Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation that is not fully reversible [1]. As a major global cause of death, COPD incurs substantial socioeconomic costs [2,3]. Moreover, acute exacerbation of chronic obstructive pulmonary disease (AECOPD) lead to accelerated decline in lung function, reduced quality of life, increased mortality, and greater socioeconomic expenses. Consequently, the prevention and early management of AECOPD are crucial for improving patient outcomes [4].
Given that respiratory tract infections may trigger AECOPD, it is essential to consider epidemiological characteristics and antimicrobial resistance when managing treatment. To date, most studies on AECOPD have been conducted in Western countries, with limited research from Asia focused on single centers or countries [5]. A recent prospective epidemiological study in the Asia-Pacific region assessed the prevalence of bacterial and viral pathogens in AECOPD via sputum samples. However, due to an insufficient number of participants, the results may not accurately reflect the disease burden in each country [6]. Furthermore, the majority of AECOPD cases examined were mild, and the study failed to assess pathogens associated with moderate to severe AECOPD adequately. Additionally, a recent domestic multicenter observational study aimed to identify pathogens linked to AECOPD, and preliminary findings have been reported. Nevertheless, further research is required to determine their clinical relevance to improve management of these exacerbations [7].
As antibiotic resistance represents a significant public health challenge globally, cases of AECOPD are frequently attributed to microorganisms such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), or Stenotrophomonas maltophilia that exhibit resistance to standard antibiotic treatments [8].
Consequently, this study sought to determine the rates of bacterial and viral identification in Korean patients hospitalized for AECOPD, explore variations in clinical characteristics depending on the pathogen, and ascertain factors associated with infections by potentially drug-resistant (PDR) pathogens unresponsive to conventional antibiotics.
Materials and Methods
1. Data recruitment
This study retrospectively evaluated data sourced from 28 hospitals in South Korea, compiled by the COPD study group of the Korean Academy of Tuberculosis and Respiratory Disease. According to the retrospective chart review, a total of 1,186 patients diagnosed with AECOPD from January 2015 to December 2018 were consecutively enrolled in our study [7]. The inclusion criteria for the study were as follows: (1) age over 40 years, (2) a history of COPD confirmed by relevant lung function tests, (3) diagnosis of moderate-to-severe AECOPD, and (4) assessment using all standard tests for pathogen detection. The exclusion criteria included: (1) antibiotic use within the previous 4 weeks for conditions other than AECOPD treatment, and (2) less than 30 days elapsed since the last acute exacerbation. COPD was diagnosed following the guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [1] employing spirometry, with a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity of less than 0.70 after bronchodilator application indicative of persistent airflow limitation. The attending physician confirmed the diagnosis of moderate-to-severe AECOPD based on the GOLD guidelines, defined by a significant worsening of respiratory symptoms such as cough, dyspnea, wheezing, and chest discomfort, necessitating treatment with antibiotics, systemic glucocorticoids, or hospitalization. Pulmonary function and COPD assessment test (CAT) scores in a stable state were documented within 6 months prior to an AECOPD event.
The study protocol received approval from the Institutional Review Board of Severance Hospital (approval number: 4-2019-1316) and was conducted adhering to the ethical standards established in the 1964 Declaration of Helsinki and subsequent amendments. Due to the retrospective nature of the study and the employment of anonymized clinical data, the requirement for informed consent was waived.
2. Microbiological evaluation
All microbiological assessments were conducted within 48 hours following the diagnosis of AECOPD, utilizing blood and lower respiratory tract specimens such as sputum, bronchial washing fluid, endotracheal aspirate, or nasopharyngeal swabs at the discretion of the treating physicians.
Sputum samples were cultured semi-quantitatively, and an etiological diagnosis was established when a predominant microorganism was isolated from group 4 or 5 sputum according to Murray and Washington’s grading system [9,10]. To confirm the presence of atypical bacterial pathogens, polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) were employed. To identify viral pathogens, PCR and rapid antigen testing (RAT) were used on nasopharyngeal swab specimens. Details of each microbiological evaluation are described in Supplementary Table S1.
3. Definition of terms
The bacterial pathogen group is characterized by the detection of organisms typically linked to respiratory tract infections, such as Haemophilus influenzae, Streptococcus pneumoniae, P. aeruginosa, Klebsiella pneumoniae, S. aureus, and Stenotrophonomas maltophilia, identified through culture methods, or atypical pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophilia, confirmed using PCR or RAT. The viral pathogen group is delineated by the identification of viruses commonly associated with respiratory tract infections, including rhinovirus, adenovirus, influenza A/B, respiratory syncytial virus (RSV), and parainfluenza, confirmed via PCR or RAT. Co-infection is identified by the simultaneous presence of both bacterial and viral pathogens associated with respiratory infections. The PDR pathogen group is defined as comprising P. aeruginosa, MRSA, and S. maltophilia.
4. Statistical analyses
Data were analyzed using SPSS version 26.0 software for Windows (IBM Corp., Armonk, NY, USA). Categorical variables are presented as absolute numbers and percentages. Continuous variables are expressed as mean±standard deviation. The chi-square test and Fisher's exact test were utilized to compare proportions between groups, whereas the Student's t-test and one-way analysis of variance were applied to continuous variables. Logistic regression analysis was conducted to identify factors associated with PDR pathogens. Variables included in the multivariable analysis were those commonly known to influence AECOPD or those statistically significant in the univariable analysis. All tests were two-tailed, and p-values <0.05 were considered statistically significant.
Results
1. Baseline characteristics
This study included a total of 1,186 patients, with 82.5% being male. The average age of the participants was 78.8 years. The mean duration since diagnosis with COPD was 7.6 years, the average percentage of predicted FEV1 was 49.5%, and the mean CAT score was 22.5. Predominant underlying lung diseases included pulmonary tuberculosis (31.8%), bronchiectasis (14.2%), and interstitial lung disease (2.3%). During episodes of acute exacerbation, the rate of admission to the intensive care unit (ICU) was 9.5%. The average length of hospital stay amounted to 12.6 days, and a majority of patients (95.8%) received antibiotic therapy during their hospitalization (Table 1).
2. Identified pathogens
The distribution of patients infected with bacterial, viral, and both bacterial and viral pathogens included 262 (22.1%), 265 (22.5%), and 129 (10.9%) individuals, respectively. Predominant bacterial pathogens identified were P. aeruginosa (17.8%), M. pneumoniae (11.2%), S. pneumoniae (9.0%), and K. pneumonia (7.8%). The most frequently identified viral pathogens included influenza A (19.0%), rhinovirus (15.8%), RSV (6.4%), and influenza B (6.0%) (Figure 1).
3. Comparison between the clinical features based on PDR pathogen identification
Table 2 shows the clinical features of patients during AECOPD according to PDR pathogen identification. The PDR pathogen group exhibited a lower body mass index (20.7 kg/m2 vs. 21.6 kg/m2, p=0.017), a lower percentage of predicted FEV1 (44.6% vs. 50.5%, p=0.021), more frequent acute exacerbation events over the past year (2.2 times vs. 1.5 times, p=0.001), and higher CAT scores (25.3 vs. 21.5, p=0.044) compared to the non-PDR pathogen group. Additionally, this group had higher rates of pulmonary tuberculosis (45.8% vs. 29.2%, p=0.001) and bronchiectasis (25.4% vs. 12.7%, p=0.001), as well as more frequent use of triple inhalers (42.3% vs. 28.8%, p=0.001) and systemic steroids (32.4% vs. 20.0%, p=0.002) within the last 6 months compared to the non-PDR pathogen group.
During an acute exacerbation event, patients in the PDR pathogen group required a longer hospital stay (15.9 days vs. 12.9 days, p=0.018) and had a higher ICU admission rate (15.9% vs. 9.5%, p=0.030) compared to those in the non-PDR pathogen group. No significant differences in the frequency and duration of symptoms between the two groups were found.
When patients were categorized based on pathogen type, those in the bacterial pathogen group required a longer hospital stay (p=0.044), a higher ICU admission rate (p=0.007), and a longer period of systemic steroid administration (p=0.013) compared to those in the other groups. Similarly, patients in the viral pathogen group exhibited higher rates of cough, sputum, and fever (p=0.001) compared to those in the other groups (Supplementary Table S2).
4. Factors associated with infection by PDR pathogens
In multivariate logistic regression analyses including ICS use within six months as a covariate, a history of pulmonary tuberculosis (odds ratio [OR], 1.66; p=0.046) and bronchiectasis (OR, 1.99; p=0.032) were identified as factors associated with infection by PDR pathogens. Additionally, ICS use within 6 months (OR, 1.62; p=0.066) was observed to potentially increase the risk of infection with PDR pathogens (Table 3, ICS model). In subsequent analyses involving triple inhaler use within the same timeframe as a covariate, bronchiectasis (OR, 1.94; p=0.043) and triple inhaler use within 6 months (OR, 2.04; p=0.005) were also linked to infection by PDR pathogens (Table 3, triple inhaler model).
Discussion
This extensive, retrospective, multi-center study explored the variety of pathogens identified in patients with AECOPD in South Korea, delineated differences in clinical features among pathogen groups, and detailed the factors associated with PDR pathogen identification. Of the patients, 22.1% were infected with bacterial, 22.5% with viral, and 10.9% with both bacterial and viral pathogens. The predominant bacteria identified were P. aeruginosa, M. pneumoniae, and S. pneumoniae. Factors such as a history of pulmonary tuberculosis, bronchiectasis, and recent triple inhaler use were linked to PDR pathogen infections. Additionally, hospital stay length and ICU admission rates significantly increased when PDR pathogens were identified.
Respiratory infection is a principal cause of AECOPD. Prior studies have determined that the identification rates of bacteria and viruses are 40%-60% and 20%-40% in patients with AECOPD, respectively [11,12]. Aligned with these results, our study recorded bacterial and viral identification rates of 33.0% and 33.2%, respectively. Environmental factors and racial demographics can influence the strains of pathogens identified. Previous research conducted in South Korea revealed that H. influenzae, S. pneumoniae, and P. aeruginosa were the predominant bacterial pathogens linked to AECOPD [13,14]. In our investigation, P. aeruginosa (9.8%), M. pneumoniae (6.2%), and S. pneumoniae (5.0%) were the most frequently identified bacteria. Typically, P. aeruginosa is commonly found in patients with severe airflow limitation and underlying structural lung diseases, such as bronchiectasis [15-17]. Our study reported a high proportion of these patients and may have identified P. aeruginosa at a more elevated rate compared to previous studies. Similarly, M. pneumoniae was identified at a greater rate than in earlier research, which can be attributed to the employment of both PCR and antibody detection testing in this analysis. In contrast, H. influenzae exhibited a lower identification rate in this investigation compared to previous reports, due to the absence of PCR testing for this bacterium. Regarding viruses, previous research in South Korea has identified the influenza A virus and the rhinovirus as the predominant viral pathogens [14]. Consistently, our findings confirm these results, with the influenza A virus (13.7%) and rhinovirus (8.7%) being the most frequently detected among patients.
Numerous clinical studies have substantiated that administering empirical antibiotics during AECOPD significantly reduces the incidence of treatment failure and decreases short-term mortality [18,19]. Nonetheless, it is crucial to consider factors associated with antibiotic-resistant strain infections when determining appropriate antibiotic therapy. Prior research indicates that the prevalence of antibiotic-resistant strains is elevated in patients with severe lung function impairment or structural lung disease during AECOPD [7,20]. In this study, significant predictors of PDR pathogen infection included a history of bronchiectasis (OR, 1.97), tuberculosis (OR, 1.69), and triple inhaler use within the previous 6 months (OR, 2.04).
Diminished mucociliary clearance, compromised innate immunity, and reduced alveolar macrophage activity lead to microbial colonization in COPD, which promotes chronic inflammation and subsequent infection or AECOPD [21]. When complicated by bronchiectasis, COPD leads to exacerbated airway inflammation, evidenced by elevated sputum levels of interleukin 6 (IL-6) and IL-8. A high incidence of bronchiectasis in COPD correlates with extensive pathogen colonization in the lower airway, increased rates of P. aeruginosa isolation, elevated airway inflammatory markers, and prolonged symptom recovery time post-exacerbation [22,23]. Previously, the incidence of post-infectious bronchiectasis was reported as 15% to 50%, with prior tuberculosis infection being the primary known cause of bronchiectasis among various factors [24].
The utilization of triple inhalers is indicative of severe COPD, characterized by frequent exacerbations and diminished pulmonary function as per the guidelines established by the Korean COPD Association [25]. A systematic review noted that patients with COPD, who have poor lung function, previous antibiotic exposure, and hospitalizations, exhibited higher incidences of infections caused by antimicrobial-resistant pathogens [26].
In the current study, patients who tested positive for pathogens were more likely to have received systemic corticosteroids previously when compared with those who tested negative, and this was particularly noted in the PDR pathogen group as opposed to the non-PDR pathogen group. However, upon adjusting for various factors, there was no increased risk of infection with PDR pathogens. Among patients with severe AECOPD requiring intubation and mechanical ventilation, previous long-term use of corticosteroids did not elevate the risk of infection with multidrug-resistant pathogens, corroborating findings from earlier studies [27]. However, ICSs tended to enhance the risk of infection with PDR pathogens in this study. It is well documented that ICS increases the incidence of pneumonia in COPD patients. Prolonged ICS therapy has demonstrated an increase in bacterial load during COPD exacerbations, particularly in patients with low eosinophil counts in blood and/or sputum [28]. Use of ICSs has also been linked to a significant dose-related risk of acquiring P. aeruginosa infection in COPD patients [29,30]. Patients with chronic respiratory diseases predominantly managed with ICSs also face an independently elevated risk of infection with potentially antibiotic-resistant pathogens, leading to community-acquired pneumonia [31,32]. After inhalation, corticosteroids are deposited as small particles on the surface of the airway mucosa and gradually dissolve in the mucosal lining fluid before being absorbed into the airway/lung tissue. Consequently, ICSs remaining in the mucosal lining fluid may contribute more to colonization with pathogenic bacteria than systemic corticosteroids do [33].
This study exhibited several strengths. Conducted in multiple centers, our results accurately represent the local potentially pathogenic microorganisms (PPMs) in patients with AECOPD necessitating hospitalization. Additionally, data were amassed from tertiary or referral hospitals equipped with PCR capabilities for the detection of viral and atypical pathogens. Over 80% of the patients underwent viral PCR testing and more than 50% underwent PCR or antigen testing for atypical bacteria, thereby providing a comprehensive approach to identifying PPMs during AECOPD episodes.
However, the current study had multiple limitations. First, the microbiological evaluation was not uniformly carried out across all patients. Although traditional bacterial culture and viral PCR were performed in nearly all cases of AECOPD, atypical pathogen testing was employed at the discretion of the clinician when deemed necessary. Second, it was challenging to ascertain whether the identified pathogens were causative of respiratory infection or mere colonization. Prior microbiology test results from the same patients could assist in making this distinction; however, such data were not accessible in this study. Third, sputum was the primary respiratory specimen used in identifying pathogens during microbiological examinations. Although some previous studies have demonstrated higher pathogen identification rates using lower respiratory tract specimens compared to sputum, only 47 out of 1,186 patients in this study underwent microbiological testing using lower respiratory tract specimens [34]. Nevertheless, sputum tests remain critical as invasive testing poses challenges in most clinical settings. Lastly, the results of this study should be interpreted with caution when extrapolating to patients with mild or moderate COPD since our cohort predominantly included patients with moderate-to-severe AECOPD.
In conclusion, respiratory infections have been identified as a significant cause of AECOPD. In South Korea, the most prevalent bacterial pathogens are P. aeruginosa, M. pneumoniae, and S. pneumoniae, while principal viral pathogens include influenza and rhinovirus. We determined that factors associated with infection by PDR pathogens include a history of pulmonary tuberculosis, bronchiectasis, and/or triple inhaler use. Nonetheless, further research is required to ascertain whether these pathogens contribute to the development and progression of AECOPD.
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