Abstract
Objective: To investigate the expression and clinical significance of eosinophil (EOS), procalcitonin (PCT) and C-reactive protein (CRP) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) complicated with pulmonary infection. Methods: All of the 167 AECOPD patients treated in our hospital were included as the research subjects for this retrospective study. The patients were divided into an infected group (n=41) and a non-infected group (n=126) according to the presence or absence of pulmonary infection. Etiological analysis and antimicrobial susceptibility test were performed on patients in the infection group, and the levels of serum PCT, CRP and EOS were compared between the two groups. According to the forced expiratory volume in one second (FEV1), the pulmonary function of the infection group was divided into 1-3 grades, and the levels of CRP, PCT and EOS in different grades were compared. The correlation between the levels of CRP, PCT, EOS and the ratio of FEV1/FVC (forced vital capacity) in infection group was analyzed. The ROC curve was used to analyze the clinical value of CRP, PCT and EOS levels in the diagnosis of AECOPD complicated with lung infection. Results: A total of 59 strains of pathogenic bacteria were isolated from 41 patients, including 41 strains of Gram-negative bacteria (69.49%), 16 strains of Gram-positive bacteria (27.12%) and 2 strains of fungi (3.39%). Among the Gram-negative bacteria, Klebsiella Pneumoniae and Pseudomonas Aeruginosa were highly resistant to Cefuroxime, Levofloxacin and Ampicillin. And among the Gram-positive bacteria, Staphylococcus Aureus and Streptococcus Pneumoniae were highly resistant to Penicillin, Gentamicin and Erythromycin. The levels of CRP, PCT and EOS in infected group were significantly higher than those in non-infected group (P<0.05); with the increase of pulmonary function grade, the levels of CRP, PCT and EOS were significant increased (P<0.05); and the levels of CRP, PCT and EOS were negatively correlated with the FEV1/FVC ratio (P<0.05). ROC curve results show that the levels of CRP, PCT and EOS have high clinical value in the diagnosis in patients of AECOPD complicated with pulmonary infection (all AUC>0.7). Conclusion: Gram-negative bacteria are the main bacteria in AECOPD complicated with pulmonary infection, and drugs should be used rationally according to the results of antimicrobial susceptibility test. The levels of CRP, PCT and EOS increased significantly and were closely related to pulmonary function, and thus have obvious clinical value in the diagnosis of AECOPD complicated with pulmonary infection.
Keywords: Acute exacerbation of chronic obstructive pulmonary disease, pulmonary infection, eosinophil, procalcitonin, C-reactive protein
Introduction
Chronic obstructive pulmonary disease (COPD) is a common lung disease with highly destructiveness and longer course, which is characterized by persistent airflow limitation. It can cause irreversible damage to the lungs with a high fatality rate [1-3]. At present, the pathogenesis of COPD is not clear, but the condition is characterized by recurrent attacks and progressive progress. The 1-2 times of acute exacerbation per year experienced by most of COPD patients is also the leading cause of death. Studies have shown that infection is one of the risk factors leading to acute exacerbation of COPD. Therefore, in addition to alleviating the condition of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), it is also necessary to actively control the infection. Exploring the biological indicators for early evaluation of infection also shows great clinical significance [4-7]. In recent years, a few studies have found that the existence of eosinophil (EOS) inflammation in COPD patients, suggests that EOS can be used as one of the biomarkers of COPD. However, there are very few reports about EOS expression in AECOPD patients complicated with pulmonary infection [8-10]. Procalcitonin (PCT) and C-reactive protein (CRP), as infectious markers, play an important role in the identification of infectious diseases such as bacterial or viral infection [11-13]. Based on this, this study aims to explore the expression of EOS, PCT and CRP in patients with AECOPD complicated with lung infection, aiming to provide relevant evidence for the clinical diagnosis and treatment of AECOPD complicated with pulmonary infection.
Materials and methods
Baseline data
A total of 167 patients with AECOPD treated in Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine from January 2017 to December 2019 were divided into infection group (n=41) and non-infection group (n=126). The diagnostic criteria of patients in the infection group referred to the relevant standards established by the Infectious Diseases Society of America (IDSA) in 2016 [14]. All patients informed consent and signed the consent form. This study was approved by the Ethics Committee of Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine.
Inclusion and exclusion criteria
Inclusion criteria
(1) All patients meet the relevant diagnostic criteria of the Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease [15]; (2) Patients aged between 20-85 years old; (3) Patients without immune disease; (4) Patients without severe hepatorenal function diseases; (5) Patients did not receive other treatment before admission; (6) The ratio of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) <70%.
Exclusion criteria
(1) Patients that complicated with other serious diseases or infections; (2) Patients with neurological or mental diseases; (3) Patients who were participating in other studies; (4) Patients had organic lesions in the lung; (5) Patients had poor compliance.
Methods
Pathogen identification and drug resistance analysis
The sputum samples of the infection group were collected and inoculated into the sterile culture flasks, which was submitted for examination immediately. The samples were streak inoculated on the blood plate culture medium (Guangdong Huankai Microbiological Technology Co., Ltd., China). Some special samples should be inoculated on the broth medium (Shijiazhuang Seamer Technology Co., Ltd., China), and then streak inoculated on the blood plate culture medium. After incubated at 37°C for 24-72 hours, the bacteria were preliminarily identified according to the results of Gram staining and colony characteristics, and finally identified by the automatic microbial identification instrument (Beckman Coulter Co., Ltd., USA). The quality control bacteria were Staphylococcus aureus (ATCC25923), Staphylococcus epidermidis (ATCC12228) and Klebsiella pneumoniae (ATCC70060), all of which were purchased from the laboratory of Chinese Center for Disease Control and Prevention. GN2011 method was used for antimicrobial susceptibility test of Gram-positive bacteria, GP method was used for antimicrobial susceptibility test of Gram-negative bacteria, and disk diffusion method was used for antimicrobial susceptibility test [16].
Detection of serum PCT, CRP and EOS levels
Each 5 mL×2 tubes of venous blood were drawn from all patients when they were enrolled before receiving any treatment. One tube of the venous blood was centrifuged at 3000 r/min for 5 min to separate the serum. Then the serum CRP level was detected by immunoturbidimetric method (AU400 automatic biochemical analyzer, Olympus, Japan), and the PCT level was detected by enzyme-linked immunofluorescence method (ELISA, Spectra-MaxParadigm multifunctional microplate reader, Molecular Devices, United States). The other tube was used for detection of EOS levels by a fully automatic biochemical analyzer (Hitachi, Japan). All the kits were purchased from Shanghai Beyotime Biotechnology Co., Ltd.
Pulmonary function grading
Grading criteria: Grade I, FEV1 ≥80% of the expected value; Grade II, FEV1 accounts for 50%-80% of the predicted value; Grade III, FEV1 accounts for less than 50% of the expected value [15].
Outcomes measurement
Main outcomes: PCT, CRP and EOS levels in the infected and non-infected groups; CRP, PCT and EOS levels in patients with different pulmonary function levels; The clinical value of ROC curve analysis of CRP, PCT and EOS levels in the diagnosis of AECOPD complicated with pulmonary infection.
Secondary outcomes: Pathogenic analysis and antimicrobial susceptibility test of patients in the infection group; The correlation between CRP, PCT and EOS levels and FEV1/FVC ratio in the infection group.
Statistical analysis
SPSS 22.0 was used for statistical analysis, and the measurement data were expressed as mean ± standard deviation (x̅ ± sd). Variance analysis was used for comparison of measurement data among multiple groups, and the t test was used for comparison between two groups. The counting data were expressed by the number of cases/percentage (n%), and it was compared by χ2 test. Perason correlation was used to analyze the correlation, and ROC curve was used to analyze the clinical value of PCT, CRP and EOS in the diagnosis of AECOPD complicated with pulmonary infection. P<0.05 is considered statistically significant.
Result
Comparison of the baseline data between the two groups
The results showed that there was no significant difference in the baseline data such as age and gender between the two groups (P>0.05), as shown in Table 1.
Table 1.
Comparison of baseline data between the two groups
| Index | Infection group (n=41) | Non-infection group (n=126) | t/χ2 | P |
|---|---|---|---|---|
| Age (years) | 64.5±3.4 | 64.1±3.7 | 0.613 | 0.541 |
| Gender (n) | 0.053 | 0.818 | ||
| Male | 22 | 65 | ||
| Female | 19 | 61 | ||
| History of hypertension (n) | 0.937 | 0.333 | ||
| Yes | 15 | 36 | ||
| No | 26 | 90 | ||
| Complicated with diabetes (n) | 2.805 | 0.094 | ||
| Yes | 16 | 32 | ||
| No | 25 | 94 | ||
| Use of prophylactic antimicrobials | 0.014 | 0.907 | ||
| Yes | 18 | 54 | ||
| No | 23 | 72 | ||
| Mechanical ventilation | 0.331 | 0.565 | ||
| Yes | 12 | 43 | ||
| No | 29 | 83 |
Distribution of pathogens in infection group
The results showed that a total of 59 strains of pathogenic bacteria were isolated from 41 patients, including 41 strains of Gram-negative bacteria (69.49%), 16 strains of Gram-positive bacteria (27.12%) and 2 strains of fungi (3.39%), as shown in Table 2 and Figure 1.
Table 2.
Distribution of pathogens in the infection group
| Pathogenic Bacteria | Strains (n=59) | Constituent ratio (%) |
|---|---|---|
| Gram-negative bacteria | 41 | 69.49 |
| Klebsiella pneumoniae | 14 | 23.73 |
| Pseudomonas aeruginosa | 12 | 20.34 |
| Acinetobacter baumannii | 8 | 13.56 |
| Enterobacter aerogenes | 5 | 8.47 |
| Escherichia coli | 2 | 3.39 |
| Gram-positive bacteria | 16 | 27.12 |
| Staphylococcus aureus | 8 | 13.56 |
| Streptococcus pneumoniae | 5 | 8.47 |
| Staphylococcus epidermidis | 3 | 5.08 |
| Fungus | 2 | 3.39 |
| Candida | 2 | 3.39 |
Figure 1.
Distribution of pathogens in the infection group.
The antibacterials resistance of major Gram-positive and Gram-negative bacteria
The results showed that Klebsiella pneumoniae and Pseudomonas aeruginosa were highly resistant to cefuroxime, levofloxacin and ampicillin among Gram-negative bacteria, while Staphylococcus aureus and Streptococcus pneumoniae were highly resistant to penicillin, gentamicin and erythromycin in Gram-positive bacteria, as shown in Tables 3, 4.
Table 3.
Results of drug resistance of major Gram-negative bacteria
| Antibacterials | Klebsiella pneumoniae (n=14) | Pseudomonas aeruginosa (n=12) | ||
|---|---|---|---|---|
|
|
|
|||
| Strains | Drug resistance rate (%) | Strains | Drug resistance rate (%) | |
| Cefuroxime | 13 | 92.86 | 10 | 83.33 |
| Levofloxacin | 12 | 85.71 | 7 | 58.33 |
| Ampicillin | 12 | 85.71 | 9 | 75.00 |
| Cefuroxime | 7 | 50.00 | 5 | 41.67 |
| Cefotaxime | 5 | 35.71 | 3 | 25.00 |
| Ceftazidime | 3 | 21.43 | 1 | 8.33 |
| Meropenem | 1 | 7.14 | 0 | 0.00 |
| Ciprofloxacin | 0 | 0.00 | 0 | 0.00 |
| Imipenem | 0 | 0.00 | 1 | 8.33 |
Table 4.
Results of drug resistance of major Gram-positive bacteria
| Antibacterials | Staphylococcus aureus (n=8) | Streptococcus pneumoniae (n=5) | ||
|---|---|---|---|---|
|
|
|
|||
| Strains | Drug resistance rate (%) | Strains | Drug resistance rate (%) | |
| Penicillin | 7 | 87.50 | 5 | 100.00 |
| Gentamicin | 7 | 87.50 | 5 | 100.00 |
| Erythromycin | 6 | 75.00 | 3 | 60.00 |
| Clindamycin | 5 | 62.50 | 2 | 40.00 |
| Tetracycline | 5 | 62.50 | 2 | 40.00 |
| Rifampicin | 3 | 37.50 | 2 | 40.00 |
| Moxifloxacin | 2 | 25.00 | 1 | 20.00 |
| Levofloxacin | 1 | 12.50 | 0 | 0.00 |
| Vancomycin | 0 | 0.00 | 1 | 20.00 |
| Teicoplanin | 0 | 0.00 | 0 | 0.00 |
Comparison of PCT, CRP and EOS levels between the two groups
The results showed that the levels of CRP, PCT and EOS in the infected group were significantly higher than those in the non-infected group (P<0.001). See Table 5 for detail.
Table 5.
Comparison of PCT, CRP and EOS levels between the two groups
| Groups | PCT (μg/L) | CRP (mg/L) | EOS (%) |
|---|---|---|---|
| Infection group (n=41) | 3.22±1.87 | 20.15±8.66 | 3.37±1.17 |
| Non-infection group (n=126) | 0.86±0.75 | 9.13±5.32 | 2.16±1.01 |
| t | 11.589 | 9.737 | 6.437 |
| P | <0.001 | <0.001 | <0.001 |
Note: EOS: eosinophil; PCT: procalcitonin; CRP: C-reactive protein.
Comparison of PCT, CRP and EOS levels in patients with different pulmonary function grades in infection group
The results showed that compared with the grade I group, the levels of CRP, PCT and EOS in the grades of II and III groups were significantly higher, and compared with the grade II group, the CRP, PCT and EOS levels in the grade III group were significantly higher (P<0.05). See Table 6 for detail.
Table 6.
Comparison of PCT, CRP and EOS levels in patients with different pulmonary function grades in infection group
| Groups | PCT (μg/L) | CRP (mg/L) | EOS (%) |
|---|---|---|---|
| Grade I (n=12) | 2.01±1.09 | 13.52±6.69 | 2.19±0.83 |
| Grade II (n=19) | 3.32±1.54* | 19.94±8.51* | 3.32±1.21* |
| Grade III (n=10) | 4.39±1.89*,# | 26.85±9.02*,# | 4.51±1.07*,# |
| F | 6.793 | 7.258 | 12.635 |
| P | 0.003 | 0.002 | <0.001 |
Note: Compared with Grade I;
P<0.05.
Compared with Grade II;
P<0.05.
EOS: eosinophil; PCT: procalcitonin; CRP: C-reactive protein.
Correlation between the levels of PCT, CRP, EOS and FEV1/FVC ratio in infected group
The results showed that the levels of PCT, CRP and EOS were negatively correlated with the ratio of FEV1/FVC in the infection group (P<0.05), as shown in Table 7.
Table 7.
Correlation between the levels of PCT, CRP, EOS and FEV1/FVC ratio in infected group
| Statistics | PCT (μg/L) | CRP (mg/L) | EOS (%) |
|---|---|---|---|
| r | -0.564 | -0.338 | -0.417 |
| P | <0.001 | 0.003 | 0.021 |
Note: EOS: eosinophil; PCT: procalcitonin; CRP: C-reactive protein; FEV1/FVC: forced expiratory volume in one second/forced vital capacity.
Results of ROC curve
The results showed that PCT has a higher diagnostic value when the cut-off value is 1.817 μg/L (AUC=0.878); CRP has a higher diagnostic value when the cut-off value is 18.292 mg/L (AUC=0.850); EOS has a certain diagnostic value (AUC=0.780) when the cutoff value is 2.963%, as shown in Table 8 and Figure 2.
Table 8.
Results of ROC curve
| Index | Cutoff value | AUC | 95% CI | Sensitivity | Specificity | Positive predictive value | Negative predictive value | P |
|---|---|---|---|---|---|---|---|---|
| PCT (μg/L) | 1.817 | 0.878 | 0.811, 0.946 | 0.732 | 0.881 | 0.666 | 0.910 | <0.001 |
| CRP (mg/L) | 18.292 | 0.850 | 0.780, 0.921 | 0.659 | 0.921 | 0.730 | 0.893 | <0.001 |
| EOS (%) | 2.963 | 0.780 | 0.698, 0.862 | 0.659 | 0.786 | 0.500 | 0.877 | <0.001 |
Note: EOS: eosinophil; PCT: procalcitonin; CRP: C-reactive protein.
Figure 2.
Results of ROC curve. EOS: eosinophil; PCT: procalcitonin; CRP: C-reactive protein.
Discussion
This study showed that the Gram-negative bacteria were the major pathogens of AECOPD complicated with pulmonary infection, and among which the Klebsiella pneumoniae (23.73%) and Pseudomonas aeruginosa (20.34%) accounted for the highest proportion. Respiratory tract is the most common site of pathogen infection of AECOPD, which might be due to the weakening of alveolar elasticity, the attenuation of bronchial ciliary motility, and the difficulty of exclusion of lung secretions in patients with AECOPD. Besides, the immune function of patients is also weakened, resulting in an increased risk of infection of this kind of pathogens. Among Gram-positive bacteria, the infection rates of Staphylococcus aureus and Streptococcus pneumoniae were also higher (13.56% and 8.47%), which may be related to invasive operation, long-term use of antibiotics and other factors [17]. The results of drug resistance showed that all bacteria had certain drug resistance, suggesting that drugs should be used rationally according to the patient’s condition.
PCT is mainly secreted by thyroid C cells. Under normal physiological conditions, the level of PCT is very low. Once infection occurs, a large amount of PCT is secreted by liver macrophages and monocytes under the stimulation of endotoxin and other factors, resulting in a significant increase in serum PCT level, and reached the peak at 12-24 hours after infection [18,19]. Studies have shown that the increase of PCT level is mainly caused by bacterial infection or endotoxin and inflammatory factors that released by bacteria. However, the viral infection or other factors do not often cause the increase of PCT level, so it is considered to have high clinical value in the diagnosis of pulmonary bacterial infection [20]. The results of this study showed that the PCT level in AECOPD patients complicated with pulmonary infection increased significantly and closely related to the severity of lung function, which was consistent with the results of related studies. The results of ROC curve showed that when the cutoff value was 1.817 μg/L, the AUC of PCT in the diagnosis of AECOPD complicated with pulmonary infection was 0.878, suggesting that PCT could be used as one of the auxiliary diagnostic indicators in the diagnosis of AECOPD complicated with pulmonary infection. CRP is a kind of acute phase reactive protein, which has the characteristics of early appearance and rapid increase. When infectious occur, the level of CRP will increase in varying degrees. Studies have also shown that when infection occurs, CRP as a sensitive indicator of systemic inflammatory response, the level of which will increase significantly, and the change is often not affected by radiotherapy/chemotherapy drugs and hormone drugs [21]. The level of CRP in patients with bacterial pneumonia is usually significantly increased, and it is believed to be closely related to the severity of the disease [22]. Indeed, this study showed that the level of CRP in patients with AECOPD complicated pulmonary infection was significantly higher than that in patients with simple AECOPD, and it is related to the severity of pulmonary function. The results of ROC curve showed that when the cutoff value was 18.292 mg/L, the AUC of PCT in the diagnosis of AECOPD with infection was 0.850, suggesting that it has a certain diagnostic value. Studies have shown that during the acute phase of COPD, local inflammatory stimulation promotes the exudation of a large number of inflammatory cells, which in turn leads to damage to lung tissue and causes airway remodeling [16]. Therefore, patients with acute exacerbation of COPD are extremely sensitive to clinical indicators. Previous studies have found a significant increase in EOS levels in sputum and bronchial biopsies in patients with AECOPD [23]. Studies have also confirmed that the invasion of eosinophilic inflammation is often closely related to the acute exacerbation of viral infections, however it’s correlation with bacterial infections is not yet clear [24]. The results of this study showed that the level of EOS in peripheral blood of patients with pulmonary infection was significantly higher than that of patients with simple AECOPD, and the worse the pulmonary function of the patients, the higher the level of EOS. The study further found that when the cut-off value was 2.963%, the AUC of EOS in the diagnosis of AECOPD complicated with pulmonary infection was 0.780, suggesting that it has a certain clinical value.
To sum up, Gram-negative bacteria are the main causes of AECOPD complicated with pulmonary infection, and drugs should be used rationally according to the results of drug sensitivity. The levels of CRP, PCT and EOS were increased significantly in patients, and they were closely related to pulmonary function. CRP, PCT and EOS have certain clinical value in the diagnosis of AECOPD complicated with pulmonary infection. However, the sample source used in this study is a single center, and the changes of various indicators have not been dynamically observed. Therefore, follow-up studies are still needed for further verification.
Disclosure of conflict of interest
None.
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