Abstract
Background:
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Critically ill patients with COPD exacerbations may require invasive mechanical ventilation (IMV). Ventilator-associated pneumonia (VAP) commonly occurs in the intensive care unit (ICU) and is usually associated with high mortality. Current studies on the association between COPD and VAP are limited. This work compared the causes and clinical outcomes of VAP in patients with and without COPD in Taiwan.
Methods:
This retrospective observational study was conducted at the Chiayi Chang Gung Memorial Hospital. Patients diagnosed with VAP were enrolled between January 2015 and December 2019. The COPD diagnosis was based on postbronchodilator pulmonary function tests. We compared the bacterial cause, ICU and hospital stay length, IMV duration and mortality rates in patients with and without COPD.
Results:
A total of 175 patients with VAP were enrolled, 44% of whom presented had preexisting COPD. The disease severity on the day of admission was similar in both groups. Microorganisms were identified in 83 (47%) patients, with Pseudomonas aeruginosa, Acinetobacter spp., and Klebsiella pneumoniae being the most common pathogens. The proportion of multidrug resistant isolates showed no significant differences between groups. Most patients underwent antibiotic treatment before VAP onset. The length of ICU and hospital stays and IMV duration after VAP onset were similar between the two groups, as well as ICU mortality, in-hospital mortality, and 14-day mortality.
Conclusion:
Our study revealed that COPD was not associated with worse clinical outcomes in patients with VAP. No significant differences in bacterial cause were observed between the two groups.
Keywords: Acinetobacter, Chronic obstructive pulmonary disease, Klebsiella pneumoniae, Pseudomonas aeruginosa, Ventilator-associated pneumonia
1. INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characterized by respiratory symptoms and irreversible airflow limitation caused by chronic inflammatory responses.1 It is the third leading cause of death worldwide and the eighth leading cause of death in Taiwan.2,3 Previous studies have shown that the incidence of COPD in Taiwan may continue to increase.4,5 Regarding the attributable economic burden, on average, more than $8700 is spent annually on severe COPD.6 An acute worsening of the respiratory symptoms requiring additional therapy is considered a COPD exacerbation.1 More than 25% of COPD exacerbations require intensive care, of which 6% to 10% involve endotracheal intubation with mechanical ventilation.7 Patients with COPD can develop ventilator-associated pneumonia (VAP) due to prolonged use of mechanical ventilation, atrophy of the diaphragmatic muscle, micro-aspiration, or general impairment of the host defense mechanism.8
VAP is commonly seen in the intensive care unit (ICU) due to the frequent use of prolonged endotracheal intubation and is associated with a high all-cause mortality rate of 20% to 50%.9,10 Various guidelines and recommendations have been developed to prevent VAP9,11–14; however, up to 10% to 20% of intubated patients develop the condition.13
Former studies supported that preexisting COPD could have a negative impact on survival in patients with VAP,15–17 whereas others found contradictory results with no significant differences.18–20 It remains unknown whether underlying COPD affects the outcomes of patients with VAP. In addition to VAP’s mortality, various causative bacteria, such as Escherichia coli, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and nonfermenting Gram-negative bacilli (GNB),19,21 have been reported to be more common in patients with COPD than in those without. However, studies on the impact of COPD on VAP in Taiwan remain limited. Therefore, our objective is to compare the clinical outcomes and causes of VAP between patients with and without COPD in this country.
2. METHODS
2.1. Study design and population
This retrospective observational study was conducted from January 2015 to December 2019 at Chiayi Chang Gung Memorial Hospital, a regional academic hospital with 1400 beds in southern Taiwan. The study population consisted of patients admitted to the ICU with discharge diagnoses of pneumonia who were older than 40 years of age, intubated, and mechanically ventilated for >48 hours. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), there is a higher COPD prevalence in patients aged >40 years than in younger patients.1 Those who had a tracheostomy tube in place before admission and those who had no reports of pulmonary function tests (PFTs) during the duration of the study were excluded. The codes used to label the discharge diagnoses of pneumonia were as follows: International Classification of Diseases (ICD) Ninth Edition, 480 to 488, 507, and 997.31 and ICD Tenth Edition, J09, J10, J11, J12, J13, J14, J15, J16, J17, J18, J22, J69, and J95.851.
The medical records of all eligible patients were reviewed to verify a VAP diagnosis. Then, patients with VAP were categorized into the COPD and non-COPD groups.
2.2. Definitions
VAP was defined as pneumonia that occurred >48 hours after endotracheal intubation. Pneumonia was diagnosed if new or progressive infiltrates were present on chest radiography with at least two of the following: temperature ≥38°C or <36°C, leukocytosis with a white blood cell count ≥12 000/μL or leukopenia with a white blood cell count ≤4000/μL, or purulent respiratory secretions.9,22 Additionally, we only analyzed the first VAP episode if several episodes were identified during the same course of intubation.
COPD diagnosis was based on the COPD GOLD criteria.1 Spirometry required for the diagnosis of COPD should have incorporated results from before and after the administration of a short-acting beta-2 agonist bronchodilator. A postbronchodilator ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) <70% confirmed airflow limitation of the airway. The severity of COPD was evaluated based on the predicted percentage of postbronchodilator FEV1.1
Lower respiratory tract samples were obtained using endotracheal aspirates or bronchoalveolar lavage. Bacterial identification and antimicrobial susceptibility tests were performed in a microbiological laboratory using standard methods. Bacterial identification was tested by biochemical reactions until the adoption of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF), which has been in practice since 2018. Antimicrobial susceptibility tests were performed by disk diffusion method or Vitek 2 system. Multidrug-resistant pathogens were defined as strains that were not susceptible to ≥3 antimicrobial categories.23
Antibiotics were considered appropriate for treatment if pathogens were susceptible to at least one of the antimicrobials in vitro and an adequate dose was used within 24 hours after the onset of VAP. Previous antibiotic use was defined as any antibiotic treatment for more than 24 hours during the two weeks preceding the VAP episode.
2.3. Data collection
All data were retrospectively collected from the Chang Gung Research Database during the index admission and reviewed by an advanced respiratory therapist and a senior pulmonologist. Demographic data, vital signs, laboratory results, chest image findings, microbiological results, comorbidities, use of antibiotics, reason for intubation, and clinical outcomes were collected. The patients were followed up until they were weaned from mechanical ventilation, tracheostomy, discharge, or death. In accordance to our institutional protocol, we utilized the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Simplified Acute Physiology Score II (SAPS II) as severity scoring systems at the time of admission.
2.4. Outcome measures
The primary outcome was the mortality rate, including ICU mortality, in-hospital mortality, and 14-day mortality after the onset of VAP. The secondary outcomes were the VAP bacterial cause, length of ICU stay, length of hospital stay, and duration of invasive mechanical ventilation (IMV) after the onset of the first VAP episode. We compared the clinical outcomes of VAP patients with and without COPD (COPD group vs non-COPD group).
2.5. Statistical analysis
Quantitative variables are described as mean ± SD and median (interquartile range [IQR]) for normal and skewed data, as appropriate. Categorical variables are expressed as numbers or frequency (%). The chi-square and Fisher exact tests were used to assess the statistical significance of categorical variables. Continuous variables were analyzed using the independent Student t test analyze normally distributed variables. In contrast, the Mann-Whitney U test was used to analyze nonnormally distributed variables. Data were managed on Excel spreadsheets (Microsoft Corp., Redmond, WA) and analyzed using SPSS software (version 26; IBM Corp., Armonk, New York, NY). Statistical significance was set at a two-tailed p value <0.05. We used logistic regression to analyze the association between ICU mortality and potential predictor variables.
3. RESULTS
3.1. Clinical characteristics of patients with VAP
Fig. 1 shows the flow chart of the included and excluded patients in this study. Among 3303 patients with potential VAP, 2888 were excluded because of the absence of PFT reports. The charts of 415 patients were reviewed to verify the VAP diagnosis. Two patients were excluded because of the absence of a postbronchodilator PFTs report, and 238 were excluded because they did not fulfill the VAP diagnostic criteria. Finally, 175 patients diagnosed with VAP were enrolled in this study, 77 of whom had preexisting COPD. Among the patients with COPD, 8 (10%) had GOLD stage I, 27 (35%) had GOLD stage II, 30 (39%) had GOLD stage III, and 12 (16%) had GOLD stage IV.
Fig. 1.
Flowchart of the included and excluded patients in this study. COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; PFT = pulmonary function test; VAP = ventilator-associated pneumonia.
In our analysis, data for the Modified Medical Research Council (mMRC) Dyspnea Scale and COPD Assessment Test (CAT) score were available for 47 patients (61%). The median (IQR) mMRC score was 3 (1 to 3), and the median (IQR) CAT score was 15 (11 to 20). Medication use patterns revealed that 37 patients (48%) were prescribed triple therapy, comprising a regimen consisting of a long-acting beta-2 agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled corticosteroid (ICS). Dual therapy involving either a LABA combined with a LAMA or an ICS was used by 32 (41%) patients, with the LABA-LAMA combination predominating (29 patients). Single bronchodilator therapy, utilizing either a LABA or a LAMA alone, was used by six (7.8%) patients.
Table 1 shows a comparison of clinical characteristics between patients with and without COPD. Compared with the non-COPD group, the COPD group had older patients with a lower body mass index. Additionally, the COPD group presented a higher proportion of patients with a history of smoking, and hypercapnic respiratory failure as intubation cause, and a smaller proportion with chronic kidney disease and diabetes mellitus compared to the group without COPD.
Table 1.
Characteristics of COPD and non-COPD patients with VAP
| COPD (n= 77) | Non-COPD (n = 98) | p | |
|---|---|---|---|
| Sex, male | 66 (85.7) | 72 (73.5) | 0.062 |
| Age (mean ± SD) | 77 ±1 0 | 72 ± 10 | 0.002 |
| BMI (mean ± SD) | 21.8 ± 3.6 | 24.1 ± 5.1 | 0.003 |
| APACHE II (mean ± SD) | 27 ± 7 | 28 ± 6 | 0.641 |
| SAPS II (mean ± SD) | 63 ± 19 | 63 ± 16 | 0.932 |
| Smoking history | 52 (67.7) | 44 (44.9) | 0.003 |
| Use of antibiotics before ICU | 28 (36) | 47 (48) | 0.124 |
| Use of antibiotics before VAP | 76 (99) | 97 (99) | 1.000 |
| Days to first VAP onset (median [IQR]) | 4 (3-7) | 4 (3-6) | 0.527 |
| Vasopressor use | 48 (62.3) | 52 (53.1) | 0.218 |
| Bacteremia | 11 (14.3) | 14 (14.3) | 1.000 |
| Comorbidity | |||
| Chronic renal disease | 16 (20.8) | 34 (34.7) | 0.043 |
| Chronic heart failure | 18 (23.4) | 25 (25.5) | 0.745 |
| Cancer | 24 (31.2) | 40 (40.8) | 0.188 |
| Liver cirrhosis | 9 (11.7) | 8 (8.2) | 0.434 |
| Chronic respiratory failure | 7 (9.1) | 3 (3.1) | 0.108 |
| Diabetes mellitus | 18 (23.4) | 43 (43.9) | 0.005 |
| Hypertension | 44 (57.1) | 54 (55.1) | 0.787 |
| Obstructive sleep apnea | 0 (0) | 4 (4.1) | 0.132 |
| Cause of intubation | |||
| Cardiac arrest | 8 (10.4) | 6 (6.1) | 0.302 |
| Hypercapnic respiratory failure | 24 (31.2) | 14 (14.3) | 0.007 |
| Hypoxemic respiratory failure | 24 (31.2) | 47 (48) | 0.025 |
| Mixed-type respiratory failure | 2 (2.6) | 5 (5.1) | 0.468 |
| Loss of consciousness | 3 (3.9) | 6 (6.1) | 0.733 |
| GI bleeding | 4 (5.2) | 1 (1) | 0.171 |
| Postoperative | 5 (6.5) | 7 (7.1) | 0.866 |
| Protect airway | 2 (2.6) | 0 (0) | 0.192 |
| Severe metabolic acidosis | 2 (2.6) | 6 (6.1) | 0.469 |
| Shock | 3 (3.9) | 6 (6.1) | 0.733 |
Data are shown as N (%) unless noted otherwise. p value <0.05 is considered statistically significant.
APACHE = Acute Physiology and Chronic Health Evaluation; BMI = body mass index; COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; ICU = intensive care unit; IQR = interquartile range; SAPS = Simplified Acute Physiology Score; VAP = ventilator-associated pneumonia.
3.2. Bacterial cause in patients with VAP
Bacterial causes were identified in 83 (47%) of 175 patients. Table 2 shows the distribution of the bacteria in the two groups. P. aeruginosa, Acinetobacter spp., and K. pneumoniae were the most common pathogens detected. No differences were observed in multidrug-resistant isolates or polymicrobial pneumonia between the COPD and non-COPD groups. No significant differences in bacterial cause were observed between the two groups but those with concomitant COPD exhibited a higher trend of infection with Acinetobacter spp. compared to those without COPD.
Table 2.
Microbiological findings in VAP patients with and without COPD
| COPD (n = 77) | Non-COPD (n = 98) | p | |
|---|---|---|---|
| Etiologic diagnosis | 37 (48) | 46 (46.9) | 0.884 |
| Diagnostic procedures | |||
| Endotracheal aspirate | 33 (42.8) | 42 (42.9) | 1.000 |
| Bronchoalveolar lavage | 10 (12.9) | 13 (13.2) | 0.957 |
| Microbiological findings | |||
| Polymicrobial pneumonia | 15 (19.4) | 19 (19.4) | 0.988 |
| MDR isolates, total | 12 (15.6) | 15 (15.3) | 0.960 |
| Gram negative | |||
| Acinetobacter spp. | 18 (23.3) | 13 (13.2) | 0.082 |
| Carbapenem-resistant | 4 (5.2) | 10 (10.2) | 0.225 |
| Multidrug resistant | 5 (6.5) | 11 (11.2) | 0.281 |
| Pseudomonas aeruginosa | 15 (19.4) | 16 (16.3) | 0.587 |
| Carbapenem-resistant | 3 (3.9) | 4 (4.1) | 1.000 |
| Multidrug resistant | 0 | 1 (1) | 1.000 |
| Klebsiella pneumoniae | 7 (9.1) | 11 (11.2) | 0.645 |
| Carbapenem-resistant | 3 (3.9) | 6 (6.1) | 0.733 |
| Multidrug resistant | 6 (7.8) | 6 (6.1) | 0.664 |
| Stenotrophomonas maltophilia | 10 (12.9) | 7 (7.1) | 0.195 |
| Escherichia coli | 2 (2.6) | 3 (3.1) | 1.000 |
| Enterobacter spp. | 2 (2.6) | 4 (4.1) | 0.592 |
| Carbapenem-resistant | 1 (1.3) | 1 (1) | 1.000 |
| Multidrug resistant | 1 (1.3) | 1 (1) | 1.000 |
| Proteus mirabilis | 1 (1.3) | 1 (1) | 1.000 |
| Citrobacter spp. | 0 | 2 (2) | 0.504 |
| Gram positive | |||
| Methicillin-sensitive Staphylococcus aureus | 3 (3.9) | 3 (3.1) | 1.000 |
| Methicillin-resistant Staphylococcus aureus | 2 (2.6) | 7 (7.1) | 0.302 |
Data are presented as N (%). The total percentage may be >100% owing to polymicrobial cases. Polymicrobial pneumonia was defined as the presence of >1 pathogen. p value <0.05 is considered statistically significant.
COPD = chronic obstructive pulmonary disease; MDR = multidrug-resistant; VAP = ventilator-associated pneumonia.
Most patients received antibiotic treatment before the VAP onset. No differences were found in the proportion of appropriate antibiotic treatment between groups (COPD group, 48%; non-COPD group, 43%; p = 0.493), neither between surviving patients with and without COPD (55% and 48%, respectively; p = 0.48).
3.3. Outcomes of VAP patients with and without COPD
Mortality, length of ICU stay, duration of IMV, and length of hospital stay were similar between groups, as shown in Table 3. We further analyzed surviving patients in both groups and found no statistical differences in the length of ICU stay, hospital stay, and duration of IMV. After conducting multivariable logistic regression analysis (Table 4), vasopressor use during intubation was the only predictor for ICU mortality.
Table 3.
Clinical outcomes of study patients
| All patients | Survived patients | |||||
|---|---|---|---|---|---|---|
| COPD (n = 77) | Non-COPD (n = 98) | p | COPD (n = 49) | Non-COPD (n = 50) | p | |
| Length of ICU stay | 11 (6-15) | 11 (6-19) | 0.317 | 12 (7-17) | 11 (6-18) | 0.875 |
| Duration of IMV | 7 (2-14) | 7 (2-21) | 0.805 | 5 (1-23) | 6 (2-21) | 0.787 |
| Length of hospital stay | 20 (11-41) | 27 (11-50) | 0.124 | 26 (16-53) | 33 (22-64) | 0.177 |
| 14-d mortality after VAP | 21 (24) | 23 (27) | 0.565 | |||
| In-hospital mortality | 28 (36) | 48 (49) | 0.095 | |||
| ICU mortality | 24 (31) | 34(35) | 0.623 | |||
Data are shown as the median with interquartile range for days and N (%) for mortality. p-value <0.05 is considered statistically significant.
COPD = chronic obstructive pulmonary disease; ICU = intensive care unit; IMV = invasive mechanical ventilation; VAP = ventilator-associated pneumonia.
Table 4.
Risk factors for ICU mortality by logistic regression
| Predictors | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p | OR | 95% CI | p | |
| APACHE II | 1.046 | 1.00-1.1 | 0.079 | 0.983 | 0.89-1.08 | 0.725 |
| SAPS II | 1.028 | 1.01-1.05 | 0.006 | 1.024 | 0.99-1.07 | 0.225 |
| Vasopressor use | 6.000 | 2.77-12.99 | <0.001 | 5.293 | 2.29-12.23 | <0.001 |
| Bacteremia | 3.066 | 1.29-7.28 | 0.011 | 2.69 | 1.00-7.27 | 0.051 |
| Smoking history | 1.933 | 1.01-3.71 | 0.047 | 2.057 | 0.96-4.39 | 0.063 |
| Polymicrobial pneumonia | 0.458 | 0.19-1.13 | 0.088 | 0.416 | 0.14-1.24 | 0.116 |
| Pseudomonas aeruginosa | 0.425 | 0.16-1.10 | 0.078 | 0.52 | 0.17-1.59 | 0.252 |
| Hypercapnic respiratory failure as intubation cause | 0.306 | 0.12-0.78 | 0.013 | 0.442 | 0.16-1.22 | 0.114 |
APACHE = Acute Physiology and Chronic Health Evaluation; OR = odds ratio; SAPS = Simplified Acute Physiology Score.
4. DISCUSSION
To our knowledge, this is the first study to investigate the effect of COPD on the clinical outcomes of patients with VAP in Taiwan. In our study, patients with COPD accounted for 44% of the overall study population. Our findings showed no significant differences in mortality between the COPD and non-COPD groups. The length of ICU and hospital stay and IMV duration were similar between groups. P. aeruginosa was the most common cause in patients with VAP, and no significant differences in bacterial cause were observed between the two groups.
Previous studies on the impact of COPD on the outcomes of patients with VAP had different definitions of COPD. Numerous studies either failed to confirm COPD using forced spirometry16,19,24 or could have incorrectly classified patients with probable COPD in the non-COPD group by solely eliminating COPD clinical diagnoses and smokers without spirometry.15 Discrepancies in results can be found if PFTs are not mandatory for diagnosis. We used rigorous COPD diagnostic criteria in this investigation, and patients were only included if they underwent postbronchodilator spirometry.1 This should have led to a well-defined group of patients with COPD, yielding more robust results.
In our study, the microbiological cause of pneumonia was determined in only 47% of the patients, similar to that reported in the literature.15,19 Varying epidemiologies have been documented in different locations and territories. E. coli, S. maltophilia, P. aeruginosa, and nonfermenting GNB have been reported to be significantly more prevalent in patients with COPD than those without COPD.19,21 In contrast, Makris et al16 found no differences in pathogens between the two groups among the VAP population. Herein, we discovered that no significant differences were observed between the two groups. These inconsistencies can be attributed to the different COPD or VAP definitions used in previous studies. In addition, different from former reports,16,19,25,26 we found that Acinetobacter spp. was the most common pathogen in COPD patients with VAP, representing 23.3% of patients with COPD.
Regarding mortality, the outcomes vary across different studies. We found no differences in mortality between the COPD and non-COPD patients with VAP. A prospective cohort study conducted in 20 countries that enrolled 439 patients with VAP also found that COPD was not associated with mortality in these patients.20 Another multinational investigation conducted in Europe also found that COPD had no significant impact on mortality in 369 patients with VAP.19 In contrast, several studies demonstrated that COPD is associated with higher ICU mortality in patients with VAP.15,16 A broad range has been reported on ICU mortality of 38% to 60% in VAP patients with COPD.16,19,20 In our study, VAP patients with COPD presented an ICU mortality of 31% and a 14-day mortality of 24%.
The effect of COPD on the duration of mechanical ventilation or hospitalization of patients with VAP has also been controversial, as different results have been reported. Rouze et al19 conducted a large multinational prospective study and concluded that COPD had no significant impact on the length of hospital stay, ICU stay, or IMV duration, even in patients without VAP. Similarly, a single-center study conducted by Makris et al16 also found no differences in the length of ICU stay and IMV duration; however, when patients were stratified using COPD GOLD staging criteria, the average length of ICU stay and IMV duration were significantly longer in GOLD stage IV patients than in non-COPD patients. Our findings also showed no differences in the length of ICU stay, hospital stay, and IMV duration, and similar results were observed among the surviving patients.
We realize that it is challenging to reach a firm conclusion because there is no agreed definition of pneumonia, and some study settings did not mandate the PFTs inclusion in COPD identification. However, because we used a rigorous definition to examine the two groups, we were able to determine more accurately whether COPD is linked to worse outcomes.
As aforementioned, this study is the first to report the effect of COPD on patients with VAP in Taiwan. We also strictly adhered to the diagnostic standards for COPD and only included individuals who had undergone postbronchodilator spirometry.1 These factors should aid in producing a well-defined homogeneous population of patients with and without COPD and provide more precise results, even though we have inevitably excluded many patients during the screening process. Nevertheless, the single-center design of this study is its primary drawback; thus, extrapolating its findings to other institutions should be performed with caution, especially the lack of a connection between COPD and mortality. Due to the retrospective nature of the data collection and current practice in our institution, which captures severity scores upon ICU admission, several patients did not receive blood workup at the onset of VAP, and thus the data were not presented to maintain accuracy.
In conclusion, the present study demonstrated that COPD was not associated with worse outcomes in patients with VAP. No significant differences in bacterial cause were observed between the two groups but those with concomitant COPD exhibited a higher trend of infection with Acinetobacter spp. compare to patients without COPD.
ACKNOWLEDGMENTS
The study was approved by the Institutional Review Board of the Chang Gung Medical Foundation (number: 202001768B0), and the requirement for informed consent was waived. All methods were performed in accordance with relevant guidelines and regulations.
We thank the Chang Gung Medical Foundation for providing the Chang Gung Research Database and the Health Information and Epidemiology Laboratory and Department of Respiratory Therapy, Chiayi Chang Gung Memorial Hospital, for administrative support.
Footnotes
Conflicts of interest: Dr. Yi-Tsung Lin, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article.
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