS
C burnetii 5 47.4 0.056
Viral etiyoloji 25 98.3 NS
L pneumophila 5 178.0 0.033

Almirall J et al, Chest 2004

 Table 2. Serum CRP values patients with CAP according to site of care

Site of care Cases, no median p value

Home 83 76.9 <0.0001
Inpatient care 118 132.0

Total 201 110.7

• Considering a cut point of 106 mg/L in men and 110

mg/L in women for deciding about the appropriateness
of inpatient care, CRP levels showed a sensitivity of
80.5% and a specificity of 80.7%

Almirall J et al, Chest 2004

¥ With suggestive symptoms of CAP, serum
CRP > 33 mg/L is a useful marker.

¥ Serum CRP levels are greater when S pneumoniae

or L pneumophila are the causative pathogens.

¥ CRP > 106 mg/L seem to predict severity of illness.

Almirall J et al, Chest 2004

• Aim: To evaluate the diagnostic value of CRP
as an indicator of the aetiology of CAP

• A cohort of 1222 patients with CAP was

assessed.
• CRP levels were analysed in 258 patients.

Vazquez EG et al, Eur Respir J 2003

Table 1. CRP levels and aetiological diagnosis

Agent Patients (n) CRP mean (mg/dl)

Typical bacterial pneumonia 141 16

Legionella pneumophila pneumonia 30 25.23*

Atypical pneumonia 52 12.64

Viral 35 14.45

Total 258 16.18

*p=0.0002

Vazquez EG et al, Eur Respir J 2003

Table 2. CRP levels and aetiological diagnosis: multivariate analysis

Agent OR 95% CI p-value

L. pneumophila pneumonia/ 5.7 2.4-13.6 <0.0001

pyogenic pneumonia
L. pneumophila pneumonia/ 13 3.6-47.7 <0.0001
atypical pneumonia
L. pneumophila pneumonia/ viral 7.8 2.0-29.0 <0.01
pneumonia
L. pneumophila pneumonia/ non- 6.9 3.02-15.8 <0.0001
L. pneumophila pneumonia

Vazquez EG et al, Eur Respir J 2003

Procalcitonin in Severe CAP
• Aim: To determine diagnostic and
prognostic values of PCT for severe CAP

• 110 patients admitted to ICU

50% PCT ≥ 2 ng/ml
30% 0.5 ≤ PCT < 2 ng/ml
20% PCT ≤ 0.5 ng/ml

Boussekey N et al, Infection 2005

Boussekey N et al, Infection 2005
Boussekey N et al, Infection 2005
• Aim: To evaluate prognostic value of PCT
in severe CAP patients

• Prospective observational study in ICU

• 100 critically-ill patients with CAP

Boussekey N et al, Intensive Care Med 2006

 P<0.001

P=0.03

PCT increased in nonsurvivors and decreased in survivors (p=0.01)

Boussekey N et al, Intensive Care Med 2006

 Can CRP be used as a marker of
infection in COPD exacerbation?
• 116 consecutive patients with exacerbation
of COPD

• Patients with exacerbation of COPD with and

without pneumonia were compared

Weis N et al, Eur J of Intern Med 2006

 Chest x-ray with changes
Chest x-ray without changes compatible with pneumonia compatible with pneumonia

Antonisen Antonisen Antonisen

Score=1 Score=2 Score=3
(N=62) (N=17) (N=36) N=51

WBC count 11 11 11.3 12

CRPa, b 8 49 37 97

a Antonisen score 1 less than score 2 or 3 (p<0.001)

b CRP significantly higher for patients with pneumonic infiltration than for those
without pneumonic infiltration (p<0.001)

* CRP values are normal in nearly 50% of patients admitted due to exacerbation of COPD

Weis N et al, Eur J of Intern Med 2006

 P<0.001

I: 64 patients without pneumonia and without increased sputum purulence

II: 51 patients without pneumonia and with increased sputum purulence
III: 51 patients with pneumonia

Weis N et al, Eur J of Intern Med 2006

 Procalcitonin-guided
treatment on antibiotic use
 PCT-guided treatment in LRTI

• Prospective, controlled, cluster

randomised, single-blinded intervention
trial
• 243 patients admitted with suspected LRTI
• Baseline characteristics were similar

Christ-Crain M, et al. Lancet 2004

 124 PCT-guided group
42 Pneumonia
29 AECOPD
28 Bronchitis
10 Asthma
15 Others

243 patients with

suspected LRTI
119 standard-treated group
45 Pneumonia
31 AECOPD
31 Bronchitis
3 Asthma
9 Others

Christ-Crain M, et al. Lancet 2004

PCT-Algorithm

PCT (ng/ml)
< 0,1 Absence of bacterial infection
Use of AB strongly discouraged
0,1 – 0,25 Bacterial infection unlikely
Use of AB discouraged
0,25 – 0,5 Bacterial infection probable
Antibiotcs recommended
> 0,5 Presence of bacterial infection
Antibiotcs strongly recommended

Christ-Crain M, et al. Lancet 2004

*The risk of antibiotic exposure was reduced by 50% (without compromising
clinical and laboratory outcome)

Christ-Crain M, et al. Lancet 2004

PCT-guidance of antibiotic therapy
in CAP
• Randomized intervention trial
• 302 consecutive patients with CAP
Control group (n=151)

Procalcitonin group (n=151)

• Baseline characteristics (clinical, laboratory,

microbiological and PSI) were similar.

Christ-Crain M, et al. AJRCCM 2006

Median AB treatment duration=12 days (control)
Median AB treatment duration=5 days (procalcitonin)
*(P<0.05)

Christ-Crain M, et al. AJRCCM 2006

 PCT-guided treatment of
exacerbations of COPD
• A randomized, controlled trial comparing
procalcitonin-guidance with standard
therapy
• Single center, single-blinded study

102 procalcitonin group

208 patients
requiring hospitalization
106 standard group

Stolz D, et al. Chest 2007

 51% < 0.1 ng/ml
29% 0.1-0.25 ng/ml
20% > 0.25 ng/ml

Stolz D, et al. Chest 2007

PCT guidance significantly reduced antibiotic prescribtions (40% vs 72 %, p<0.0001)

Stolz D, et al. Chest 2007

Stolz D, et al. Chest 2007
Stolz D, et al. Chest 2007
Stolz D, et al. Chest 2007
Potential limitations
 CRP

• Protracted response with late peak levels.

• Suboptimal specificity (especially in
patients with severe inflammation and
infection)
• Reduced increase in patients with steroid
or other immunosuppressive therapies.
 Procalcitonin
• The optimal cut-off ranges are variable
• False-negative and false-positive results
• Different assays available with different
test performances
• It is not a very early marker of infection
• A single PCT value is not very good
prognostic marker
• May remain low in localized bacterial
infections
CRP vs. PCT
 Differences of procalcitonin and CRP

PCT CRP

Secretion begins at 4h 8h
Peaks at 8h 36 h
Costs ~10 $ ~5 $
Performing Easy Easy
Results available 2h 4 min
 PCT, CRP: which one is better?
(A systematic review and meta-analysis)

13 studies
N=1497

Overall accuracy of PCT markers is higher than that of CRP markers both to
differentiate bacterial infections from viral infections and to differentiate bacterial
infections from other noninfective causes of systemic inflammation

Simon L,et al. CID 2004

 Conclusions-I

• The CRP and PCT test is only an adjunct

to the clinical diagnosis.
• Antibiotic treatment can usually be
avoided when the CRP (<10 mg/L) and
PCT value (<0.1 µg/L) is low.
• PCT testing can safely and markedly
reduce antibiotic prescribing in patients
with LRTI.
 Conclusions-II

• The prognosis of bacterial infection seems

correlates with PCT levels.
• PCT is both more sensitive and more
specific than CRP in the diagnosis of
bacterial infection.
• Clinicans must bear in mind the limitations
of every biomarker.