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Medicine Government Medical College Srinagar Jammu and Kashmir India
ISSN: 0976-3031
Research Article
PROCALCITONIN AS A GUIDE FOR ANTIBIOTIC THERAPY IN PATIENTS ADMITTED
WITH ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Mohammadd Ashraf Khan1., Irfan Gul2*., Abid Rasool3., Rafi Ahmad Jan4
and Shujat Gul5
1,3Medicine SKIMS Soura, Jammu and Kashmir India
2Medicine Government Medical College Srinagar Jammu and Kashmir India
4Pulmonary and Internal Medicine SKIMS Soura, Jammu and Kashmir India
5Government Medical College Srinagar Jammu and Kashmir India
DOI: http://dx.doi.org/10.24327/ijrsr.2017.0807.0578
ARTICLE INFO ABSTRACT
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable, but progressive
disease and hospital admissions of patients with COPD are frequently due to acute exacerbations.
Recently, measurement of procalcitonin (PCT) levels appears to be useful in order to minimize this
problem as acute phase reactants does not difference between bacterial and non-bacterial causes of
inflammation. Aim; The aim of this study was to investigate whether the measurement of
Procalcitonin can be used in the differentiation of bacterial and non-bacterial infectious causes of
COPD exacerbation, thus helping in planning the treatment, reduce overuse of antibiotics in
patients admitted with acute exacerbation of COPD thus reducing economic burden and
decrease drug resistance. 86 patients with known COPD and admitted in emergency department
with symptoms of acute exacerbation of COPD were included in this study after obtaining written
informed consent. At presentation before putting antibiotics blood samples were taken for
procalcitonin level, routine blood tests including sputum and blood culture. Patients were allocated
in to three groups based on procalcitonin value.
Group A; procalcitonin value below < 0.25 ng/ml. (normal) (n=57)
Group B; procalcitonin value between 0.25- 0.5 ng/ml (local bacterial infection) (n=8)
Group C; procalcitonin value between 0.5-2 ng/ml (systemic bacterial infection) (n=21)
Results ; In our study a correlation was seen between procalcitonin value in each group and WBC
count, fever, ESR, CRP, Vaccination, Chest X ray, smoking and microbiology i.e. blood and sputum
culture. A significant correlation was seen between serum procalcitonin value and WBCCount,
fever, chest x ray, CRP, blood and sputum culture. (P valve ≤ 0.0001) but no significant correlation
was seen between serum procalcitonin level in each group with ESR which is one of acute phase
reactant p valve 0.043
Conclusions: This study demonstrates that procalcitonin is a good marker for differentiation
between bacterial and nonbacterial acute exacerbation of COPD and could be used to guide
initiation and assessing response to antibiotic therapy in patients. Procalcitonin- guided antibiotic
therapy has the potential to decrease unnecessary antibiotic use in nonbacterial COPD
exacerbations, thereby decreasing the spread of antibiotic-resistant bacteria and reducing antibiotic-
related adverse reactions.
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a
preventable as well as treatable disease that might also have
extra-pulmonary manifestations. It is characterized by an
abnormal inflammatory response of the lungs against harmful
particles or gases (1) COPD constitutes a major health problem
[2]. Acute exacerbations of COPD (AECOPD) have
considerable impact on morbidity, mortality and quality of life
[3] An exacerbation of COPD is an event in the natural course
of COPD characterised by an acute change in the patient’s
Available Online at http://www.recentscientific.com
International Journal of
Recent Scientific
Research
International Journal of Recent Scientific Research
Vol. 8, Issue, 7, pp. 18839-18843, July, 2017
Copyright © Mohammadd Ashraf Khan et al, 2017, this is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the
original work is properly cited.
Article History:
Received 06th April, 2017
Received in revised form 14th
May, 2017
Accepted 23rd June, 2017
Published online 28th July, 2017
DOI: 10.24327/IJRSR
CODEN: IJRSFP (USA)
Key Words:
Chronic obstructive pulmonary disease
(COPD), procalcitonin (PCT), Antibiotic ,
Acute Exacerbation
Mohammadd Ashraf Khan et al., Procalcitonin as a Guide for Antibiotic Therapy in Patients Admitted
With acute Exacerbation of Chronic obstructive Pulmonary Disease
18840 | P a g e
baseline dyspnoea or breathing difficulty, cough and/or sputum
production beyond day-to-day variability sufficient to warrant a
change in management (Gold definition) [4] . It is essential to
determine the cause of worsening of symptoms for appropriate
clinical management. The available evidence suggests that at
least 80% of the COPD exacerbations are infectious in origin.
Of these infections, 40% to 50% are caused by bacteria,
30% by viruses, and 5% to 10% by atypical bacteria [5-15]
The role of bacteria in exacerbations has not been established
with reasonable certainty since bacterial species are present in
the airways of 25%–50% patients with COPD even in stable
conditions [16-19] While there is well- established evidence for
the use of steroids and bronchodilators in acute exacerbation of
COPD, the debate continues over the appropriate use of
antibiotics in the treatment of acute exacerbations. There are
multiple potential factors leading to acute exacerbation of
COPD, including viruses, bacteria, and common pollutants; as
such, antibiotic treatment may not be indicated for all patients
presenting with exacerbations. Further, the risks of antibiotic
treatment-including adverse drug events, selection for drug-
resistant bacteria, and associated costs-are not insignificant.
Classical diagnostic parameters including CRP and leukocyte
count do not have sufficient specificity in differentiating
between bacterial infections, non-infectious systemic
inflammations or viral infections. Therefore, more specific and
reliable markers that might be helpful in deciding the treatment
are needed in these patients [20]. Serum procalcitonin levels
are suggested to be one of the biomarkers for predicting a
bacterial infection [21]. Procalcitonin (PCT) is a protein having
a molecular weight of 13 kDa and it consists of 116 amino acid
residues. The exact regions of its secretion are not yet clear
[22].
Some literature suggests that PCT is secreted from
neuroendocrine cells of the liver, small intestine and thyroid
cells. In healthy humans, its normal serum level is 0.1 ng/mL.
In a previous study, administration of bacterial endotoxin to
healthy Individuals resulted in an increase in PCT levels
starting two hours after administration, with a peak value
reached in 12 h [23]. Consequently, the serum level remains
constant for another12 h and decreases back to normal level in
20–24 h.PCT gives rapid response to bacterial infections [24].
Studies performed in patients with pneumonia revealed that
serum PCT levels have high sensitivity and specificity in
showing the inflammatory response caused by pneumonia [25].
It has also been suggested in some studies that serum PCT
levels might have a relatively higher sensitivity and specificity
in differentiating pneumonias of bacterial origin from those of
viralorigin [26].
Aim
The aim of this study was to investigate whether the
measurement of PCT can be used in the differentiation of
bacterial and non-bacterial infection causes of COPD
exacerbation, thus helping in planning the treatment.
MATERIAL AND METHODS
Between November 2012 and April 2014 86 patients (47 males
and 39 females) with known copd and admitted in emergency
department with symptoms of acute exacerbation of COPD
(worsenening of cough, increased sputum production,
increased breathlessness) were included in this prospective
study after taking written informed consent.
Inclusion Criteria were patients of age 18 who were already
diagnostic cases of COPD [Gold criteria, PFT documented] and
have not received antibiotics in last 2 weeks nor have been
hospitalized in last 2 weeks. Exclusion Criteria were Age< 18
years, Pregnant women, Patients with absolute neutropenia and
Immunocomprised patients.
Definition
The diagnosis of COPD was based on clinical history, physical
examination findings, and spirometric criteria according to the
Global Initiative for Chronic Obstructive Lung Disease
(GOLD) guidelines [14]. An exacerbation of COPD was
defined as ‘‘a sustained worsening of the patient’s condition,
from the stable state and beyond normal day-to-day variations,
that is acute in onset and necessitates a change in regular
medication in a patient with underlying COPD[15].
METHODS
Complete medical history.
General and local chest examination.
Chest radiography.
Routine blood tests (including CBC, ESR and CRP).
Blood cultures, sputum culture (Sputum was induced with
hypertonic saline if subjects were unable to expectorate an
adequate sputum sample spontaneously).
Procalcitonin level by ELISA method
OBSERVATIONS AND RESULTS
Characteristics of subjects with acute exacerbation of COPD
stratified by procalcitonin value above and below threshold i.e
0.25 ng/ml are summarized in table I
In our study we observed potential correlation of Procalcitonin
value in each group with clinical parameters like WBC count,
fever, ESR, CRP, Vaccination, Chest X ray and
microbiological parameter blood and sputum culture.
A significant correlation was seen between procalcitonin value
and WBC count as showing in table 1 with p value ≤ 0.001
between various groups. There is also significant corelation
noted between procalcitonin valve and chest x ray as described
in table 1 with p value ≤ 0.001. A significant correlation was
also noted between patients who were smokers and
procalcitonin level with p value 0.0019. When procalcitonin
level was correlated with CRP level (it was found that among
57 patients with normal Procalcitonin level i.e. < 0.25ng/ml
(Group A) CRP was positive in only 14 patients (24.6%)
whereas among 8 patients in group B with high Procalcitonin
value (0.25-0.5ng/ml) and among 21 patients in group C (Pct.
value >0.5ng/ml) CRP was positive in 4(50%) patients and 17
(80.9%) respectively which is statistically significant p value
<0.001. However there was no significant correlation seen
between procalcitonin value in each group and ESR with p
value 0.43, A significant correlation was also seen between
procalcitonin valve and fever (p valve≤ 0.001ng/ml) However
there was no significant correlation between Pct. valve and
International Journal of Recent Scientific Research Vol. 8, Issue, 7, pp. 18839-18843, July, 2017
18841 | P a g e
vaccination p value 0.133, A significant correlation was seen
between procalcitonin value and blood culture.
Patients in group A blood culture was positive in only 4
patients(7%) where as in patients of group B(n= 8) with local
bacterial infections blood culture was positive in all 8
patients(100%) and in patients of group C with systemic
bacterial infection blood culture was positive in 16 patients
(76.2%). P value ≤ 0.001. A significant correlation was also
seen between procalcitonin value and sputum culture In group
A patients sputum culture was positive in only 3 patients
(5.3%) where as in group B patients with local bacterial
infections sputum culture was positive in 3 patients (37.5%)
and in group C patients with systemic bacterial infection (pct
>0.5ng/ml) sputum culture was positive in 12 patients (57.1%)
which is statistically significant.(p value 0.001)
The 2 showing that there is significant increase in blood culture
positivity rate with higher procalcitonin level in Group C with
76.2% than in Group A with only 7 % (p≤0.001)
The above table 4 shows significant relation between
procalcitonin level with sputum culture with highest percentage
of positive culture in group C and p valve ≤0.001
DISCUSSION
Procalcitonin levels are increased in moderate to severe
bacterial infections but remain at comparatively low levels in
viral infections and nonspecific inflammatory diseases
[27].There are only a limited number of studies investigating
the diagnostic role of procalcitonin in invasive fungal
infections. However, these studies were inconclusive because
of limited sample size and different procalcitonin cut off values
employed [28] This is the first study in the Kashmir valley to
examine the utility of procalcitonin levels in patients with
COPD, and consistent with the European literature, we found
that a high procalcitonin level was relatively specific for
invasive bacterial disease such as pneumonia.[29, 30]. In our
study we classified patients into three groups:-
Group A with normal procalcitonin level ≤ 0.25ng/ml Group
B with procalcitonin level between 0.25ngml-0.5ng/ml (local
bacterial infection). Infection which does not affect whole
body of individual, Rather, it is limited to specific portion of
body and does not affect the blood stream. e.g, infected wound,
thrombophlebitis, gonorrhoea. Sometimes a pneumonia can be
localized infection, as it is only located in one specific place in
the lung.
Group C with systemic bacterial infection (Procalcitonin level≥
0.5/ml). A systemic bacterial infection is so named because the
Table No 1 Showing Characteristic Features of Various
Groups
Characteristic
GROUP A
Pct ≤ 0.25
ng/ml
N 57
GROUP B
Pct 0.25-0.50
ng/ml
N 8
GROUP C
≥ 0.5ng/ml
N 21
P valve
ng/ml
Age (mean±s.d)
65.02 ± 10.05
58.75± 7.4 61.8± 6.8 0.118
TLC COUNT(mean±s.d) 8.69 ± 2.5 12.2 ± 3.2 12.1 ± 3.8 ≤0.001
E.S.R (Mean± s.d) 17.02 ± 8.7
23.13± 7.2 21.6 ±9.0 0.43
C.R.P (POSITIVE) 14 4 17 ≤0.001
Chest x ray infiltrates 15 6 17 ≤0.001
Smoker 23 6 15 0.0019
Vaccinated
Influenza 0 1 2 0.133
Pneumococcal 5 1 0
Both influenza and
pneumococcal 3 0 0
Fever 20 2 19 ≤0.001
Positive sputum culture
3 3 12 ≤0.001
Positive blood culture 4 0 16 ≤0.001
Table 2 Correlation between procalcitonin and blood
culture
Procalcitonin(ng/ml) Sterile
Positive
Total
Group A( Procalcitonin value i.e< 0.25ng/ml ) 93.0%
7.0% 100.0%
Group B( procalcitonin value between 0.25- 0.5 ng/ml)
100.0%
0.0% 100.0%
Group C (procalcitonin value between 0.5-2 ng/ml) 23.8%
76.2%
100.0%
0
20
40
60
80
100
120
GROUP A GROUP B GROUPC
PROCALCITATION AND BLOOD CULTURE
POSITIVE STERILE TOTAL
Table 3 Showing Various Bacteria Growth in Culture and
Relation With Procalcitonin
Blood culture organism Procalcitonin(ng/ml) Total
Group A
Group B Group C
No organism 93.0% 100.0% 23.8% 76.7%
Klebsiella 0.0% 0.0% 19.0% 4.7%
Acinetobacter 0.0% o.o% 4.8% 1.2%
Streptococcus 1.8% 0.0% 4.8% 2.3%
Pseudomonas 1.8% 0.0% 9.5% 3.5%
Candida 0.0% 0.0% 4.8% 1.2%
Coaglase negative stap aureus
0.O% 0.0% 9.5% 2.3%
Enterococcus 1.8% 0.0% 4.8% 2.3%
MRSA 0.0% 0.0% 14.3% 3.5%
Staph aureus 1.8% 0.0% 4.8% 2.3%
Table 4 Correlation between procalcitonin and sputum
culture
Procalcitonin(ng/ml)
Sputum
culture
Sterile
Sputum
culture
Positive
Total
Group A( Procalcitonin value i.e.< 0.25ng/ml ) 94.7 %
5.3 % 100.0%
Group B( procalcitonin value between 0.25- 0.5
ng/ml) 62.5 %
37.5% 100.0%
Group C procalcitonin value between 0.5-2 ng/ml)
42.9%
57.1.2%
100.0%
Table 5 Showing Sputum culture 0rganism and serum
procalcitonin (ng/ml) level
Sputum culture
organism Procalcitonin(ng/ml) Total
No organism Group A
Group B
Group C
79.1%
Klebsiella 1.8% 0.0% 23.8% 4.7%
Acinetobacter 0.0% 12.5% 9.5% 1.2%
Streptococcus 1.8% 12.5% 0.0% 2.3%
Pseudomonas 0.0% 12.5% 9.5% 3.5%
Candida 0.0% 0.0% 4.8% 1.2%
Coaglase negative stap
aureus 0.O% 1.0% 9.5% 2.3%
Enterococcus 1.8% 0.0% 4.8% 2.3%
MRSA 0.0% 0.0% 4.3% 3.5%
Staph aureus 1.8% 1.0% 4.8% 2.3%
Mohammadd Ashraf Khan et al., Procalcitonin as a Guide for Antibiotic Therapy in Patients Admitted
With acute Exacerbation of Chronic obstructive Pulmonary Disease
18842 | P a g e
pathogen that causes it, and often the symptoms that it causes,
are spread through the systems of body, instead of being
localized in one area, as they are in local infection.
In our study we correlate procalcitonin values in each group
with higher temperature, white blood cell count, CRP, ESR,
chest radiograph, bacteriology in sputum and blood culture,
suggesting the possibility of occult pneumonia.
In this study we demonstrate a strong correlation of pct valve
with, WBC count, CRP and x ray findings. (p valve ≤ 0.0001)
which is in consistent with study conducted by K.H. Mohamed
et al where significant correlation was seen between PCT level
and temperature (pct<0.05), leukocyte count (p<0.05), CRP
(P<0.05) but in our study we don’t find strong correlation of
pct valve and ESR which is against same study [31]. Our study
is also in agreement with study Conducted by CanturkTasci et
al (2008) where they have found strong correlation of pct valve
with temperature, CRP, leucocyte count, temperature, Blood
culture and x ray infiltrates, a similar result was found in our
study but in Our study we do not found strong correlation of
pct valve and ESR which is against same study. [32] Chang et
al. (33) showed that patients admitted with COPD exacerbation
and positive sputum cultures for bacterial pathogen ha
significantly higher PCT values. A similar result was found in
another study of the same investigator performed in2006 [34]
A similar result was found in our study. In our study we found
that pct valve is strongly correlated with sputum culture and
blood culture. Based on our data, low serum procalcitonin
concentrations of ≤ 0·25 _g/L can identify patients without
clinically relevant bacterial infections; in these individuals
antimicrobial therapy can be safely withheld. Our study had
several limitations. The number of patients with documented
bacterial infection was relatively small. Second limitation of
our study is that our findings are based on single measurement
and sequential testing might improve the diagnostic value of
procalcitonin. Third we did not test for viruses, common
pathogens in this population, although this omission does not
invalidate the findings for those patients with a viral or
bacterial infection identified.
Reference
1. Global strategy for the diagnosis, management and
prevention of chronic obstructive pulmonary disease
2006
2. C.J. Murray, et al Evidence-based health policy-lessons
from the Global Burden of Disease Study, Science 274
(5288) (1996) 740-743.
3. T.A. Seemungal, et al, Time course and recovery of
exacerbations in patients with chronic obstructive
pulmonar disease, Am. J. Respir. Crit. Care Med.161 (5)
(2000) 1608-1613.
4. Wilson R, et al Clinical studies in chronic bronchitis: a
need for better definition and classification of severity. J
AntimicrobChemother1996;37:205-208
5. Sethi S. et al Infectious etiology of acute exacerbations
of chronic bronchitis Chest. 2000;117:380S–5
6. Wedzicha JA.et al Exacerbations, etiology and
pathophysiologimechanisms. Chest. 2002; 121:136S-41.
7. Sethi S, et al. Bacterial infection in chronic obstructive
pulmonar disease in 2000: a state-of-the-art review. Clin
Microbiol Rev. 2001;14: 336-63
8. Miratviles M, et al and Study Group of Bacterial
Infection in COPD. Relation between bacterial flora in
sputum and functional impairment in patients with acute
exacerbations of COPD. Chest. 1999;116:40-6
9. Sethi S, et al. New strains of bacteria and exacerbations
of chronic obstructive pulmonary disease. N Eng J Med.
2002;347:465-71
10. Murphy TF, Sethi S et al. Chronic obstructive
pulmonary disease: role of bacteria and guide to
antibacterial selection in the older patient. Drugs Aging.
2002;19:761-75
11. Lieberman D et al. Chlamydia pneumoniae infection in
acute exacerbations of chronic obstructive pulmonary
disease: analysis of 250 hospitalizations. Eur J Clin
Microbiol InfectDis. 2001;20:698-704
12. Lieberman D, et al. Infectious etiologies in acute
exacerbation of COPD. Diagnostic Microbiology and
Infectious Disease. 2001; 40:95-102.
13. Lieberman D, et al. Serological evidence of Legionella
species in acute exacerbations of COPD. EurRespir J.
2002; 19:392-7.
14. Greenberg SB, et al Respiratory viral infections in adults
with and without chronic obstructive pulmonary disease.
Am J RespirCrit Care Med. 2000; 162:167-73.
15. Seemungalet al. Detection of rhinovirus in induced
sputum at exacerbation of chronic obstructive
pulmonary disease. EurRespir J. 2000;16:677-83
16. MacIntyre N et al. Acute Exacerbations and Respiratory
Failure in Chronic Obstructive Pulmonary Disease. Proc
Am Thorac Soc. 2008;5: 530-5
17. McHardy VU et al. A study of infective and other
factors in exacerbations of chronic bronchitis. Br J Dis
Chest. 1980;74:228-38
18. Mobbs KJ, et al Oropharyngeal gram negative bacillary
carriage in chronic obstructive pulmonary disease:
relation to severity of disease. Resp Med. 1999; 93:540-
5.
19. MacNee W. et al Acute exacerbations of COPD. Swiss
Med Wkly. 2003; 133: 247-57[20 [20] T. Canturk, B. et
al, The importance of serum procalcitonin levels in
patients with chronic obstructive pulmonary disease
exacerbations, Turk. J. Med. Sci. 38
20. L. Simon, F. Gauvin, D.K. Amre, et al, Serum
procalcitonin and C-reactive protein levels as markers of
bacterial infection: a systematic review and meta-
analysis, Clin. Infect. Dis. 39 (2004) 206-217.
21. B. Mu¨ ller, et al, Calcitonin precursors are reliable
markers of sepsis in a medical intensive care unit, Crit.
Care Med. 28 (2000) 977-983
22. E.D. Carrol et al, Procalcitonin as a marker of sepsis,
Int. J. Antimicrob. Agents 20 (2002) 1-9.
23. H.J. Van Leeuwen et al, Procalcitonin concentrations in
the diagnosis of acute inflammatory reactions, Ned
TijdschrGeneeskd 146 (2) (2002) 55-59.
24. B. Mulle, et al Markers of acute inflammation in
assessing and managing lower respiratory tract
International Journal of Recent Scientific Research Vol. 8, Issue, 7, pp. 18839-18843, July, 2017
18843 | P a g e
infections: focus on procalcitonin, Clin. Microbiol.
Infect. 12 (Suppl. 9) (2006) 8-16.
25. M. Christ-Crain, et al, Procalcitonin guidance of
antibiotic therapy in community-acquired pneumonia: a
randomized trial, Am. J. Respir. Crit. Care Med. 174
(2006) 84-93.
26. Muller B, et al. Calcitonin precursors are reliable
markers of sepsis in a medical intensive care unit. Crit
Care Med 2000; 28:977-83
27. Yu-Hong-Dou, et al The role of procalcitonin in the
identification of invasive fungal infection- Asystemic
review and meta analysis. Diagn Microbiol Infect Dis.
2013 Aug; 76(4):464-9
28. Lacoma A, et al. Value of procalcitonin, C-reactive
protein, and neopterin in exacerbations of chronic
obstructive pulmonary disease. Int J Chron Obstruct
Pulmon Dis. 2011; 6:157-169.
29. Bafadhel M, et al. Procalcitonin and C-reactive protein
in hospitalized adult patients with community-acquired
pneumonia or exacerbation of asthma or COPD. Chest.
2011;139(6):1410-1418
30. K.H. Mohamed a et al. The Egyptian Society of Chest
Diseases and Tuberculosis. Procalcitonin as a diagnostic
marker in acute exacerbation of COPD
31. CanturkTasic et al. The Importance of Serum
Procalcitonin Levels in Patients with Chronic
Obstructive Pulmonary Disease Turk J Med Sci
2008;38(2): 139-144
32. Chang C, Yao et al. The changes and clinical
implications of serum procalciton in in acute
exacerbations of chronic obstructive pulmonary disease.
ZhounghaJie He He Hu Xi Za Zhi 2006; 29(7): 444-7.)
33. Chang C, et al. Value of serum procalcitonin in
diagnosing bacterial lower respiratory tract infections in
people with exacerbation of chronic obstructive
pulmonary disease. Beijing Da XueXueBao 2006; 38(4):
389-92.
*******
How to cite this article:
Mohammadd Ashraf Khan et al.2017
, Procalcitonin as a Guide for Antibiotic Therapy in Patients Admitted With acute
Exacerbation of Chronic obstructive Pulmonary Disease. Int J Recent Sci Res. 8(7), pp. 18839-18843.
DOI: http://dx.doi.org/10.24327/ijrsr.2017.0807.0578