American Journal of Emergency Medicine (2012) 30, 1248-1254

Brief Report

The value of procalcitonin level in community-acquired pneumonia in the ED^?,??

Jeong Ho Park MD, Jung Hee Wee MD, Seung Pill Choi MD, PhD?, Sang Hoon Oh MD

Department of Emergency Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea The Catholic University of Korea, Yeouido St Mary’s hospital, Seoul 150-713, Korea

Received 18 July 2011; revised 11 August 2011; accepted 12 August 2011

Abstract

Objectives: The aim of this study was to investigate the value of procalcitonin level in patients with community-acquired pneumonia in the emergency department (ED).

Methods: We conducted a prospective study of patients with CAP in the ED. Patients presenting with a clinical and radiographic diagnosis of CAP were enrolled. The authors measured inflammatory biomarkers. The severity of CAP was assessed by 3 prediction rules. We performed an analysis to assess the value of each biomarker for the prediction of mortality and CAP severity.

Results: A total of 126 patients with CAP are included. Sixteen patients who were older and belonged to high-risk group died within 28 days. Nonsurvivors had significantly increased median PCT level (1.96 vs 0.18 ng/mL) and high-sensitivity C-reactive protein (158.57 vs 91.28 mg/dL) compared with survivors. The median PCT levels were significantly higher in more severe disease, on 3 prediction rules. In regression logistic analyses, the area under the receiver operating characteristic curve of PCT level were 0.828 (95% confidence interval, 0.750-0.889). The addition of PCT level to three prediction rules significantly increased the area under the receiver operating characteristic curve. These results suggest that PCT measurement is more versatile tool for predicting mortality and the Severity of disease among patients with CAP in the ED.

Conclusions: Procalcitonin level is valuable for predicting mortality and the severity of disease among patients with CAP at ED admission. Procalcitonin level as an adjunct to CAP prediction rules may be valuable for prognosis and Severity assessment.

(C) 2012

Introduction

Community-acquired pneumonia is an important health problem and a common disease that frequently leads to hospitalization and death. The assessment of disease severity

^? Prior presentations: American College of Emergency Medicine Scientific Assembly 2010, Las Vegas, NV, September 2010.

^?? Funding sources/disclosures: None.

* Corresponding author.

E-mail address: [email protected] (S.P. Choi).

and outcome prediction are necessary for adequate allocation of Health care resources and therapeutic options in manage- ment of CAP. For accurate assessment, professional organi- zations have developed prediction rules and propagated guidelines to stratify patients with CAP based on the predicted risk of mortality. The pneumonia severity index developed in the United States is a well-validated scoring system that assesses the risk of death in a 2-step algorithm [1,2]. In Europe, the CURB65 (confusion, urea N7 mmol/L, respiration rate >=30 breaths per minute, low blood pressure [systolic value b90 mm Hg or diastolic value <=60 mm Hg],

0735-6757/$ – see front matter (C) 2012 doi:10.1016/j.ajem.2011.08.009

and age >=65 years) score was developed mainly as a means of identifying patients with severe CAP at a high-risk mortality [3]. The Infectious Disease Society of America and the American Thoracic Society (ATS) issued guidelines, which defined severe CAP when 1 of 2 major criteria (the need for invasive mechanical ventilation or vasopressors) or

3 of 9 minor criteria (respiration rate >=30 breaths/min, PaO2/FiO2 <=250, multilobar infiltrates, confusion, serum urea nitrogen level >=20 mg/dL, white blood cell [WBC] count

<=4000 cells/mm³, platelet count <=100 000 cells/mm³, core temperature b36?C, hypotension requiring aggressive fluid resuscitation) are fulfilled [4]. Each of the prediction rules has advantage, and the tools have been extensively studied and repeatedly validated [5-8]. However, they have some limitations and may not be practical for routine application in a busy hospital emergency department (ED).

Additional Prognostic biomarkers potentially enhance the prognostic performance of these established risk score in patients with CAP. Several inflammatory biomarkers, such as WBC counts, C-reactive protein (CRP), and erythrocyte sedimentation rate , are traditionally used in the evaluation of infections. However, the value of these biomarkers remains very limited. The common problem for these biomarkers is their nonspecific nature, and the correlation between biomarkers and the severity of disease is not always clear [9]. procalcitonin has recently emerged as a promising alternative. Procalcitonin is a peptide precursor of the hormone calcitonin and rises in response to inflammatory stimulus. Procalcitonin has been proposed as a marker of bacterial infection in ill patients. In bacterial infection and sepsis, its level is related to the severity [10]. Several recent investigations used PCT level in serum to measure CAP severity and to predict outcome. Masia et al

[11] suggest that PCT contribution to the evaluation of patients with CAP varies according to severity of pneumo- nia. Boussekey et al [12] were unable to find a PCT level to predict mortality; a significant and positive relationship between the initial PCT level and the mortality rate was observed. In Geriatric patients, PCT level may be a promising parameter for estimating the severity of CAP [13]. In children, serum PCT level was a better marker than CRP level or ESR for diagnosis of lobar pneumonia [14]. Although many studies focused on severity and mortality of CAP, however, only a few studies directly compare the value of PCT and other inflammatory biomarkers on CAP.

The aim of this study was to investigate the predictive value of PCT level compared with conventional inflamma- tory biomarker and prediction rules. Second, we analyzed the correlation of PCT level and the prediction rules compared with inflammatory biomarkers.

Methods

We conducted a single-center, prospective, observational study of patients presenting to the ED. The study was

approved by the institutional research ethics board of the hospital. Individual consent was not required by the institutional research ethics board because the results were obtained during the course of treatment.

The current study was carried out in hospital, a 500-bed teaching hospital. The study was conducted between May 2009 and August 2010 in ED, with an annual census of 28 000 visits. Eligible subjects were older than 18 years. Community-acquired pneumonia was defined as a new pulmonary infiltrate diagnosed by chest radiograph together with at least 1 respiratory symptom (fever, cough, sputum production, dyspnea, tachypnea, and pleuritic pain). Patients who were hospitalized within 14 days before the onset of symptoms or discharged home from the ED, immunocom- promised patients (with HIV infection or hematologic malignancies), and patients who were subsequently diag- nosed with tuberculosis were excluded.

Patients were examined on admission to the ED by a resident supervised by a board-certified specialist in emer- gency medicine. The testing physicians collected all patient information using a standardized data collection form. demographic factors and comorbid illnesses, including age, sex, diabetes mellitus and liver diseases, congestive heart failure, cerebrovascular disease, renal failure, malignancy, coronary artery disease, lung disease, and hypertension, were evaluated. The first available physical examination findings were collected: altered mental status, pulse rate, respiration rate, blood pressure, and body temperature. Laboratory findings were collected: PCT level, ESR, high-sensitivity CRP (hs-CRP) level, WBC counts, hematocrit, platelet counts, blood urea nitrogen, sodium, blood glucose, arterial pH, arterial oxygen tension (PaO2), and oxygen saturation with the fraction of inspired oxygen (FiO2). radiologic findings were collected: pleural effusion and unilobular vs multilobular infiltrates. All data collection forms and medical records were reviewed by investigators to ensure accuracy. These data were used to determine PSI, CURB65, and IDSA/ATS guidelines for severe CAP.

The primary end point for this study was mortality within 28 days. At the end of the study, a specialist in pulmonology and emergency medicine physicians reviewed all data collection forms. Outcome was assessed at hospital dis- charge and by standardized telephone interviews blinded specialists in emergency medicine.

At the time of admission, venous blood was drawn from all the patients and transported immediately to the biochem- istry laboratory. Procalcitonin analyses were performed by laboratory technicians at the Departments of Laboratory Medicine using a chemiluminescence sandwich immunoas- say (Roche Diagnostics, Zurich, Switzerland). The direct measuring range of the assay is from 0.02 to 100 ng/mL. The functional assay sensitivity is 0.06 ng/mL.

The WBC count was determined by flow cytometry (TOA Medical Electronics, Kobe, Japan), according to the manufacturer’s instructions. The ESR was determined using a quantitative capillary photometry method (Alifax,

Padova, Italy). The hs-CRP was measured using an automatic biochemical analyzer (Hitachi High-Technolo- gies, Tokyo, Japan).

Statistical analysis was performed with SAS 9.1 (SAS Institute, Inc, Cary, NC). The ?2 and Fisher exact tests were used for categorical variables. The Student t test, Wilcoxon rank sum test, Kruskal-Wallis test, and 1-way analysis of variance were used for continuous variables and expressed as the mean (SD) or median (interquartile range). The correlation was analyzed using Spearman ? correlation analysis.

To predict 30-day mortality, multivariable logistic regression was performed for several combinations. The logistic regression models included WBC count, ESR, hs- CRP, and PCT as independent variables and were adjusted for the PSI, CURB65, or IDSA/ATS guidelines.

For each regression logistic model, the area under the receiver operating characteristic (ROC) curve (AUC) was calculated for a 28-day Mortality prediction. For all tests, P b

.05 was considered statistically significant.

Table 1 Characteristics and initial severity of the prediction rules with and without mortality 28-days mortality

Results

Characteristics of the study population

A total of 126 patients with a definite diagnosis of CAP are included in the analysis. Most patients were male (52%). The mean age of the patients at the time of study enrollment was 64 years. The main demographic characteristics, comorbid- ity, and initial severity, measured by the 3 prognostic scales (the PSI, CURB65, and IDSA/ATS guidelines), are shown in Table 1.

Approximately 16% of patients were classified as high- risk groups by CURB65 score (classes 2-5) and the IDSA/ATS guidelines (minor criteria >=3 or any major criteria). However, around 44% of patients were classified as high-risk groups by PSI score (class IV or V). Patients who died were older and had more liver disease and high initial severity; in addition, more intensive care unit (ICU)- hospitalized patients died.

Survivor, n = 110 (87.30%)		Nonsurvivor, n = 16 (12.70%)	P
Characteristic
Age, mean (SD)	62.4 (17.64)	75.69 (10.77)	b.01
Sex, female/male (%)	5/60 (45.45/54.55)	11/5 (68.75/31.25)	.08
Comorbidity, n (%)
DM type 2	29 (26.36)	4 (25.00)	.99
Liver disease	1 (0.91)	2 (12.5)	.04
CHF	3 (2.73)	0 (0.00)	.99
Cerebrovascular disease	22 (20.00)	4 (25.00)	.74
Renal failure	8 (8.27)	1 (6.25)	.99
Malignancy	18 (16.36)	5 (31.25)	.17
Coronary artery disease	11 (10.00)	1 (6.00)	.99
Lung disease	23 (0.91)	3 (18.75)	.99
Hypertension	51 (46.36)	9 (56.25)	.46
PSI, n (%)			b.01
I	26 (23.64)	0 (0.00)
II	23 (20.91)	0 (0.00)
III	21 (19.09)	1 (6.25)
IV	28 (25.45)	4 (25.00)
V	12 (10.91)	11 (68.75)
CURB65 score, n (%)			b.01
0	38 (34.55)	0 (0.00)
1	63 (57.27)	5 (31.25)
2	7 (6.36)	6 (37.50)
3	2 (1.82)	3 (18.75)
4	0 (0.00)	2 (12.50)
5	0 (0.00)	0 (0.00)
IDSA/ATS guideline, n (%)			b.01
Minor 0	39 (35.45)	1 (6.25)
Minor 1	46 (41.82)	2 (12.50)
Minor 2	15 (13.64)	2 (12.50)
Minor >=3	6 (5.45)	9 (56.25)
Major >=1	4 (3.64)	2 (12.50)
ICU admission, n (%)	13 (11.82)	14 (87.50)	b.01
Values are presented as n (%), unless otherwise indicated. DM indicates diabetes mellitus; CHF, congestive heart failure; PSI, pneumonia severity index.

	PSI				P
	I-II	III	IV	V
PCT (ng/mL) a	0.10 (0.06-0.19)	0.40 (0.14-1.62)	0.61 (0.13-1.37)	2.21 (0.43-8.49)	b.01
hs-CRP (mg/L) a	67.91 (38.45-134.97)	125.84 (76.30-204.94)	78.67 (27.16-224.60)	153.97 (87.08-227.93)	.02
ESR (mm/h) b	62.45 (30.01)	55.95 (33.34)	69.38 (33.12)	66.96 (34.35)	.47
WBC count (/mm3) b	11,725 (6,646)	12,972 (5,559)	13,006 (6,662)	11,303 (5546)	.65
	CURB65 score				P
	0-1	2	>=3
PCT (ng/mL)	0.19 (0.08-0.96)	1.03 (0.25-2.59)	4.75 (2.27-23.56)	b.01
hs-CRP (mg/L)	95.92 (44.67-169.05)	84.29 (26.18-161.72)	155.61 (98.49-295.33)		.23
ESR (mm/h)	63.57 (31.08)	60.15 (41.82)	75.86 (60.42)		.56
WBC count (/mm3)	12 036 (6126)	13 126 (7327)	12 798 (5133)		.81
	IDSA/ATS guideline				P
	Minor 0-1	Minor 2	Minor >=3 and major >=1
PCT (ng/mL)	0.14 (0.08-0.69)	1.01 (0.74-1.62)	2.27 (0.53-8.19)		b.01
hs-CRP (mg/L)	79.81 (38.27-157.03)	108.76 (36.64-250.36)	140.45 (98.49-202.42)		.08
ESR (mm/h)	65.78 (31.62)	52.06 (26.76)	65.57 (37.42)		.27
WBC count (/mm3)	12 585 (5771)	12 025 (7823)	10 673 (6404)		.44

CAP severity and mortality

Table 2 The severity of CAP and inflammatory biomarkers

^a Data are presented as median (interquartile range).

^b Data are presented as mean (SD).

The median was significantly higher in more severe disease cases for PCT level on 3 prediction rules. The PCT level of the PSI scores I and II was 0.10 ng/mL; the PCT level of the PSI score V was 0.61 ng/mL. The PCT level that correlated with CURB65 scores of 0 and 1 was 0.19 ng/mL; the PCT level that correlated with a CURB65 score of 3 or higher was 4.75 ng/mL. The PCT level for IDSA/ATS minor criteria 0 and 1 was 0.14 ng/mL; the PCT level for 3 or higher IDSA/ATS minor criteria and any major criterion was

1.54 ng/mL. These differences were statistically significant (P b .01). High-sensitivity CRP level and ESR increased with increasing severity. However, we did not find a significant

difference for any conventional inflammatory biomarkers (Table 2).

Nonsurvivors had significantly increased median PCT level on admission compared with survivors (1.96 vs 0.18 ng/mL; P b .01). High-sensitivity CRP level on admission was also increased (158.57 vs 91.28 mg/dL; P b .01). However, ESR and WBC count were not increased (Table 3).

A correlation analysis of biomarkers with initial severity showed that PCT level had the highest positive correlation with the PSI, CURB65, and IDSA/ATS guidelines. The PCT level had a positive correlation with the PSI (?, 0.51; P b

.01), CURB65 (?, 0.43; P b .01), and IDSA/ATS guidelines (?, 0.44; P b .01). High-sensitivity CRP level also showed a low positive but significant correlation with the PSI, CURB65, and IDSA/ATS guidelines (Table 4).

Table 3 Inflammatory biomarkers with and without mortality 28-day mortality

Table 4 Correlation between inflammatory biomarkers and prediction rules

Prediction rules Biomarkers

PCT hs-CRP ESR WBC count

Survivor (n = 110)		Nonsurvivor P (n = 16)
PCT (ng/mL) a	0.18 (0.08-0.97)	1.96 (0.96-6.54) b.01
hs-CRP (mg/L) a	91.28	158.67 b.01
	(38.09-158.98)	(103.83-242.80)
ESR (mm/h) b	63.27 (31.17)	68.19 (39.13) .57
WBC count (/mm3) b	12 476 (6190)	10 239 (5853) .18
a Data are presented as median (interquartile range). b Data are presented as mean (SD).

PSI	0.51	0.22	0.12	0.08	?
	b.01	.01	.18	.38	P
CURB65 score	0.43	0.18	0.09	0.13	?
	b.01	.04	.30	.15	P
IDSA/ATS guideline	0.44	0.21	-0.09	-0.08	?
	b.01	.02	.34	.37	P

Prognostic value of PCT level to predict CAP mortality

In ROC curve analysis for the prediction of 30-day mortality, initial PCT level had an AUC of 0.828, which was significantly higher compared with conventional inflamma- tory biomarkers (Fig. 1). The AUCs of hs-CRP, ESR, and WBC count were 0.695, 0.550, and 0.587. Three prediction rules had an AUC of 0.875 (PSI), 0.864 (CURB65), and 0.844 (IDSA/ATS guidelines). This is similar to the AUC observed for PCT level. The AUCs of different logistic models with combinations of markers added to any of the prediction rules were calculated. The AUC of PCT level to predict mortality increased significantly when the PCT level was added to the 3 prediction rules. Upon combination of PCT level and the prediction rules, AUC increased from 0.828 to 0.903 (PSI), 0.810 (CURB65), and 0.868

(IDSA/ATS guidelines).

The prognostic value of PCT level to predict mortality with a cutoff point of 0.35 ng/mL reaches a sensitivity of 68.75%, a specificity of 92.73%, a positive predictive value of 57.90%, and a negative predictive value of 95.30%.

Procalcitonin in positive blood cultures

Bacteremia was present in 16 patients (12.7%): Staphy- lococcus aureus, n = 3 (18.75%); Klebsiella species, n = 3 (18.75%); Escherichia coli, n = 2 (12.5%); Streptococcus pneumoniae, n = 3 (18.75%); Staphylococcus epidermis,n = 4 (25%); and other, n = 1 (6.25%). Bacteremic patients had significantly higher levels of PCT and hs-CRP (Table 5).

Fig. 1 Prognostic value of inflammatory biomarkers for CAP. The ROC curves for prognostic value of inflammatory biomarkers to predict mortality of CAP. Sky line, PCT (AUC, 0.828); black line, hs-CRP (AUC, 0.695); blue line, WBC count (AUC, 0.587); green line, ESR (AUC, 0.550).

PCT (ng/mL) a	0.19 (0.08-0.97)	1.54 (0.98-8.34)	b.01
hs-CRP (mg/L) a	91.28	180.72	b.01
	(38.09-156.89)	(119.95-272.85)
ESR (mm/h) b	64.56 (31.50)	59.31 (37.12)	.54
WBC count (/mm3) b 11 949 (5936)		13 859 (7603)	.25

Discussion

Table 5 Inflammatory biomarkers with and without bacteremia

blood culture results

Negative Positive P

(n = 110, 87.3%) (n = 16, 12.7%)

^a Data are presented as median (interquartile range).

^b Data are presented as mean (SD).

The purpose of this study is to measure the value of PCT level to predict mortality of CAP. For this single-center study, PCT level at ED admission had Prognostic ability to predict 28-day mortality of CAP. Procalcitonin levels significantly improved prediction rules, such as the PSI, CURB65, and IDSA/ATS guidelines, in combined logistic regression analysis.

Prediction of CAP related mortality may be relevant to initial severity as evaluated with the prediction rules. The PSI identified the patients with CAP who were at low risk for death and other adverse outcomes, but it has practical limitations related to its complexity, which may restrict its widespread adoption. The CURB65 score can be used to stratify patients with CAP into different management groups and can be further simplified to include only data obtained by clinical examination. However, this measure does not generally account for comorbid illness and may not be easily applied in older patients who may still have a substantial mortality risk. The IDSA/ATS guidelines predict hospital mortality and guide ICU admission for inpatients with CAP. However, the use of this measure is limited to patients with severe CAP.

The results of a recent study suggest that serum biomarkers, such as PCT level, can be used to measure CAP severity and to predict outcome. Muller et al [15] found that PCT level improves the diagnostic value of the clinical assessment. Procalcitonin level has been used upon admis- sion to predict subsequent bacteremia findings and to assess the severity of CAP. A study from the CAPNETZ Study Group reported that PCT levels on admission predict the severity and outcome of CAP and involve a higher Prognostic accuracy compared with CRP level and WBC count [16]. Conversely, the ProHOSP Study Group found that initial PCT level provides only moderate prognostic information concerning mortality risk and did not improve clinical risk scores [17].

Our finding clarifies the value of PCT level upon ED admission in predicting the severity and mortality from CAP. This compares with the value of conventional inflammatory

biomarkers. Previous studies found that although PCT level was a good predictor of CAP severity, CRP level and WBC count were not correlated with the severity of CAP [18-21]. A direct comparison of ESR and WBC count upon admission reveals no correlation in either of the 2 groups of patients. Although CRP levels were correlated with mortality and each prediction rule, they were unrelated to the initial severity on prediction rules. Procalcitonin level correlated more strongly not only with initial severity but also in the prediction of mortality from CAP.

The prognostic value for 28-day mortality prediction was assessed with the estimation of AUCs obtained with logistic regression models. Menendez et al [22] confirm that adding CRP level to prediction rules improves the 28-day mortality prediction. We have found similar results. First, adding hs- CRP and PCT level to 3 prediction rules improves the 28-day mortality prediction. Second, the highest predictive value is reached with a combination of CURB65 score and PCT, hs- CRP level. However, we have found some differences. First, PCT level significantly improved the prognostic value of

3 prediction rules. Second, hs-CRP was statistically significant, but AUC was lower than the PCT level.

The prognostic value of PCT level to predict mortality with a cutoff point is 0.35 ng/mL. Previous studies suggest that using a cutoff value of 0.5 ng/mL serum PCT, patients with

0.5 ng/mL or higher had significantly shorter survival than those with less than 0.5 ng/mL [21,23]. This is similar to our findings, and we should be verified through further research.

The criterion standard for the detection of bacteremia continues to be the performance of at least 2 blood cultures. However, the usefulness and cost-effectiveness of this practice have been criticized. Serum PCT is a marker of systemic inflammation, and thus, it may help to predict bacteremia. Recent studies found that PCT level, CRP level, and ESR were significantly higher in bacteremic patients than in nonbacteremic patients [24,25]. Our study found that bacteremic patients with CAP had higher levels of PCT. Laboratory values such as CRP level were also higher in bacteremic patients. However, ESR and WBC count did not differ in any significant way. We analyzed 16 patients with positive blood cultures according to the causative agent. The mean PCT level in S epidermis-positive patients and other agents-positive patients was 1.78 and 8.19 ng/mL. However, there was no statistically significant.

Limitations

This study had several limitations that must be considered in relation to these findings. First, the relatively small scale of research has been an obstacle in generalizing the results of the study. Secondly, information on antibiotic use was excluded; we did not discuss in detail the possible causal relationship between antibiotics and PCT level. In addition, we used PCT level only upon ED admission; therefore, the

PCT level may not represent the peak PCT level among these patients.

Conclusions

Procalcitonin level is more valuable than conventional biomarkers for predicting the mortality and severity of CAP upon ED admission. Procalcitonin level may be valuable as an adjunct to CAP prediction for prognosis and severity assessment.

Acknowledgments

This work was supported by the CMC Clinical Research Coordinating Center, The Catholic University of Korea. The authors thank the center for assistance with the statistical analysis.

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