- Email: [email protected]
The prognostic utility of plasma osteopontin in CAP patients
Egyptian Journal of Chest Diseases and Tuberculosis 66 (2017) 713–715
Contents lists available at ScienceDirect
Egyptian Journal of Chest Diseases and Tuberculosis journal homepage: www.sciencedirect.com
The prognostic utility of plasma osteopontin in CAP patients Ahmed Sh. Mohamed a, Ibrahim S. Ibrahim a, Ragia S. Sharshar b,⇑, Amira Y. Abd El-Naby c a
Chest Department, Faculty of Medicine, Tanta University, Tanta, Egypt Chest Department, Tanta University, Tanta, Egypt c Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt b
a r t i c l e
i n f o
Article history: Received 18 September 2017 Accepted 16 October 2017 Available online 31 October 2017 Keywords: Community acquired pneumonia Severity indices Osteopontin
a b s t r a c t Background: Osteopontin (OPN) is a soluble cytokine glycoprotein widely expressed in many benign and malignant conditions. Purpose of study: was to investigate role of plasma OPN as new biomarker affects prognosis in CAP. Methodology: study was done on 50 subjects divided into 2 groups each 25, CAP (group I), healthy controls (group II). Plasma OPN levels were measured on initial hospitalization and after 3 days of treatment and correlated to severity of CAP by CRP and CURB-65. We concluded that: plasma levels of OPN is increased in pneumonia patients than in healthy controls also before than after 3 days of treatment of CAP. OPN levels significantly correlated with CURB-65 scores but not with CRP levels. Thus, OPN can be used as a novel additional marker, reflecting severity and response to treatment in CAP. Ó 2017 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction
Objective
In community acquired pneumonia (CAP), management is mainly based on severity assessment; helping the most important decision of treatment as an inpatient or outpatient [1,2]. However, the severity scoring tools may be too complicated and not practical. This made the use of blood biomarkers as a single test more interesting to asses severity and prognosis of CAP. To date, several molecules have been estimated as CRP, pro-calcitonin, and pro-vasopressin [3–6]. Osteopontin is phosphorylated glycoprotein found to be part of the extracellular matrix, also as circulating cytokine secreted by a different types of cell [7–9]. OPN is an activation, differentiation chemotactic factor for neutrophils, T lymphocytes and macrophages [10]. Osteopontin could be involved in the inflammatory response due to several pulmonary diseases as obstructive airways disorders, pneumonia, pulmonary fibrosis [11–13]. So, once such inflammatory diseases are diagnosed, OPN may be used to predict prognosis and assist the management.
This Study was designed to detect utility of plasma osteopontin as a severity and prognostic tool in CAP patients, and its correlation with CURB-65 score, CRP.
Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis. ⇑ Corresponding author. E-mail address: [email protected] (R.S. Sharshar).
Methodology Study population This prospective case-controlled study was conducted in Chest Department, Tanta University, from September 2016 to June 2017, and fulfilled the ethical committee considerations. 50 subjects were divided into: Group I: included 25 non-smoker CAP patients, diagnosed and managed according to IDSA/ATS guidelines [14], and their disease severity was assessed by CURB-65 score and CRP. Group II: included 25 non-smoker healthy controls who were matched (age and sex) with group I. Excluded patients including those with; concomitant cardiopulmonary, liver, renal and diabetes mellitus, increased risk of tuberculous or malignant pneumonia, and immunocompromized states. Blood Sampling: 2 ml venous blood clotted then centrifuged for 20 min and stored at 20 °C, for estimation serum CRP, 3 ml venous blood on EDTA, 1 ml for CBC & 2 ml for plasma divided into aliquots and frozen at 70 °C for Measurement of plasma OPN (ng/ ml) by using R&D system Quantikine ELISA kit for human OPN (Cat#SOST00). Ref range: 0.3–20 ng/mL.
https://doi.org/10.1016/j.ejcdt.2017.10.010 0422-7638/Ó 2017 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
714
A.Sh. Mohamed et al. / Egyptian Journal of Chest Diseases and Tuberculosis 66 (2017) 713–715
Table 1 Characteristic data of studied groups.
*
Variable
Group I (mean ± SD)
Group II (mean ± SD)
Test
P value
Age Sex (%) (m/f) OPN CRP WBC NEUTROPHILS
56.2 ± 11.2 15 (60%)/10 (40%) 74.12 ± 8.38 13.22 ± 2.07 13500 ± 2592.5 10700 ± 872.39
54.4 ± 9.9 17 (68%)/8 (32%) 13.65 ± 2.78 1.87 ± 0.92 5900 ± 505.68 3750 ± 464.07
t: 1.802 X2: 0.142 t: 28.942 t: 17.320 t: 11.144 t: 27.240
.645 .705 .001* .001* .001* .001*
Statistically significant.
Statistics Data were statistical analyzed using (SPSS) version 20.0. t-test was used. for quantitative data, expressed as mean ± SD, Chisquare (X2) test for qualitative data. Pearson’s correlation (r) test P < 0.05 was considered to be significant. Results The characteristic data of the studied groups were summarized in (Table 1). The mean values of CURB-65 scores in CAP patients were 1.8 ± 0.78, with 9 low, 10 moderate, and 6 high risk patients. Table 2 The mean values at baseline and after follow up in group I.
*
Variable
Before (mean ± SD)
After (mean ± SD)
Test
P value
OPN CRP WBC NEUTROPHILS
74.77 ± 7.69 13.22 ± 2.07 13500 ± 2592.5 10700 ± 872.39
38.69 ± 5.05 5.87 ± 1.13 8800 ± 1248.57 6250 ± 650.55
15.184 10.568 6.326 15.837
.001* .001* .001* .001*
The mean value of plasma Osteopontin levels were significantly higher in group I (74.12 ± 8.38 ng/ml) than in group II (13.65 ± 2. 78 ng/ml). Also, our results showed significant higher mean values of CRP (13.22 ± 2.078 vs. 1.87 ± 0.9 mg/dl), total WBCs (13500 ± 2593 vs. 5900 ± 505.7 cells/mm3), and neutrophils (10700 ± 872.39 vs. 375 0 ± 464.07 cells/mm3) in CAP group I than in control group respectively (Table 1). In CAP patients, there were significant decrease in mean values of OPN before and 3 days after treatment (74.12 ± 8.38 vs. 38.69 ± 5.05), CRP levels (13.22 ± 2.078 mg/dl vs. 5.87 ± 1.13 mg/dl), WBCs (13500 ± 2593 cells/mm3 vs. 8800 ± 1249 cells/mm3), and Neutrophils (10700 ± 872.39 cells/mm3 vs. 8800 ± 1249 cells/mm3) (Table 2). The mean values between plasma OPN and CURB-65 scores showed significant positive correlation (r = 0.710, p < .001), but correlation was non-significant with CRP (r = 0.094, P = .738). There was no correlation between CURB-65 and CRP (r = 0.117, p = .678) (Table 3, Figs. 1 and 2).
Statistically significant.
Discussion Table 3 Correlations between CURB 65, OPN, CRP in group I (before treatment.). At group I, Baseline
CURB -65
OPN CRP
R
P
0.710 0.322
.003* .109
OPN
CRP
P
0.094
.738
Statistically significant.
18 90
16 80
14
70
12
60
10
CRP
OPN
*
R
Diagnosis and assessment of severity in CAP patients as early as possible are crucial for better prognosis and outcome of the disease [15,16]. Elevated concentrations of plasma osteopontin was detected in many inflammatory conditions, suggesting that OPN may play potential role as a new biomarker in several infectious disorders. [17,18]. Therefore we aimed of this study to assess whether OPN plasma levels can predict severity and prognosis of CAP. In this study, we compared OPN levels in CAP and healthy controls also OPN was measured before and after 3 days of treatment in CAP group.
50 .5
1.0
1.5
2.0
2.5
3.0
CURB 65 Fig. 1. Correlation between CURB-65 and OPN in CAP patients.
3.5
5
.5
1.0
1.5
2.0
2.5
3.0
CURB 65 Fig. 2. Correlation between CURB-65 and CRP in CAP patients.
3.5
A.Sh. Mohamed et al. / Egyptian Journal of Chest Diseases and Tuberculosis 66 (2017) 713–715
The study revealed highly significant plasma osteopontin levels in CAP patients compared to healthy controls, and before than after treatment. These results were in consistent with other studies that concluded OPN could be a potential biomarker of severity degree and outcomes in patients with CAP [19,20]. But, the ability of OPN to recognize the causative pathogenesis not clear to date [19]. In our study, we found significant positive correlations on comparing plasma OPN levels, and CAP severity based on CURB-65 (r = 0.710, p < .001), but not with CURB-65 and CRP (r = 0.117, p = .678). these results were in agreement with previous studies, that found no correlation between different severity indices and CRP or WBC counts [19,21]. This can be explained by fact that CRP and OPN both induced by inflammatory cytokines but CRP is mostly secreted by hepatocytes, while OPN being not only circulating cytokine but also a part of extracellular matrix [19]. Limitations of our study were small study-population that interfering with finding cut-off value to clarify the different degrees of severity and short duration of follow-up. Conclusion In conclusion, we have clearly demonstrated increased plasma levels of OPN in pneumonia patients than in healthy controls also before and after 3 days of treatment of CAP. OPN levels significantly correlated with CURB-65 scores but not with CRP levels. Thus, OPN can be used as a novel additional marker, reflecting severity and response to treatment in CAP. Further studies are needed to define the exact cut-off values associated with different severity degrees. References [1] J.G. Bartlett, S.F. Dowell, L.A. Mandell, et al., Practice guidelines for the management of community-acquired pneumonia in adults. Infectious diseases society of America, Clin. Infect. Dis. 31 (2000) 347–382. [2] L.A. Mandell, T.J. Marrie, R.F. Grossman, et al., Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian infectious diseases society and the Canadian thoracic society. The Canadian community- acquired pneumonia working group, Clin. Infect. Dis. 31 (2000) 383–421. [3] J.D. Chalmers, A. Singanayagam, A.T. Hill, C-reactive protein is an independent predictor of severity in community-acquired pneumonia, Am. J. Med. 121 (2008) 219–225.
715
[4] A. Polzin, M. Pletz, R. Erbes, M. Raffenberg, H. Mauch, S. Wagner, et al., Procalcitonin as a diagnostic tool in lower respiratory tract infections and tuberculosis, Eur. Respir. J. 21 (2003) 939–943. [5] S. Kruger, J. Papassotiriou, R. Marre, K. Richter, C. Schumann, H. von Baum, et al., CAPNETZ Study Group. Pro-atrial natriuetic peptide and provasopression to predict severity and prognosis in community-acquired pneumonia: results form the German competence network CAPNETZ, Intensive Care Med. 33 (2007) 2069–2078. [6] B. Muller, N. Morgenthaler, D. Stolz, P. Schuetz, C. Muller, R. Bingisser, et al., Circulating levels of copeptin, a novel biomarker in lower respiratory tract infections, Eur. J. Clin. Invest. 37 (2007) 145–152. [7] K.X. Wang, D.T. Denhardt, Osteopontin: role in immune regulation and stress responses, Cytokine Growth Factor Rev. 19 (2008) 333–345. [8] T. Nystrom, P. Duner, A. Hultgardh-Nilsson, A constitutive endogenous osteopontin production is important for macrophage function and differentiation, Exp. Cell Res. 313 (2007) 1149–1160. [9] A. Koh, A.P. da Silva, A.K. Bansal, et al., Role of osteopontin in neutrophil function, Immunology 122 (2007) 466–475. [10] M. Scatena, L. Liaw, C.M. Giachelli, Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 2302–2309. [11] A. Papaporfyriou, S. Loukides, K. Kostikas, D.C. Simoes, G. Papatheodorou, E. Konstantellou, et al., Increased levels of osteopontin in sputum supernatant in patients with COPD, Chest 146 (2014) 951–958. [12] G.J. van der Windt, J.J. Hoogerwerf, A.F. de Vos, S. Florquin, T. van der Poll, Osteopontin promotes host defense during Klebsiella pneumoniae-induced pneumonia, Eur. Respir. J. 36 (2010) 1337–1345. [13] A. Kato, T. Okura, C. Hamada, S. Miyoshi, H. Katayama, J. Higaki, et al., Cell stress induces upregulation of osteopontin via the erk pathway in type II alveolar epithelial cells, PLoS One 9 (2014) e100106. [14] L.A. Mandell, R.G. Wunderink, A. Anzueto, J.G. Bartlett, G.D. Campbell, N.C. Dean, et al., Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults, Clin. Infect. Dis. 44 (Suppl. 2) (2007) S27–S72. [15] P.M. Houck, D.W. Bratzler, W. Nsa, A. Ma, J.G. Bartlett, Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia, Arch. Intern. Med. 164 (2004) 637–644. [16] M. Kanwar, N. Brar, R. Khatib, M.G. Fakih, Misdiagnosis of communityacquired pneumonia and inappropriate utilization of antibiotics: side effects of the 4-h antibiotic administration rule, Chest 131 (2007) 1865–1869. [17] Y.S. Chang, H.J. Kim, J. Chang, et al., Elevated circulating level of osteopontin is associated with advanced disease state of nonsmall cell lung cancer, Lung Cancer 57 (2007) 373–380. [18] C.K. Wong, L.C. Lit, L.S. Tam, et al., Elevation of plasma osteopontin concentration is correlated with disease activity in patients with systemic lupus erythematosus, Rheumatology (Oxford) 44 (2005) 602–606. [19] J.H. Chang, W.Y. Hung, et al., Utility of plasma osteopontin levels in management of community-acquired pneumonia, Int. J. Med. Sci. 13 (9) (2016) 673–679. [20] C. Roderburg, F. Benz, D.V. Cardenas, M.T. Lutz, et al., Persistently elevated osteopontin serum levels predict mortality in critically ill patients, Crit. Care 19 (2015) 271. [21] K. Tateda, E. Kusano, T. Matsumoto, K. Kimura, K. Uchida, K. Nakata, et al., Semi quantitative analysis of Streptococcus pneumoniae urinary antigen: kinetics of antigen titers and severity of diseases, Scand. J. Infect. Dis. 38 (2006) 166–171.
Contents lists available at ScienceDirect
Egyptian Journal of Chest Diseases and Tuberculosis journal homepage: www.sciencedirect.com
The prognostic utility of plasma osteopontin in CAP patients Ahmed Sh. Mohamed a, Ibrahim S. Ibrahim a, Ragia S. Sharshar b,⇑, Amira Y. Abd El-Naby c a
Chest Department, Faculty of Medicine, Tanta University, Tanta, Egypt Chest Department, Tanta University, Tanta, Egypt c Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt b
a r t i c l e
i n f o
Article history: Received 18 September 2017 Accepted 16 October 2017 Available online 31 October 2017 Keywords: Community acquired pneumonia Severity indices Osteopontin
a b s t r a c t Background: Osteopontin (OPN) is a soluble cytokine glycoprotein widely expressed in many benign and malignant conditions. Purpose of study: was to investigate role of plasma OPN as new biomarker affects prognosis in CAP. Methodology: study was done on 50 subjects divided into 2 groups each 25, CAP (group I), healthy controls (group II). Plasma OPN levels were measured on initial hospitalization and after 3 days of treatment and correlated to severity of CAP by CRP and CURB-65. We concluded that: plasma levels of OPN is increased in pneumonia patients than in healthy controls also before than after 3 days of treatment of CAP. OPN levels significantly correlated with CURB-65 scores but not with CRP levels. Thus, OPN can be used as a novel additional marker, reflecting severity and response to treatment in CAP. Ó 2017 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction
Objective
In community acquired pneumonia (CAP), management is mainly based on severity assessment; helping the most important decision of treatment as an inpatient or outpatient [1,2]. However, the severity scoring tools may be too complicated and not practical. This made the use of blood biomarkers as a single test more interesting to asses severity and prognosis of CAP. To date, several molecules have been estimated as CRP, pro-calcitonin, and pro-vasopressin [3–6]. Osteopontin is phosphorylated glycoprotein found to be part of the extracellular matrix, also as circulating cytokine secreted by a different types of cell [7–9]. OPN is an activation, differentiation chemotactic factor for neutrophils, T lymphocytes and macrophages [10]. Osteopontin could be involved in the inflammatory response due to several pulmonary diseases as obstructive airways disorders, pneumonia, pulmonary fibrosis [11–13]. So, once such inflammatory diseases are diagnosed, OPN may be used to predict prognosis and assist the management.
This Study was designed to detect utility of plasma osteopontin as a severity and prognostic tool in CAP patients, and its correlation with CURB-65 score, CRP.
Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis. ⇑ Corresponding author. E-mail address: [email protected] (R.S. Sharshar).
Methodology Study population This prospective case-controlled study was conducted in Chest Department, Tanta University, from September 2016 to June 2017, and fulfilled the ethical committee considerations. 50 subjects were divided into: Group I: included 25 non-smoker CAP patients, diagnosed and managed according to IDSA/ATS guidelines [14], and their disease severity was assessed by CURB-65 score and CRP. Group II: included 25 non-smoker healthy controls who were matched (age and sex) with group I. Excluded patients including those with; concomitant cardiopulmonary, liver, renal and diabetes mellitus, increased risk of tuberculous or malignant pneumonia, and immunocompromized states. Blood Sampling: 2 ml venous blood clotted then centrifuged for 20 min and stored at 20 °C, for estimation serum CRP, 3 ml venous blood on EDTA, 1 ml for CBC & 2 ml for plasma divided into aliquots and frozen at 70 °C for Measurement of plasma OPN (ng/ ml) by using R&D system Quantikine ELISA kit for human OPN (Cat#SOST00). Ref range: 0.3–20 ng/mL.
https://doi.org/10.1016/j.ejcdt.2017.10.010 0422-7638/Ó 2017 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
714
A.Sh. Mohamed et al. / Egyptian Journal of Chest Diseases and Tuberculosis 66 (2017) 713–715
Table 1 Characteristic data of studied groups.
*
Variable
Group I (mean ± SD)
Group II (mean ± SD)
Test
P value
Age Sex (%) (m/f) OPN CRP WBC NEUTROPHILS
56.2 ± 11.2 15 (60%)/10 (40%) 74.12 ± 8.38 13.22 ± 2.07 13500 ± 2592.5 10700 ± 872.39
54.4 ± 9.9 17 (68%)/8 (32%) 13.65 ± 2.78 1.87 ± 0.92 5900 ± 505.68 3750 ± 464.07
t: 1.802 X2: 0.142 t: 28.942 t: 17.320 t: 11.144 t: 27.240
.645 .705 .001* .001* .001* .001*
Statistically significant.
Statistics Data were statistical analyzed using (SPSS) version 20.0. t-test was used. for quantitative data, expressed as mean ± SD, Chisquare (X2) test for qualitative data. Pearson’s correlation (r) test P < 0.05 was considered to be significant. Results The characteristic data of the studied groups were summarized in (Table 1). The mean values of CURB-65 scores in CAP patients were 1.8 ± 0.78, with 9 low, 10 moderate, and 6 high risk patients. Table 2 The mean values at baseline and after follow up in group I.
*
Variable
Before (mean ± SD)
After (mean ± SD)
Test
P value
OPN CRP WBC NEUTROPHILS
74.77 ± 7.69 13.22 ± 2.07 13500 ± 2592.5 10700 ± 872.39
38.69 ± 5.05 5.87 ± 1.13 8800 ± 1248.57 6250 ± 650.55
15.184 10.568 6.326 15.837
.001* .001* .001* .001*
The mean value of plasma Osteopontin levels were significantly higher in group I (74.12 ± 8.38 ng/ml) than in group II (13.65 ± 2. 78 ng/ml). Also, our results showed significant higher mean values of CRP (13.22 ± 2.078 vs. 1.87 ± 0.9 mg/dl), total WBCs (13500 ± 2593 vs. 5900 ± 505.7 cells/mm3), and neutrophils (10700 ± 872.39 vs. 375 0 ± 464.07 cells/mm3) in CAP group I than in control group respectively (Table 1). In CAP patients, there were significant decrease in mean values of OPN before and 3 days after treatment (74.12 ± 8.38 vs. 38.69 ± 5.05), CRP levels (13.22 ± 2.078 mg/dl vs. 5.87 ± 1.13 mg/dl), WBCs (13500 ± 2593 cells/mm3 vs. 8800 ± 1249 cells/mm3), and Neutrophils (10700 ± 872.39 cells/mm3 vs. 8800 ± 1249 cells/mm3) (Table 2). The mean values between plasma OPN and CURB-65 scores showed significant positive correlation (r = 0.710, p < .001), but correlation was non-significant with CRP (r = 0.094, P = .738). There was no correlation between CURB-65 and CRP (r = 0.117, p = .678) (Table 3, Figs. 1 and 2).
Statistically significant.
Discussion Table 3 Correlations between CURB 65, OPN, CRP in group I (before treatment.). At group I, Baseline
CURB -65
OPN CRP
R
P
0.710 0.322
.003* .109
OPN
CRP
P
0.094
.738
Statistically significant.
18 90
16 80
14
70
12
60
10
CRP
OPN
*
R
Diagnosis and assessment of severity in CAP patients as early as possible are crucial for better prognosis and outcome of the disease [15,16]. Elevated concentrations of plasma osteopontin was detected in many inflammatory conditions, suggesting that OPN may play potential role as a new biomarker in several infectious disorders. [17,18]. Therefore we aimed of this study to assess whether OPN plasma levels can predict severity and prognosis of CAP. In this study, we compared OPN levels in CAP and healthy controls also OPN was measured before and after 3 days of treatment in CAP group.
50 .5
1.0
1.5
2.0
2.5
3.0
CURB 65 Fig. 1. Correlation between CURB-65 and OPN in CAP patients.
3.5
5
.5
1.0
1.5
2.0
2.5
3.0
CURB 65 Fig. 2. Correlation between CURB-65 and CRP in CAP patients.
3.5
A.Sh. Mohamed et al. / Egyptian Journal of Chest Diseases and Tuberculosis 66 (2017) 713–715
The study revealed highly significant plasma osteopontin levels in CAP patients compared to healthy controls, and before than after treatment. These results were in consistent with other studies that concluded OPN could be a potential biomarker of severity degree and outcomes in patients with CAP [19,20]. But, the ability of OPN to recognize the causative pathogenesis not clear to date [19]. In our study, we found significant positive correlations on comparing plasma OPN levels, and CAP severity based on CURB-65 (r = 0.710, p < .001), but not with CURB-65 and CRP (r = 0.117, p = .678). these results were in agreement with previous studies, that found no correlation between different severity indices and CRP or WBC counts [19,21]. This can be explained by fact that CRP and OPN both induced by inflammatory cytokines but CRP is mostly secreted by hepatocytes, while OPN being not only circulating cytokine but also a part of extracellular matrix [19]. Limitations of our study were small study-population that interfering with finding cut-off value to clarify the different degrees of severity and short duration of follow-up. Conclusion In conclusion, we have clearly demonstrated increased plasma levels of OPN in pneumonia patients than in healthy controls also before and after 3 days of treatment of CAP. OPN levels significantly correlated with CURB-65 scores but not with CRP levels. Thus, OPN can be used as a novel additional marker, reflecting severity and response to treatment in CAP. Further studies are needed to define the exact cut-off values associated with different severity degrees. References [1] J.G. Bartlett, S.F. Dowell, L.A. Mandell, et al., Practice guidelines for the management of community-acquired pneumonia in adults. Infectious diseases society of America, Clin. Infect. Dis. 31 (2000) 347–382. [2] L.A. Mandell, T.J. Marrie, R.F. Grossman, et al., Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian infectious diseases society and the Canadian thoracic society. The Canadian community- acquired pneumonia working group, Clin. Infect. Dis. 31 (2000) 383–421. [3] J.D. Chalmers, A. Singanayagam, A.T. Hill, C-reactive protein is an independent predictor of severity in community-acquired pneumonia, Am. J. Med. 121 (2008) 219–225.
715
[4] A. Polzin, M. Pletz, R. Erbes, M. Raffenberg, H. Mauch, S. Wagner, et al., Procalcitonin as a diagnostic tool in lower respiratory tract infections and tuberculosis, Eur. Respir. J. 21 (2003) 939–943. [5] S. Kruger, J. Papassotiriou, R. Marre, K. Richter, C. Schumann, H. von Baum, et al., CAPNETZ Study Group. Pro-atrial natriuetic peptide and provasopression to predict severity and prognosis in community-acquired pneumonia: results form the German competence network CAPNETZ, Intensive Care Med. 33 (2007) 2069–2078. [6] B. Muller, N. Morgenthaler, D. Stolz, P. Schuetz, C. Muller, R. Bingisser, et al., Circulating levels of copeptin, a novel biomarker in lower respiratory tract infections, Eur. J. Clin. Invest. 37 (2007) 145–152. [7] K.X. Wang, D.T. Denhardt, Osteopontin: role in immune regulation and stress responses, Cytokine Growth Factor Rev. 19 (2008) 333–345. [8] T. Nystrom, P. Duner, A. Hultgardh-Nilsson, A constitutive endogenous osteopontin production is important for macrophage function and differentiation, Exp. Cell Res. 313 (2007) 1149–1160. [9] A. Koh, A.P. da Silva, A.K. Bansal, et al., Role of osteopontin in neutrophil function, Immunology 122 (2007) 466–475. [10] M. Scatena, L. Liaw, C.M. Giachelli, Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 2302–2309. [11] A. Papaporfyriou, S. Loukides, K. Kostikas, D.C. Simoes, G. Papatheodorou, E. Konstantellou, et al., Increased levels of osteopontin in sputum supernatant in patients with COPD, Chest 146 (2014) 951–958. [12] G.J. van der Windt, J.J. Hoogerwerf, A.F. de Vos, S. Florquin, T. van der Poll, Osteopontin promotes host defense during Klebsiella pneumoniae-induced pneumonia, Eur. Respir. J. 36 (2010) 1337–1345. [13] A. Kato, T. Okura, C. Hamada, S. Miyoshi, H. Katayama, J. Higaki, et al., Cell stress induces upregulation of osteopontin via the erk pathway in type II alveolar epithelial cells, PLoS One 9 (2014) e100106. [14] L.A. Mandell, R.G. Wunderink, A. Anzueto, J.G. Bartlett, G.D. Campbell, N.C. Dean, et al., Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults, Clin. Infect. Dis. 44 (Suppl. 2) (2007) S27–S72. [15] P.M. Houck, D.W. Bratzler, W. Nsa, A. Ma, J.G. Bartlett, Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia, Arch. Intern. Med. 164 (2004) 637–644. [16] M. Kanwar, N. Brar, R. Khatib, M.G. Fakih, Misdiagnosis of communityacquired pneumonia and inappropriate utilization of antibiotics: side effects of the 4-h antibiotic administration rule, Chest 131 (2007) 1865–1869. [17] Y.S. Chang, H.J. Kim, J. Chang, et al., Elevated circulating level of osteopontin is associated with advanced disease state of nonsmall cell lung cancer, Lung Cancer 57 (2007) 373–380. [18] C.K. Wong, L.C. Lit, L.S. Tam, et al., Elevation of plasma osteopontin concentration is correlated with disease activity in patients with systemic lupus erythematosus, Rheumatology (Oxford) 44 (2005) 602–606. [19] J.H. Chang, W.Y. Hung, et al., Utility of plasma osteopontin levels in management of community-acquired pneumonia, Int. J. Med. Sci. 13 (9) (2016) 673–679. [20] C. Roderburg, F. Benz, D.V. Cardenas, M.T. Lutz, et al., Persistently elevated osteopontin serum levels predict mortality in critically ill patients, Crit. Care 19 (2015) 271. [21] K. Tateda, E. Kusano, T. Matsumoto, K. Kimura, K. Uchida, K. Nakata, et al., Semi quantitative analysis of Streptococcus pneumoniae urinary antigen: kinetics of antigen titers and severity of diseases, Scand. J. Infect. Dis. 38 (2006) 166–171.