Procalcitonin and CRP in Lower Respiratory Tract

Infections

Doç. Dr. Aykut ÇilliAkdeniz 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.

NH3COOH

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

Müller B et al, BMC Infect Dis 2007

545 patients with suspected LRTI

373 CAP

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=0.36PCT, CRP > temp,WBC,chest ausc,sputum p<0.001

PCT > CRP, p=0.04PCT > 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 suspected CAP (included non-infectious origin)

D. Diagnostic accuracy to predict bacteremic CAP

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

Müller B et al, BMC Infect Dis 2007

Diagnostic accuracy of C reactive protein in detecting radiologically proved pneumonia

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

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

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

Hedlund J et al, Infection 2000

p<0.03

Beovic et al, CMI 2005

•116 patients with mild CAP•Aetiology was established

for 62 patients•PCT levels seems to be a

useful tool to rule out an

atypical aetiology. P=0.021

P<0.0001

• 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

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

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

Almirall J et al, Chest 2004

• 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

Site of care Cases, no median p value

Home 83 76.9 <0.0001

Inpatient care 118 132.0

Total 201 110.7

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

¥ 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

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

Table 1. CRP levels and aetiological diagnosis

Vazquez EG et al, Eur Respir J 2003

*p=0.0002

Agent OR 95% CI p-value

L. pneumophila pneumonia/ pyogenic pneumonia

5.7 2.4-13.6 <0.0001

L. pneumophila pneumonia/ atypical pneumonia

13 3.6-47.7 <0.0001

L. pneumophila pneumonia/ viral pneumonia

7.8 2.0-29.0 <0.01

L. pneumophila pneumonia/ non- L. pneumophila pneumonia

6.9 3.02-15.8 <0.0001

Table 2. CRP levels and aetiological diagnosis: multivariate analysis

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 ICU50% 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

Boussekey N et al, Intensive Care Med 2006

P=0.03

P<0.001

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

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

Antonisen

Score=1

(N=62)

Antonisen

Score=2

(N=17)

Antonisen

Score=3

(N=36) N=51

WBC count 11 11 11.3 12

CRPa, b 8 49 37 97

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

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)

Weis N et al, Eur J of Intern Med 2006

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

I: 64 patients without pneumonia and without increased sputum purulenceII: 51 patients without pneumonia and with increased sputum purulenceIII: 51 patients with pneumonia

P<0.001

Weis N et al, Eur J of Intern Med 2006

Procalcitonin-guided treatment on antibiotic use

• Prospective, controlled, cluster randomised, single-blinded intervention trial

• 243 patients admitted with suspected LRTI

• Baseline characteristics were similar

PCT-guided treatment in LRTI

Christ-Crain M, et al. Lancet 2004

243 patients with suspected LRTI

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

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

Christ-Crain M, et al. Lancet 2004

PCT (ng/ml)< 0,1 Absence of bacterial infection

Use of AB strongly discouraged0,1 – 0,25 Bacterial infection unlikely

Use of AB discouraged0,25 – 0,5 Bacterial infection probable

Antibiotcs recommended> 0,5 Presence of bacterial infection

Antibiotcs strongly recommended

PCT-Algorithm

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

• Randomized intervention trial

• 302 consecutive patients with CAP

• Baseline characteristics (clinical, laboratory, microbiological and PSI) were similar.

PCT-guidance of antibiotic therapy in CAP

Christ-Crain M, et al. AJRCCM 2006

Control group (n=151)

Procalcitonin group (n=151)

Christ-Crain M, et al. AJRCCM 2006

Median AB treatment duration=12 days (control)Median AB treatment duration=5 days (procalcitonin)

*(P<0.05)

PCT-guided treatment of exacerbations of COPD

• A randomized, controlled trial comparing procalcitonin-guidance with standard therapy

• Single center, single-blinded study

Stolz D, et al. Chest 2007

208 patientsrequiring hospitalization

102 procalcitonin group

106 standard group

Stolz D, et al. Chest 2007

51% < 0.1 ng/ml29% 0.1-0.25 ng/ml20% > 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

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 4 h 8 h

Peaks at 8 h 36 h

Costs ~10 $ ~5 $

Performing Easy Easy

Results available 2 h 4 min

PCT, CRP: which one is better?(A systematic review and meta-analysis)

Simon L,et al. CID 2004

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

13 studies N=1497

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.

• 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.

Conclusions-II