Serum procalcitonin levels in chronic obstructive pulmonary disease patients in North Indian Population.

Background: Exacerbations in Chronic obstructive pulmonary disease (COPD) have a considerable impact on morbidity, mortality, and quality of life. Procalcitonin (PCT) a polypeptide normally produced in neuroendocrine cells of the thyroid and lungs is a marker of systemic inflammation and bacterial infection.
Objectives: The aim of this study was to determine the levels of PCT in serum of acute exacerbation of COPD patients (AECOPD) and stable COPD patients in North Indian population. Materials and
Methods: The study was conducted on 80 AECOPD and 80 stable COPD patients in respiratory medicine department at tertiary care hospital in north India. PCT levels were measured in serum by ELISA kit. GraphPad Prism version 6.01 (GraphPad software Inc.; La, Jolla, CA, USA) was used for analysis of data.
Results: The present study showed that mean serum PCT levels were significantly higher in AECOPD group (1.31 ± 0.79) as compared to stable COPD group (0.1 ± 0.09) (P < 0.001).
Conclusion: The study confirms that PCT levels were higher in AECOPD patients as compared to stable COPD patients. PCT could be used as a biomarker of exacerbations of COPD and can be used to target management and guiding the treatment in patients with acute exacerbations of COPD.

INTRODUCTION

Chronic obstructive pulmonary disease (COPD), a progressive lung disease characterized by pulmonary and systemic inflammation, has become a major and increasing global health problem that is predicted to be a third-most common cause of death and disability by 2020.[1] The Global Burden of Disease Study reports a prevalence of 251 million cases of COPD globally in 2016. It is estimated that 3.17 million deaths were caused by the disease in 2015 (i.e. 5% of all deaths globally in that year) and more than 90% of COPD deaths occur in low- and middle-income countries.

Exacerbations in COPD (associated with worsening of COPD symptoms dyspnea, cough, and/or sputum production) and comorbidities have a considerable impact on morbidity, mortality, and quality of life[23] as it affects the health status of patients by accelerating the progression of the disease. These are caused either due to bacterial infection, viral infection, or some other trigger factors. It has been estimated that approximately 40%–50% of acute exacerbation of COPD (AECOPD) cases are due to bacterial infections.[4]

Procalcitonin (PCT) has been found to be more sensitive, and specific in differentiating bacterial infection from noninfectious inflammation.[5] PCT a calcitonin precursor is a polypeptide composed of 116 amino acids with a molecular weight of 13 kDa[67] that is normally produced in neuroendocrine cells of the thyroid and lungs. The high level of PCT found in serum during severe sepsis, and septic shock is a reflection of the severity of bacterial infections. Antibiotics are used in the treatment of exacerbation of COPD, but it is seen that not all patients get equal benefit from antibiotics, therefore, there is a need of biomarker that potentially detect such episodes. The previous study by Müller et al.[8] shows that PCT can be used as a favorable clinical marker as it increases within 6–12 h on stimulation and it levels get reduced when infection subsides either by antibiotics or by host immune system. Recently, PCT guidance has been found to be helpful in providing clinically relevant information as well as safely reduce antibiotic use in patients with respiratory illness.[910111213141516] Delay in diagnosis and treatment of COPD exacerbations and its associated comorbidities increases the mortality risk, but timely recognition of these patients and intervention is important. The level of PCT has been seen to be raised in response to a proinflammatory stimulus especially of bacterial origin, and the levels of it can be detected within 3–4 h after the invasion. We aimed to examine PCT levels in stable COPD patients as well as in acute exacerbation of COPD patients.

MATERIALS AND METHODS

The study was a single-center study conducted in the Department of Respiratory Medicine at King George's Medical University, Lucknow, Uttar Pradesh, India, a tertiary care hospital of North India. A total of 160 patients, 80 stable and 80 patients with acute exacerbation of COPD were included in the study. The COPD patients were recruited randomly from the outpatient department (OPD) of respiratory medicine as well as those admitted to the ward. The study was approved by Institutional Ethics Committee. The patients fulfilling the inclusion and exclusion criteria were recruited only after their written informed consent. Inclusion criteria for patients were age over 35 years, postbronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC <0.7), FEV1change <12% (FEV1) and who has symptoms of persistent cough, sputum production, or dyspnea, and/or a history of exposure to risk factors for the disease. Patients were excluded if they had a history of TB, asthma, and active cancer. At the enrolment visit, all patients underwent a detailed history, clinical evaluation (by a specialized respiratory physician), chest X-ray, spirometry, and venous blood sampling. The demographic information was obtained from self-reported responses to the predesigned questionnaire that includes demographic details, smoking history, pack-years, respiratory symptoms, and health status. The diagnosis of COPD was confirmed by spirometry according to GOLD criteria: FEV1/FVC < 0.7 and reversibility to inhaled bronchodilator in FEV1 <12% or <200 mL after administration of 200 μg salbutamol (2 puffs) using a pressurized metered dose inhaler with a spacer. The clinical severity of COPD was determined as per the criteria defined in the Global Initiative for chronic obstructive lung disease guidelines based on the postbronchodilator FEV1 values.[17]

Based on the patient self-reported smoking history, they were classified as current, ex-smoker, and never-smokers. Ex-smokers were those who did not smoke from the past 1 year. Venous blood samples (5 mL) were collected from all patients and centrifuged for analysis of PCT levels in serum. The obtained serum was kept at −80°C until the time of the analysis. PCT level was assessed in serum by ELISA kit according to manufacturer protocol.

Statistical analysis

GraphPad Prism version 6.01 was used for analysis of data. Values have been represented in mean ± SD (in case of the continuous variable) and expressed as number and percentages (in case of categorical variables). Analysis of variance was used for comparison of continuous data. P < 0.05 was considered statistically significant in all analysis.

RESULTS

In the present study, 80 stable COPD patients and 80 patients with acute exacerbation of COPD were recruited. The baseline characteristics of the study groups are shown in Table 1. Mean age of stable COPD patients was (57.08 ± 9.93) and in AECOPD patients were (56.68 ± 9.09) years, respectively, but there was no significant difference between both groups with respect to age (P = 0.79). The mean BMI was lower in patients with acute exacerbation of COPD as compared to the stable group, but the difference was not statistically significant (P = 0.13). In both groups, majority of patients were males. Dyspnea and cough were the most important symptoms observed in 97% of patients. There were nearly 75% of patients having a history of smoking in both groups, but the mean value of pack-years was higher in AECOPD group compared to the stable group. Spirometric values such as mean FEV1% predicted (pred), FVC, and FEV1/FVC ratio as mentioned in Table 1, were higher in AECOPD patients when compared to the stable group. According to GOLD criteria, stable COPD patients were grouped into four stages based on their severity [Table 2]. There were two patients in stage 1, 33 patients in stage 2, 37 patients in stage 3 while 8 patients in stage 4. PCT showed a negative correlation with FEV1% pred and FVC which denotes that increase in its levels in serum of AECOPD patients is correlated with the severity of airway obstruction. Mean value of serum PCT levels was significantly higher in the AECOPD patients as compared to stable COPD patients (1.3 ± 0.77 vs. 0.1 ± 0.09, P < 0.001 [Table 1]. Higher levels of PCT were also observed in AECOPD patients having higher no of exacerbation episodes in the previous year leading to hospitalization.

Table 1

Characteristics of stable chronic obstructive pulmonary disease and acute exacerbation of chronic obstructive pulmonary disease patients

Parameters	Stable COPD (n=80)	AECOPD (n=80)
Age (years)	57.08±9.93	56.68±9.09
Height (cm)	158.95±8.09	160.5±8.54
Weight (kg)	52.11±12.09	50.32±12.15
BMI (kg/m2)	20.71±4.78	19.71±3.63
Male	59	67
Female	21	13
Spirometry parameters
Post-FVC (L)	2.16±0.66	1.65±0.50
Post-FEV1 (L)	1.25±0.40	0.83±0.32
Post-FEV1/FVC	56.96±9.22	51.00±10.04
Post-FEV1% pred	48.78±14.48	44.25±11.46
Smoking history
Smoker (%)	29 (36.2)	35 (43.7)
Nonsmoker (%)	20 (25)	18 (22.5)
Ex-smoker (%)	31 (38.7)	27 (33.7)
Pack-years	17.3±14.24	20.05±11.73
Duration of hospital stay (AECOPD patients)	-	6.31±2.04
Previous hospitalization (preceding year) (%)	10 (12.5)	25 (31.5)
PCT (ng/ml)	0.1±0.09	1.3±0.77

BMI=Body mass index, COPD=Chronic obstructive pulmonary disease, FEV1/FVC=Force expiratory volume in 1 s/forced vital capacity, FEV1% pred=Force expiratory volume in 1 s percentage predicted, AECOPD=Acute exacerbation of chronic obstructive pulmonary disease, PCT=Procalcitonin

Table 2

Demographic and spirometric characteristics of stable chronic obstructive pulmonary disease patients on the basis of severity

Parameters	Mild (n=2)	Moderate (n=33)	Severe (n=37)	Very severe (n=8)	P
Age	55.5±3.53	58.36±10.16	56.70±9.41	51.75±6.75	0.69
Height (cm)	155±14.14	158±8.18	158±7.56	164.25±8.64	0.26
Weight (kg)	48.5±4.94	51.72±11.03	52.27±12.82	52.0±15.43	0.97
BMI (kg/m2)	20.65±5.81	20.56±4.25	20.98±5.40	18.98±4.14	0.77
FEV1% pred	87±1.41	60.12±7.87	41.75±5.31	25±3.03	<0.0001*
FVC post (L)	2.89±0.08	2.51±0.61	1.95±0.57	1.55±0.25	<0.0001*
FEV1 post (L)	1.75±0.02	1.5±0.4	1.1±0.23	0.74±0.11	<0.0001*
FEV1/FVC post	60.35±2.33	60.06±7.59	55.64±9.46	49.41±10.61	0.014*

*Significant at P<0.05. FEV1/FVC=Forced expiratory volume in 1 s/forced vital capacity, FEV1% pred=Force expiratory volume in 1 s percentage predicted, BMI=Body mass index

DISCUSSION

PCT levels were found to be significantly higher in AECOPD patients in comparison to stable COPD patients. PCT has been seen to be useful in guiding clinical decisions regarding antibiotic use. The present study evaluated the levels of PCT in COPD and AECOPD patients, and we found that the mean serum PCT levels were significantly higher in AECOPD group as compared to COPD group (P < 0.001) [Figure 1] which was consistent with previous studies.[181920] In a study by Chang et al.,[21] it was seen that patients with COPD exacerbation and positive sputum cultures for bacterial pathogen had significantly higher PCT values. We in our study too found high PCT levels in AECOPD group in comparison to stable COPD group which was also observed in other studies.[181920] Another study by Falsey et al.[22] showed that elevated serum PCT levels to be associated with more severe illness in patients hospitalized with symptoms of AECOPD and that high values may alert clinicians to the possibility of pneumonia. We also in our study found high levels of PCT in patients who were severely ill, AECOPD group and stage 4 (very severe) patients in stable COPD group. A significant correlation was found in our study between the PCT level and FEV1% pred and FVC in AECOPD patients indicating that high PCT may point to increasing severity of AECOPD. The present study in concordance with previous studies[23] suggests that COPD is independently associated with systemic inflammation of low grade than that observed in healthy subjects and this inflammatory activity increases as severity of disease increases. Our findings suggest that serum PCT levels have high sensitivity and specificity in displaying the inflammatory response in patients admitted with COPD exacerbation. In the stable COPD group, patients in stage 1 and 2 have serum PCT levels within normal limits. These findings agree with previous studies by Lacoma et al. and Bafadhel et al.[2425] Bafadhel et al.[25] in their study said that using PCT threshold levels of >0.25 ng/mL to guide antibiotic therapy in patients with exacerbation of COPD, antibiotic use can be reduced from 76% to 7%. In a study by Daniels et al.[26] a significant benefit of doxycycline was seen in patients with PCT levels below 0.1 ng/mL. Verduri et al.[27] in their study also emphasize that measuring PCT levels in patients may help to identify patients in whom shorter duration of antibiotic treatment could be safely prescribed, but they also suggested the need of few more studies. Halim and Sayed[18] in their study showed that at cutoff 1.495 ng/mL, PCT had 83.7% sensitivity and 78.3% specificity for predicting AECOPD patient that need ventilator support. Previous studies find PCT to be a good biomarker for predicting AECOPD patient that need ventilator support. We also measured PCT level in few AECOPD patients (n = 20) during admission as well as when the same patient returned to stable state after a month (patients visited OPD for their follow-up) and found that the levels of PCT decreased. The limitation of the present study was that patients were few in number and as this was not a follow-up study so the effects on health outcomes in every patient individually and their response to treatment cannot be evaluated, but we do found that elevated serum PCT levels are associated with more severe illness in patients hospitalized with symptoms of AECOPD and that high values may also alert clinicians to the possibility of pneumonia. Antibiotics are used in the treatment of exacerbations of COPD but not all patient equally experience benefit from antibiotics. AECOPD patients selected on the basis of evidence of bacterial infection or by the severity of illness are more likely to benefit than those patients who are less ill. Using PCT as a biomarker for guiding treatment in COPD patients would have important implications in clinical practice as overuse of antibiotics can be substantially reduced, thereby decreasing antibiotic resistance and its related side effects and lower medical costs for hospital systems and the patient. Hence, we do suggest that PCT could be used as a biomarker of exacerbations of COPD, and can be used to target management and treatment of COPD patients.

Figure 1

Serum procalcitonin levels in stable chronic obstructive pulmonary disease and Acute Exacerbation of Chronic obstructive pulmonary disease patients

CONCLUSION

Biomarker directed therapy and biomarker evaluation can help in proper treatment of disease, reducing unnecessary resistance developed against drugs and any change in its levels can be associated with complications and recovery. Serum PCT measurements may be effective in guiding the treatment in patients with acute exacerbations of COPD and its proper management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.