J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Review

Volume 10, Number 7, July 2018, pages 545-551

The Use of Serum Procalcitonin as a Diagnostic and Prognostic Biomarker in Chronic Obstructive Pulmonary Disease Exacerbations: A Literature Review Update

**Table 1.** Summary of Studies
First author	Publication year/country Design	Participants/arms	Relative findings	Association between PCT and bacterial AECOPD
Chang C[10]	2006/China Case-control	45 AECOPD 15 bacterial 30 non-bacterial	PCT levels in the bacterial group were significantly higher than in the non-bacterial (P = 0.00). PCT levels did not significantly differ in the stable state.	YES
Stolz D[11]	2007/Switzerland Prospective cohort	167 AECOPD	PCT levels were significantly elevated (P < 0.001) during the exacerbation, but they were not associated with a longer hospital stay or long-term clinical failure.
Stolz D[12]	2007/Switzerland Randomized control trial	208 hospitalized for AECOPD 102 procalcitonin-guided treatment 106 standard treatment	PCT guidance reduced antibiotic prescription (40% versus 72%, respectively; P < 0.0001) and antibiotic exposure (relative risk (RR): 0.56; 95% confidence interval (CI): 0.43 - 0.73; P < 0.0001) compared to standard therapy. Within 6 months the rehospitalization rate and the mean time to the next exacerbation were similar in both groups.
Nseir S[13]	2008/France Prospective cohort	98 AECOPD requiring intubation and mechanical ventilation	PCT levels > 0.5 ng/mL and positive Gram stain of endotracheal aspirate, were independently associated with bacterial isolation in severe AECOPD.	YES
Daubin C[14]	2008/France Prospective cohort	39 hospitalized for AECOPD	There was no association between the PCT_max levels and the severity of COPD (P = 0.07). Patients with PCT_max > 0.25 µg/L were more critically ill. A low likelihood of bacterial infection correlated with a PCT less than 0.1 µg/L.
Rammaert B[15]	2009/France Prospective cohort	116 AECOPD requiring intubation and mechanical ventilation	PCT level was independently associated with increased risk for ICU mortality (P = 0.018).
Daniels JMA[16]	2010/Netherlands Retrospective cohort	243 AECOPD of 205 patients	Most patients (75%) had low PCT levels, with mostly elevated CRP levels. CRP levels were higher in the presence of bacteria. Doxycycline had a significant effect in patients with a PCT level < 0.1 µg/L.	NO
Hu XJ[17]	2010/China Case-control	114 56 AECOPD 58 healthy controls	The sensitivity, specificity, PPV, NPV and diagnostic accuracy rate of PCT were higher than those of CRP.
Kherad O[18]	2010/Switzerland Prospective cohort	86 AECOPD	PCT levels did not significantly differ between virus-associated exacerbations and others.
Lacoma A[19]	2011/Spain Case-control	318 COPD 46 stable 217 AECOPD 55 pneumonia	PCT and CRP levels showed significant differences among the three groups, being higher in the pneumonia group, followed by the AECOPD group (P < 0.0001).
Falsey AR[20]	2012/USA Prospective cohort	224 AECOPD	Mean PCT levels were significantly higher in patients with pneumonia but they were not useful in the distinction between bacterial and viral or noninfectious causes of AECOPD.	NO
Soler N[21]	2012/Spain Case-control	73 hospitalized AECOPD 39 with purulent sputum 34 with non-purulent sputum	Serum PCT was similar in both groups on admission and after 72 h.	NO
Pazarli AC[22]	2012/Turkey Case-control	118 COPD 68 AECOPD 50 stable	PCT levels were higher in AECOPD patients than in stable COPD patients and were especially increased in cases of severe AECOPD and in those receiving NPPV among them.
Huerta A[23]	2013/Spain Prospective cohort	249 hospitalized COPD 133 AECOPD 116 CAP + COPD	PCT levels were significantly higher at day 1 and day 3 in patients with CAP + COPD than in those hospitalized for AECOPD.
Zhang Y[24]	2014/China Case-control	369 AECOPD	Before treatment, PCT levels in the infective group were significantly higher than those in the non-infective group.	YES
Verduri A[25]	2015/Italy Randomized control trial	184 AECOPD	The AECOPD rate at 6 months between standard and PCT-guided antibiotic treatment was not significant. The results regarding the non-inferiority of the PCT-guided plan were inconclusive.
Grolimund E[26]	2015/Switzerland Prospective cohort	469 hospitalized AECOPD 252 pneumonic 217 non-pneumonic	Weak statistical significant correlations were found between discharge PCT levels and 5 - 7 year non-survival.
Tanrıverdi H[27]	2015/Turkey Prospective cohort	77 hospitalized AECOPD	Mean PCT levels were significantly higher in patients with positive sputum cultures than in those with negative sputum cultures. The AUC value of PCT was significantly better for predicting bacterial infection as compared to the CRP level or the neutrophil to lymphocyte ratio (P = 0.042) but the specificity, sensitivity (< 80%) and the AUC value were low.	YES
Chang CH[28]	2015/Taiwan Prospective cohort	72 AECOPD in the Emergency Department	PCT levels (as well as WBC and CRP) of the bacteria-positive and bacteria-negative groups were not statistically different. PCT, WBC and CRP levels also did not significantly differ between the virus-positive and virus-negative group.	NO
Ergan B[29]	2016/Turkey Retrospective cohort	63 AECOPD admitted in the ICU	Admission PCT levels were significantly higher in patients who died during hospitalization (0.66 versus 0.17 ng/mL; P = 0.014). The optimal admission PCT threshold was 0.25 ng/mL in order to identify patients who had a bacterial exacerbation.	YES
Wang JX[30]	2016/China Randomized control trial	191 hospitalized for AECOPD with PCT< 0.1 ng/mL 95 antibiotic 96 control	There was no significant difference (P = 0.732) in the overall treatment success rate between the control group (95.8%) and the antibiotic group (93.7%).
Corti C[31]	2016/Denmark Randomized control trial	120 hospitalized for AECOPD 62 PCT guided therapy 58 control	The median duration of antibiotic exposure was 3.5 in the PCT-arm versus 8.5 days in the control arm (P = 0.0169). A composite harm end-point consisting of rehospitalization, death or ICU admission, all within 28 days, showed no significant difference.
Picart J[32]	2016/Reunion Retrospective cohort	245 hospitalized AECOPD 124 patients before PCT-guided protocol 121 after PCT-guided protocol	Prescription of antibiotics decreased by 41% after protocol introduction (59% versus 35%, P < 0.001), without any increase in morbidity and mortality at day 30. Antibiotic duration and length of hospital stay did not change.
Zhu JJ[33]	2016/China Case-control	153 AECOPD admitted in the ICU	PCT and blood lactic acid levels reflect the infection severity and are influenced by the effectiveness of NIV in the treatment of AECOPD during ICU stay.
Pizzini A[34]	2017/Austria Case-control	102 48 CAP 20 CAP + COPD 34 AECOPD	PCT levels were significantly higher in patients with CAP compared to those with AECOPD upon hospital admission.
Flattet Y[35]	2017/Switzerland Retrospective cohort	359 AECOPD	Higher PCT levels were significantly associated with a worse prognosis (HR: 1.009 (1.001 - 1.017)).
Kawamatawong T[36]	2017/Thailand Prospective cohort	68 AECOPD in the Emergency Department	Higher PCT levels were observed in patients with longer hospitalization (≥ 7 days) when compared to those shorter stay (< 7 days) (0.38 ng/mL versus 0.1 ng/mL; P = 0.035). PCT levels did not show any statistical significant difference among bacterial exacerbations.	NO
Gao D[37]	2017/China Case-control	35 AECOPD & healthy 8 purulent sputum 12 non-purulent sputum 15 healthy controls	PCT levels in the AECOPD patients were significantly higher compared to the control group. The differences between the purulent and the non-purulent group were statistically insignificant.	NO
Çolak A[38]	2017/Turkey Case-control	116 76 AECOPD 40 pneumonia	Serum PCT levels were significantly higher in the pneumonia group compared to the AECOPD group (P < 0.001).
Li Y[39]	2017/China Case-control	214 AECOPD & healthy 98 infection 66 non-infection 50 healthy controls	PCT levels of the infection group were significantly higher than those of the non-infection and the normal control group before treatment (P < 0.05).	YES
Bremmer DN[40]	2018/USA Retrospective cohort	305 AECOPD 166 before PCT guidance 139 after PCT guidance	PCT-guided treatment was associated with a reduced number of antibiotic days (5.3 versus 3.0; P = 0.01) and inpatient length of stay (4.1 days versus 2.9 days; P = 0.01). 30-day readmission rates due to respiratory causes were unaffected.

Table 1. Summary of Studies

First author

Publication year/country
Design

Participants/arms

Relative findings

Association between PCT and bacterial AECOPD

Chang C[10]

2006/China
Case-control

45 AECOPD
15 bacterial
30 non-bacterial

PCT levels in the bacterial group were significantly higher than in the non-bacterial (P = 0.00). PCT levels did not significantly differ in the stable state.

YES

Stolz D[11]

2007/Switzerland
Prospective cohort

167 AECOPD

PCT levels were significantly elevated (P < 0.001) during the exacerbation, but they were not associated with a longer hospital stay or long-term clinical failure.

Stolz D[12]

2007/Switzerland
Randomized control trial

208 hospitalized for AECOPD
102 procalcitonin-guided treatment
106 standard treatment

PCT guidance reduced antibiotic prescription (40% versus 72%, respectively; P < 0.0001) and antibiotic exposure (relative risk (RR): 0.56; 95% confidence interval (CI): 0.43 - 0.73; P < 0.0001) compared to standard therapy. Within 6 months the rehospitalization rate and the mean time to the next exacerbation were similar in both groups.

Nseir S[13]

2008/France
Prospective cohort

98 AECOPD requiring intubation and mechanical ventilation

PCT levels > 0.5 ng/mL and positive Gram stain of endotracheal aspirate, were independently associated with bacterial isolation in severe AECOPD.

YES

Daubin C[14]

2008/France
Prospective cohort

39 hospitalized for AECOPD

There was no association between the PCT_max levels and the severity of COPD (P = 0.07). Patients with PCT_max > 0.25 µg/L were more critically ill. A low likelihood of bacterial infection correlated with a PCT less than 0.1 µg/L.

Rammaert B[15]

2009/France
Prospective cohort

116 AECOPD requiring intubation and mechanical ventilation

PCT level was independently associated with increased risk for ICU mortality (P = 0.018).

Daniels JMA[16]

2010/Netherlands
Retrospective
cohort

243 AECOPD of 205 patients

Most patients (75%) had low PCT levels, with mostly elevated CRP levels. CRP levels were higher in the presence of bacteria. Doxycycline had a significant effect in patients with a PCT level < 0.1 µg/L.

Hu XJ[17]

2010/China
Case-control

114
56 AECOPD
58 healthy controls

The sensitivity, specificity, PPV, NPV and diagnostic accuracy rate of PCT were higher than those of CRP.

Kherad O[18]

2010/Switzerland
Prospective cohort

86 AECOPD

PCT levels did not significantly differ between virus-associated exacerbations and others.

Lacoma A[19]

2011/Spain
Case-control

318 COPD
46 stable
217 AECOPD
55 pneumonia

PCT and CRP levels showed significant differences among the three groups, being higher in the pneumonia group, followed by the AECOPD group (P < 0.0001).

Falsey AR[20]

2012/USA
Prospective cohort

224 AECOPD

Mean PCT levels were significantly higher in patients with pneumonia but they were not useful in the distinction between bacterial and viral or noninfectious causes of AECOPD.

Soler N[21]

2012/Spain
Case-control

73 hospitalized AECOPD
39 with purulent sputum
34 with non-purulent sputum

Serum PCT was similar in both groups on admission and after 72 h.

Pazarli AC[22]

2012/Turkey
Case-control

118 COPD
68 AECOPD
50 stable

PCT levels were higher in AECOPD patients than in stable COPD patients and were especially increased in cases of severe AECOPD and in those receiving NPPV among them.

Huerta A[23]

2013/Spain
Prospective cohort

249 hospitalized COPD
133 AECOPD
116 CAP + COPD

PCT levels were significantly higher at day 1 and day 3 in patients with CAP + COPD than in those hospitalized for AECOPD.

Zhang Y[24]

2014/China
Case-control

369 AECOPD

Before treatment, PCT levels in the infective group were significantly higher than those in the non-infective group.

YES

Verduri A[25]

2015/Italy
Randomized control trial

184 AECOPD

The AECOPD rate at 6 months between standard and PCT-guided antibiotic treatment was not significant. The results regarding the non-inferiority of the PCT-guided plan were inconclusive.

Grolimund E[26]

2015/Switzerland
Prospective cohort

469 hospitalized AECOPD
252 pneumonic
217 non-pneumonic

Weak statistical significant correlations were found between discharge PCT levels and 5 - 7 year non-survival.

Tanrıverdi H[27]

2015/Turkey
Prospective cohort

77 hospitalized AECOPD

Mean PCT levels were significantly higher in patients with positive sputum cultures than in those with negative sputum cultures. The AUC value of PCT was significantly better for predicting bacterial infection as compared to the CRP level or the neutrophil to lymphocyte ratio (P = 0.042) but the specificity, sensitivity (< 80%) and the AUC value were low.

YES

Chang CH[28]

2015/Taiwan
Prospective cohort

72 AECOPD in the Emergency Department

PCT levels (as well as WBC and CRP) of the bacteria-positive and bacteria-negative groups were not statistically different. PCT, WBC and CRP levels also did not significantly differ between the virus-positive and virus-negative group.

Ergan B[29]

2016/Turkey
Retrospective cohort

63 AECOPD admitted in the ICU

Admission PCT levels were significantly higher in patients who died during hospitalization (0.66 versus 0.17 ng/mL; P = 0.014). The optimal admission PCT threshold was 0.25 ng/mL in order to identify patients who had a bacterial exacerbation.

YES

Wang JX[30]

2016/China
Randomized control trial

191 hospitalized for AECOPD with PCT< 0.1 ng/mL
95 antibiotic
96 control

There was no significant difference (P = 0.732) in the overall treatment success rate between the control group (95.8%) and the antibiotic group (93.7%).

Corti C[31]

2016/Denmark
Randomized control trial

120 hospitalized for AECOPD
62 PCT guided therapy
58 control

The median duration of antibiotic exposure was 3.5 in the PCT-arm versus 8.5 days in the control arm (P = 0.0169). A composite harm end-point consisting of rehospitalization, death or ICU admission, all within 28 days, showed no significant difference.

Picart J[32]

2016/Reunion
Retrospective cohort

245 hospitalized AECOPD
124 patients before PCT-guided protocol
121 after PCT-guided protocol

Prescription of antibiotics decreased by 41% after protocol introduction (59% versus 35%, P < 0.001), without any increase in morbidity and mortality at day 30. Antibiotic duration and length of hospital stay did not change.

Zhu JJ[33]

2016/China
Case-control

153 AECOPD admitted in the ICU

PCT and blood lactic acid levels reflect the infection severity and are influenced by the effectiveness of NIV in the treatment of AECOPD during ICU stay.

Pizzini A[34]

2017/Austria
Case-control

102
48 CAP
20 CAP + COPD
34 AECOPD

PCT levels were significantly higher in patients with CAP compared to those with AECOPD upon hospital admission.

Flattet Y[35]

2017/Switzerland
Retrospective cohort

359 AECOPD

Higher PCT levels were significantly associated with a worse prognosis (HR: 1.009 (1.001 - 1.017)).

Kawamatawong T[36]

2017/Thailand
Prospective cohort

68 AECOPD in the Emergency Department

Higher PCT levels were observed in patients with longer hospitalization (≥ 7 days) when compared to those shorter stay (< 7 days) (0.38 ng/mL versus 0.1 ng/mL; P = 0.035). PCT levels did not show any statistical significant difference among bacterial exacerbations.

Gao D[37]

2017/China
Case-control

35 AECOPD & healthy
8 purulent sputum
12 non-purulent sputum
15 healthy controls

PCT levels in the AECOPD patients were significantly higher compared to the control group. The differences between the purulent and the non-purulent group were statistically insignificant.

Çolak A[38]

2017/Turkey
Case-control

116
76 AECOPD
40 pneumonia

Serum PCT levels were significantly higher in the pneumonia group compared to the AECOPD group (P < 0.001).

Li Y[39]

2017/China
Case-control

214 AECOPD & healthy
98 infection
66 non-infection
50 healthy controls

PCT levels of the infection group were significantly higher than those of the non-infection and the normal control group before treatment (P < 0.05).

YES

Bremmer DN[40]

2018/USA
Retrospective cohort

305 AECOPD
166 before PCT guidance
139 after PCT guidance

PCT-guided treatment was associated with a reduced number of antibiotic days (5.3 versus 3.0; P = 0.01) and inpatient length of stay (4.1 days versus 2.9 days; P = 0.01). 30-day readmission rates due to respiratory causes were unaffected.