The Diagnostic and Prognostic Value of Serum Procalcitonin among Ventilator Associated Pneumonia Patients*

doi:10.4236/ojrd.2013.32012

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Open Journal of Respiratory Diseases, 2013, 3, 73-78

http://dx.doi.org/10.4236/ojrd.2013.32012 Published Online May 2013 (http://www.scirp.org/journal/ojrd)

The Diagnostic and Prognostic Value of

Serum Procalcitonin among Ventilator

Associated Pneumonia Patients*

Ashraf Abd El Halim1, Adel Attia1#, Taysser Zytoun2, Hosam Eldeen Salah3

1Chest Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

2Critical Care Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

3Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Email: #[email protected]

Received April 2, 2013; revised May 3, 2013; accepted May 10, 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Ventilator-associated pneumonia (VAP) is a complication in as many as 28% of patients who receive mechanical venti-

lation. Studies have consistently shown that a delay in diagnosis and treatment increases the mortality risk. The aim of

this work was to clarify the role of the serum procalcitonin (PCT) in the diagnosis and the prognosis of ventilator asso-

ciated pneumonia. Methods: Forty two VAP patients, 20 non VAP-ICU (on mechanical ventilation) admitted patients

and 20 healthy control subjects of similar age and sex were included in the study. PCT levels in serum samples were

measured in all subjects. Results: There was a highly statistically significant difference (p value < 0.001) between VAP

patients on one side and non VAP-ICU patients and healthy control subjects on the other side regarding the mean values

of PCT. Also, the mean values of PCT were statistically significantly higher (p < 0.001) among died VAP group than

the survivor VAP group. There was a statistically positive correlation (p < 0.01) between mortality prediction scores

(APACHE II (R = 0.449), CRIP (R = 0.403) and SOFA (R = 0.437)) and initial PCT serum levels. Conclusions: This

study found that the increased PCT serum level is an important diagnostic tool for VAP and the PCT serum levels can

predict the outcome of VAP patients. We recommend other larger studies to augment our findings.

Keywords: Ventilator-Associated Pneumonia (VAP); Procalcitonin (PCT); Acute Physiology and Chronic Health

Evaluation II (APACHE II); The Sequential Organ Failure Assessment Score (SOFA); Clinical Pulmonary

Infection Score (CPIS)

1. Introduction

Ventilator-associated pneumonia (VAP) is pneumonia

that develops 48 hours or longer after mechanical venti-

lation is given by means of an endotracheal tube or tra-

cheostomy. Ventilator-associated pneumonia (VAP) re-

sults from the invasion of the lower respiratory tract and

lung parenchyma by microorganisms. Intubation com-

promises the integrity of the oropharynx and trachea and

allows oral and gastric secretions to enter the lower air-

ways [1]. Ventilator associated pneumonia (VAP) is a

complication in as many as 28% of patients who receive

mechanical ventilation. The incidence of VAP increases

with the duration of mechanical ventilation. Estimated

rates are 3% per day for the first 5 days, 2% per day for

days 6 - 10, and 1% per day after day 10 [2]. The crude

mortality rate of VAP is 27% - 76%. Studies have con-

sistently shown that a delay in starting appropriate and

adequately dosed antibiotic therapy increases the mortal-

ity risk.

One of the causes of the high mortality rate is the di-

agnosis delay [1].

Unlike community-acquired pneumonia, it may be dif-

ficult to determine whether pneumonia has developed in

a hospitalized ventilator-dependent patient. Symptoms

and signs usually are not conclusive. Although the plain

chest roentgenogram remains an important component in

the evaluation of hospitalized patients with suspected

pneumonia, it is most helpful when it is normal and rules

out pneumonia. Microscopy evaluation and culture of

tracheal secretions and/or expectorated sputum are also

frequently inconclusive for patients clinically suspected

of having pneumonia, because the upper respiratory tract

*The authors declare no conflict of interest.

#Corresponding author.

A. ABD EL HALIM ET AL.

of most patients in the ICU is colonized with potential

pulmonary pathogens, whether or not parenchymal pul-

monary infection is present [3]. Procalcitonin (PCT) is a

peptide precursor of the hormone calcitonin, the latter

being involved with calcium homeostasis. It is composed

of 116 amino acids and is produced by parafollicular

cells (C cells) of the thyroid and by the neuroendocrine

cells of the lung and the intestine. The level of procalci-

tonin raises in a response to a proinflammatory stimulus,

especially of bacterial origin [4]. Measurement of pro-

calcitonin can be used as a marker of sepsis caused by

bacteria and generally grades well with the degree of sep-

sis [5]. PCT has the greatest sensitivity (85%) and speci-

ficity (91%) for differentiating patients with systemic

inflammatory response syndrome (SIRS) from those with

sepsis [6].

The aim of the work: was to clarify the role of the

serum procalcitonin in the diagnosis and the prognosis of

ventilator associated pneumonia.

2. Subjects and Methods

This study was conducted at the ICU of King Fahad Spe-

cialist Hospital, Dammam, Kingdom of Saudi Arabia.

The study was approved by Ethics and Research Com-

mittee. All patients or their families and control subjects

gave their written informed consent before participating

in the study. This study included 3 groups of subjects (Ta-

ble 1):

Group 1: It included 42 VAP patients that were ad-

mitted at the ICU. The mean age was 58.09 ± 13.07 years.

There were 27 (64.28%) males and 15 (35.72%) fe-

males.

Group 2: It included 20 non VAP-ICU admitted pa-

tients (on mechanical ventilation). The mean age was

56.90 ± 10.54 years. There were 12 (60%) males and 8

(40%) females.

Group 3: It included 20 healthy control subjects. The

mean age was 53.85 ± 11.26 years. There were 13 (65%)

males and 7 (35%) females.

The three groups were matched for age and sex (p val-

ue > 0.05)

All subjects included in this study were undergone for

the following:

1) Complete history taking and thorough physical ex-

amination.

2) Chest x ray examination.

3) Complete blood picture (CBC), C reactive protein

(CRP), liver and kidney functions tests.

4) Arterial blood gases analysis (ABGs).

5) Acute Physiology and Chronic Health Evaluation II

(APACHE II) score was calculated for patient groups

only.

6) The Sequential Organ Failure Assessment score

Table 1. Some basal characteristic data for the subjects in-

cluded in this study.

VAP patients

(No = 42)

Non VAP

patients

(No = 20)

Healthy

Subjects

(No = 20)

Age (Mean ±SD)

Sex (Male/Female)

CRP (mg/L)

WBC (×103/µL)

APACHE II

SOFA

58.09 ± 13.07

27/15

160.4 ± 4.7

14.5 ± 3.53

24.11 ± 4.57

7.88 ± 2.92

56.90 ± 10.54

12/8

28.53 ± 2.6

9.6 ± 0.45

16 ± 3.25

3.56 ± 2.04

53.85 ± 11.26

13/7

5.38 ± 1.1

6.5 ± 1.04

Associated conditions

COPD

Renal failure

Heart diseases

Malignancy

Neurologic diseases

Liver cirrhosis

(SOFA) was calculated for patient groups only.

7) The Clinical Pulmonary Infection Score (CPIS) was

calculated for patient groups only.

8) Measurement of procalcitonin: this was done in all

subjects included in this study. Blood samples were taken

and the sera were separated and stored at −80˚C for fur-

ther procalcitonin analysis. Procalcitonin levels were

determined with the commercially available automated

immunochemistry method (Brahms Kryptor, Brahms Li-

aison, Berlin, Germany) [7]. For VAP patients; PCT

measurement was done on the first day of diagnosis (for

comparisons with other subject groups) and then repeated

on the 5th day of diagnosis.

Pneumonia was classified as VAP if it occurred after

48 hours of mechanical ventilation and was not incu-

bated before the initiation of the mechanical ventilation.

Early-onset VAP was defined as that occurring during

the first 4 days on mechanical ventilation, whereas VAP

developed thereafter was classified as late-onset [8]. A

diagnosis of pneumonia was suspected when a new, per-

sistent infiltrate, consolidation, cavitation or pleural effu-

sion was seen on chest X-rays and at least two of the fol-

lowing were observed: a body temperature below 36˚C

or above 38˚C; a white blood cell count lower than

4000/mm3 or higher than 11,000/mm3; and macroscopi-

cally purulent tracheal aspirate. Tracheal aspirate was

classified as purulent or non purulent after visual inspec-

tion. Tracheal aspirate for quantitative culture had been

obtained before antimicrobial treatment was started. Tra-

cheal aspirate cultures yielding ≥105 CFU/ml were con-

sidered positive. We calculated the clinical pulmonary

infection score (CPIS). Patients were assumed to have

VAP when the CPIS was >6. Patients received a diagno-

sis of VAP only after other medical conditions to which

the presenting symptoms, signs or radiological findings

could be attributed had been ruled out. For all patients in

A. ABD EL HALIM ET AL. 75

whom the clinical suspicion of VAP was confirmed, em-

pirical antimicrobial therapy was started immediately and

modified after culture results if needed. Patients were

followed until resolution of pneumonia or death [9].

2.1. Exclusion Criteria

Any patient has any one of the followings was excluded

from this study: 1) Age below 18 years; 2) The develop-

ment of pneumonia within 48 hours of beginning of me-

chanical ventilation; 3) Evidence of bacterial infection

elsewhere; 4) Immunosuppression; 5) Expected early

death.

2.2. Statistical Analysis

Statistical analysis was performed with the Statistical

Package for the Social Sciences, version 16 for Windows

(SPSS Inc., Chicago, IL, USA). Values of p < 0.05 were

considered statistically significant.

3. Results

The total duration of mechanical ventilation among pa-

tients with VAP was 15.35 ± 9.21 days compared with

10.67 ± 8.52 days in patients without VAP (p value <

0.01). There were 15 (35.71%) early onset VAP patients

and 27 (64.29%) late onset VAP patients. The causative

microbes among VAP patients were shown in Table 2.

There was a highly statistically significant difference

(p value < 0.001) between VAP patients on one side and

both non VAP-ICU patients and healthy control subjects

on the other side regarding the mean values of PCT (1.54

± 0.50 ng/ml among VAP patients, 0.06 ± 0.03 ng/ml

among non VAP patients, and 0.04 ± 0.02 ng/ml among

healthy control subjects) (Table 3 and Figure 1). No

statistically significant difference (p value > 0.05) in the

mean values of PCT was present between non VAP-ICU

patients and healthy control subjects (0.06 ± 0.03 ng/ml

among non VAP patients and 0.04 ± 0.02 ng/ml among

healthy control subjects) (Table 3 and Figure 1).

22 (52.38%) patients out of 42 VAP patients survived

while 20 (47.62%) patients died. No patient died in the

first 5 days after diagnosis. The mean values of PCT

were statistically significantly higher (p value < 0.001)

among died VAP group than the survivor VAP group on

both first day (1.92 ± 0.41 ng/ml vs 1.19 ± 0.29 ng/ml

respectively) and 5th day measurements (4.49 ± 0.59

ng/ml vs 0.81 ± 0.21 ng/ ml respectively) (Table 4 and

Figure 2). The mean values of PCT increased signify-

cantly from (1.92 ± 0.41 to 4.49 ± 0.59) among died

group while decreased significantly from (1.19 ± 0.29 to

0.81 ± 0.21) among the survivor group on repeated test-

ing on the 5th day in comparison with the first day meas-

urement (Table 4 and Figure 2). There was a high statis-

tically positive correlation (p value < 0.01) between mor-

Table 2. The microbiological profile among the VAP pa-

tients.

Microbes No of the VAP patients (%)

Staphylococcus aureus

Pseudomonas aeruginosa

Klebsiella pneumoniae

Haemophilus influenzae

Acinetobacter

Enterobacter

Proteus

Serratia

Mixed

Unidentified

7 (16.67%)

5 (11.91%)

4 (9.52%)

3 (7.14%)

2 (4.76%)

1 (2.38%)

2 (4.76%)

16 (38.10%)

Table 3. Comparison between the different subject groups

regarding initial PCT levels (ng/ml).

PCT (ng/ml)

Groups ( No) MinimumMaximum Mean ± SD p value

1. VAP patients

(No = 42) 0.65 2.82 1.546 ± 0.5091 vs 2 <

0.001

2. Non VAP

patient (No = 20)0.01 0.12 0.061 ± 0.0361 vs 3 <

0.001

3. Healthy control

subjects (No = 20)0.01 0.09 0.0438 ± 0.0272 vs 3 >

0.05

Table 4. Comparison of some measurements between the

survivor and died groups among VAP patients.

Outcome APACHEII SOFA CPIS PCT 1

(ng/ml)

PCT 5

(ng/ml)

Survivors

(No=22)

(Mean ± SD)

22.31 ±

3.73

6.40 ±

2.90

7.68 ±

1.04

1.198 ±

0.29

0.81 ±

0.21

Died

(No = 20)

(Mean ± SD)

26.10 ±

4.66

9.50 ±

1.69

9.25 ±

2.02

1.92 ±

0.41

4.49 ±

0.59

p value p < 0.01p < 0.001 p < 0.01 p < 0.001p < 0.001

tality prediction scores (APACHE II (R = 0.449), CRIP

(R = 0.403) and SOFA (R = 0.437)) and initial PCT se-

rum levels.

4. Discussion

In this study, there was a highly statistically significant

difference (p value < 0.001) between VAP patients on

one side and both non VAP-ICU patients and healthy

control subjects on the other side regarding the mean

values of PCT (1.54 ± 0.5 ng/ml among VAP patients,

0.06 ± 0.03 ng/ml among non VAP patients, 0.04 ± 0.02

ng/ml among healthy control subjects). These results are

in agreement with that of other investigators. Lee JY, et

al., [10] found that the PCT level in the patients with

pneumonia (2.06 ± 0.60 ng/ml) was significantly higher

than that in the healthy controls (0.05 ± 0.02 ng/ml). In

case-control study carried out by Polzen et al., [11]

which included 26 patients with pneumonia found higher

PCT levels among pneumonia patients with a cut-off of

A. ABD EL HALIM ET AL.

Figure 1. Comparison between the different subject groups re-

garding initial PCT levels (ng/ml).

PCT 1

day PCT 5

day

Figure 2. Comparison of the mean PCT levels between the survivor

and died groups among VAP patients (first and 5th days respec-

tively).

0.5 ng/ml. Another study done by Müller and his col-

leagues [12] with a cohort of 373 subjects demonstrated

that PCT with an AUC of 0.85 (0.80 - 0.91) was associ-

ated with a diagnosis of pneumonia and that PCT im-

proved the ability of clinical findings to diagnose pneu-

monia (p < 0.001). This study postulated that a PCT <

0.1 ng/ml indicates another diagnosis than pneumonia

even with an infiltrate on X-ray. Bafadhel et al. [13] con-

ducted a cohort trial with 319 patients of whom 96 had

pneumonia. Patients with pneumonia had a higher PCT

(p < 0.0001) than those with acute exacerbation of

chronic obstructive pulmonary disease (AECOPD). At a

cut-off of 0.08 ng/ml, PCT had an AUC of 0.93 (0.88 -

0.98) for differentiation between pneumonia and COPD;

sensitivity 89% (95% CI 78 - 95) and specificity 78%

(95% CI 72 - 82). Likewise Seligman and his group [14]

found the biomarkers procalcitonin, MR-proANP, and

copeptin are increased among VAP patients and can pre-

dict mortality in VAP, as can the SOFA score. Procalci-

tonin alone has the greatest predictive power for such

mortality.

There are accumulating data that explain our and other

researchers’ results. The investigations identified PCT as

part of the complex pro-inflammatory response of the

innate immune system [15]. In vitro stimulation of

macrophages with either bacteria or endotoxin results in

rapid synthesis and release of PCT within 4 hours [16].

In a hamster model of Escherichia coli peritonitis, tran-

scription and translation of PCT synthesis was demon-

strated in virtually all organs tested and in macrophages

[17]. In vitro , endotoxin stimulated adipocytes to synthe-

size PCT in the absence of macrophages, but synthesis

was augmented if adipocytes were incubated with en-

dotoxin-sensitized macrophages [18]. PCT differs from

other biomarkers of the invasion by bacterial pathogens

by several aspects. Serum PCT serum levels are detect-

able as early as 3 - 4 h after invasion, which is much ear-

lier than the increase in the C-reactive protein level or

erythrocyte sedimentation rate [19]. Also, elevated PCT

levels have not been noted for other inflammatory condi-

tions, such as acute respiratory distress syndrome, pol-

yarteritis nodosa, systemic lupus erythematosis [8-20].

Available data also indicate that PCT levels are not in-

fluenced by therapy with glucocorticoids or nonsteroidal

anti-inflammatory agents. PCT levels do not increase in

patients with infection due to respiratory viruses [15].

Our study revealed that the mean values of PCT were

statistically significantly higher (p value < 0.001) among

died VAP group than the survivor VAP group on both first

day (1.92 ± 0.41 ng/ml vs 1.19 ± 0.29 ng/ml respectively)

and 5th day measurements (4.49 ± 0.59 ng/ml vs 0.81 ±

0.21 ng/ml respectively). Other studies found similar

results. Duflo et al. [21] found PCT was significantly

elevated in non-survivors: the best cut-off for serum PCT

in the non-survivors in the VAP group was 2.6 ng/ml

with a sensitivity of 74% and a specificity of 75%. Like-

wise, Luyt et al. [22] found high median PCT levels of

about 3 ng/ml at Day 1 in patients with unfavorable out-

comes during the clinical course of microbiologically

proven VAP (n = 63). These results are explained intui-

tively by that the severe and non respondent pneumonia

among the died patients are associated with high bacte-

rial and toxin loads that stimulate excess release of the

PCT.

In this study the mean values of PCT increased signi-

ficantly (from (1.92 ± 0.41 to 4.49 ± 0.59) among died

group while decreased significantly (from 1.19 ± 0.29 to

0.81 ± 0.21 among the survivor group on repeated testing

on the 5th day in comparison with the first day measure-

ment. Other studies showed similar results. Harbarth et

al., [23] and Jensen and his colleagues [24] found that

unsuccessful source control and poor outcome is associ-

ated with persistent elevated PCT levels. Also Bloos et

al., [25] found that high PCT levels are associated with

increased severity of illness in patients with severe pneu-

monia and appears to be a prognostic marker mortality

comparable to the APACHE II score. These results are

explained by that the severe and non respondent pneu-

A. ABD EL HALIM ET AL. 77

monia among died patients are associated with sustained

high bacterial and toxins load that stimulate a continuous

release of the PCT. While survivors are associated with

continuous decrease of bacterial and toxin load with less

stimulation of PCT release.

Our study found a statistically positive correlation (p

value < 0.01) between mortality prediction scores

(APACHE II (R = 0.449), CRIP (R = 0.403) and SOFA

(R = 0.437)) and initial PCT serum levels. Similar ob-

servations were reported by Meisner et al., [26] and by

Schroder et al., [27] in critically ill patients. Hedlund et

al., [28] showed that the severity of disease measured by

the APACHE II score was strongly associated with ad-

mission levels of PCT in 96 adult patients with CAP. In

study included 110 patients with pneumonia, Bousse-

key et al., [29] found higher PCT levels in bacteremic

patients and/or septic shock patients (4.9 ng/ml vs 1.5

ng/ml) and in patients who developed infection-related

complications (septic shock, multiorgan dysfunction,

acute respiratory distress syndrome and disseminated

intravascular coagulation) during their ICU stay. Like-

wise, Bloos et al., [25] found a significant association

between PCT levels and organ dysfunction as assessed

by the SOFA score. These results suggest that the PCT

level can be used as a prognostic factor among VAP pa-

tients.

There were some limitations in this study. The number

of subjects was small and therefore a study on a larger

number of subjects is needed.

5. Conclusion

This study found that the increased PCT serum level is

an important diagnostic tool for VAP and the PCT serum

levels can predict the outcome of VAP patients. We

recommend other larger studies to augment our findings.

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