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* From the Departments of Medicine and Therapeutics (Drs. Ko, Fok, M.C.H. Chan, Ngai, and D.P.S. Chan) Microbiology (Drs. Ip, P.K.S. Chan, and Hui), The Chinese University of Hong Kong, Hong Kong, New Territories, Peoples Republic of China.
Correspondence to: Fanny W.S. Ko, MBChB, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, 30–32 Ngan Shing St, Shatin, New Territories, Hong Kong, Peoples Republic of China; e-mail: fannyko{at}cuhk.edu.hk
Abstract
Introduction: Infection is a major cause of acute exacerbations of COPD (AECOPDs). We aimed to study the infectious etiology related to AECOPD.
Methods: Patients admitted to an acute care hospital in Hong Kong with an AECOPD were recruited prospectively from May 1, 2004, to April 30, 2005. Sputum samples, nasopharyngeal aspirate (NPA) samples, and paired serology specimens were collected. Spirometry was performed with patients in the stable phase 2 to 3 months after hospital discharge.
Results: There were 643 episodes of AECOPD among 373 patients. Their mean age was 75.3 years (SD, 7.9 years) with 307 male patients. The mean FEV1 was 40.4% predicted (SD, 18.7% predicted), and the mean FEV1/FVC ratio was 58.4% (SD, 16.0%). Among sputum samples from the 530 episodes of AECOPD hospital admissions that were saved, 13.0%, 6.0%, and 5.5%, respectively, had positive growth of Haemophilus influenzae, Pseudomonas aeruginosa, and Streptococcus pneumoniae. Among the 505 hospital admissions with patients who had NPA samples saved, 5.7%, 2.3%, 0.8%, and 0.8%, respectively, had influenza A, respiratory syncytial virus (RSV), influenza B, and parainfluenza 3 isolated from viral cultures. Paired serology test results revealed a fourfold rise in viral titers in 5.2%, 2.2%, and 1.4% of patients, respectively, for influenza A, RSV, and influenza B. Very severe airflow obstruction (stable-state spirometry) was associated with a higher chance of a positive sputum culture (FEV1 
30% predicted, 28.2%; FEV1 < 30% predicted, 40.4%; p = 0.006).
Conclusion: H influenzae and influenza A were the most common etiologic agents in patients who were hospitalized with AECOPDs. More severe airflow obstruction was associated with a higher chance of a positive sputum culture finding.
Key Words: bacteria, COPD • exacerbation • Hong Kong • viruses
COPD is a common airway disease worldwide. In Hong Kong, COPD was the fifth leading cause of death and accounted for at least 4% of all public hospital acute admissions in 2003. Previous studies12 have shown that pulmonary function and quality of life were adversely affected by frequent exacerbations, particularly in active smokers.
Acute exacerbations of COPD (AECOPDs) may be due to factors such as infection,34 air pollution,5 withdrawal of medication,6 or change in temperature.7 It is important to examine the infectious agents that are responsible for AECOPDs as this has important therapeutic implications. We conducted a retrospective study8 in 2000 to assess the sputum bacteriology in patients who had been admitted to our hospital in Hong Kong with AECOPDs, but viral etiology could not be assessed. To the best of our knowledge, there had been no prospective study conducted in Asia on sputum bacteriology together with viral etiologies in patients who had been admitted to the hospital for AECOPDs. The aim of this prospective study was to assess the bacterial and viral etiology related to AECOPD by examining respiratory specimens (ie, sputum and nasopharyngeal aspirate [NPA]) and paired serology findings from the subjects. This can potentially advance our current knowledge of etiologies related to AECOPD. In addition, we examined whether there was any association between the potential infectious agents and lung function and clinical outcomes, such as the need for ICU admission, noninvasive positive-pressure ventilation (NPPV) use, invasive mechanical ventilation (IMV), length of hospital stay, 12-month mortality rate, and 12-month rate of readmission for COPD.
Materials and Methods
Subject Recruitment
Patients who had been admitted to the Prince of Wales Hospital with AECOPDs between May 1, 2004, and April 30, 2005, were recruited for this study. AECOPD was defined as occurring when a patient with background COPD9 presented with at least two major symptoms (ie, increased dyspnea, increased sputum purulence, or increased sputum volume), or one major and one minor symptom (ie, nasal discharge/congestion, wheeze, sore throat, or cough) for at least 2 consecutive days.110 Written informed consent was obtained from each subject, and the study was approved by the Joint Committee of the Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee of the Chinese University of Hong Kong.
Demographic Data and Management in Hospital
Demographic data and length of hospital stay for patients with AECOPDs were recorded. Comorbid conditions were noted and scored using the Charlson index.11 The scoring of the Charlson index ranged from 0 to 33, with a higher score indicating more in the number and severity of the coexisting illnesses. In addition, chest radiographs (CXRs) were assessed by the investigators (respiratory physicians), and abnormalities such as pneumonic changes were noted. Only those patients without pneumonic changes on their CXRs were included for analysis in this study. The use of NPPV and IMV, and ICU admission were recorded.
Microbiological Examination
Expectorated sputum was collected into a sterile container and was processed according to standard procedures.12 Microscopy by Gram staining was used to examine specimens for the presence of leukocytes, epithelial cells, and organism morphotypes. Specimens consisting of > 10 epithelial cells per low-power field were not cultured unless the specimen appeared purulent or bloodstained. After homogenization with sputolysin, culture was performed using a 1-µL standard loop onto blood agar and chocolate blood agar plates, which were incubated in 5% CO2 at 35°C for 18 to 24 h. Culture plates were reincubated for a further 24 h if there was no growth after overnight incubation or a predominant morphotype seen in Gram smear had not yet been isolated. Common lower respiratory tract pathogens (eg, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were reported semi-quantitatively when isolated. Isolates with higher than 105 cfu were reported as having positive growth. Potential pathogens (eg, Pseudomonas spp, Klebsiella and other Enterobacteriaceae spp, Staphylococcus aureus, Candida spp, Pasteurella spp, and b-hemolytic streptococci) were reported only when there was heavy or predominant growth or in pure cultures. The antibiotic susceptibilities to the common pathogens and reported organisms were tested by the disk method according to the Clinical and Laboratory Standards Institute.13 Acid-fast staining and cultures for Mycobacterium spp onto Lowenstein-Jensen medium after the decontamination of sputum specimens were performed according to standard procedures.14
NPA samples were obtained by catheter aspiration from the posterior nasal pharyngeal space via the nostril with the patient in the sitting position. The NPA sample was saved in 3 mL of viral transport medium containing gentamycin (4 mg/mL), penicillin/streptomycin (50,000 IU per 50,000 µg/mL), and amphotericin B (Fungizone; Bristol-Myers Squibb; New York, NY) [1 mg/mL], and was processed (usually within 12 h). Briefly, the aspirate was centrifuged at 2,000 revolutions per minute for 5 min, and the cell pellet was washed with phosphate-buffered saline solution and coated onto glass slides. The supernatant was inoculated into a rhesus monkey kidney (LLC-MK2), human laryngeal carcinoma (HEp-2) cells, Mardin Darby Canine Kidney (MDCK) cells, and human embryonic lung fibroblast cell monolayers. All cell cultures were incubated at 37°C, except for MDCK cells, which were incubated at 33°C. Cell monolayers were examined daily for cytopathic effect. After 14 days of incubation, a hemadsorption test for LLC-MK2 and MDCK monolayers was performed. When a suspicious cytopathic effect was observed or when the hemadsorption test result was positive, the presence of virus growth was confirmed by immunofluorescence staining using specific monoclonal antibodies.
Paired serum samples for serology were obtained on hospital admission and at 14 to 28 days later. The presence of antibodies specific for influenza A and B, parainfleunza 1, 2, and 3, respiratory syncytial virus (RSV), adenovirus, Mycoplasma pneumoniae, and Chlamydia psittaci was detected by complement fixation test. Seroconversion or a fourfold or greater rise in the antibody titer was regarded as evidence of current infection.
Follow-up of Progress of Patients After Hospital Discharge
Spirometry before and after bronchodilator therapy was performed at 2 to 3 months after hospital discharge (free of AECOPDs) according to the American Thoracic Society standard15 using a spirometer (Vitalograph; Buckingham, UK). The updated predicted spirometry values for Hong Kong Chinese were adopted.16 The patients were contacted by phone, and their medical records were reviewed 12 months later to check for any deaths or hospital readmissions.
Statistical Analysis
Data were analyzed using a statistical software package (SPSS for Windows, version 11.5; SPSS Inc; Chicago, IL). The associations between the identification of an organism during an AECOPD (eg, bacteria in sputum, viruses in the NPA, or viral serology), and the lung function and clinical outcomes of patients (eg, mortality, ICU admission, NPPV use, and length of hospital stay) were assessed by Mann-Whitney U test, 
2 test, and Fisher exact test, as appropriate. Values were presented as the mean (SD), and a p value of < 0.05 was considered to be significant.
Results
There were 750 episodes of AECOPD that were screened for this study. Cases with, for instance, pneumonic changes seen on CXR or predominant congestive heart failure were excluded. Among those cases that fitted the inclusion criteria, 20 patients refused to consent for the study. Altogether, 643 episodes of AECOPD were included in this study during the 1-year study period among 373 patients (participation rate, 94.6%). A total of 313 subjects (83.9%) had returned to undergo lung function tests at a mean duration of 116.3 days (SD, 72.7 days) after discharge from the hospital for AECOPD. Thirty-one subjects died (either as inpatients or after discharge) before a lung function test could be arranged, whereas 29 defaulted follow-up. For those who died or defaulted follow-up, the lung function data from tests performed in the stable state within 1 year prior to hospital admission for AECOPD were used for statistical analysis (data available for 10 deceased subjects and 7 defaulters). Thus, 43 subjects did not have recent lung function data, and they were not included in the analyses involving lung function parameters. Our subjects had moderate-to-severe COPD with a mean post-bronchodilator therapy FEV1 of 40.4% predicted (SD, 18.7% predicted). The mean length of stay in an acute care hospital was 6.2 days (SD, 4.4 days). After the first episode of hospitalization for AECOPD, 70 patients (18.8%) died, whereas 210 patients (56.3%) were readmitted to the hospital for another episode of AECOPD within 12 months. Among all of the patients experiencing episodes of AECOPD, 4 episodes (0.6%), 3 episodes (0.5%), and 66 episodes (18%), respectively, required ICU admission, IMV support, and NPPV support. The demographic data for the subjects are presented in Table 1 .
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NPAs and Serology
NPA specimens were saved in 505 episodes (78.5%) of AECOPD. Positive viral cultures were identified in 49 specimens (9.7%). The NPA results are shown in Figure 1
. Paired serology test results were available from 364 episodes (56.6%) of AECOPD. Among these, 37 patients (10.2%) had at least a fourfold increase in the convalescent titers. The serology results are shown in Figure 2
. The seasonal change of the NPA and serology results are illustrated in Figure 3
. We noted two peaks of viral infection in our COPD patients over a period of 1 year. The first peak occurred in spring (ie, March and April), whereas another peak was noted in summer. Among the 463 episodes of AECOPD with specimens sent for both bacterial and viral investigations (ie, with sputum plus NPA or paired serology), specimens from 10 episodes (2.2%) had both positive growth from sputum and NPA or serology. A summary of the positive sputum culture, NPA, and serology results is shown in Table 3
.
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30% predicted), the former patients had a higher rate of positive sputum culture (40.4% vs 28.2%, respectively; p = 0.006). However, there was no such observation when analyzing the NPA culture and serology results. The sputum culture, NPA culture, and serology results in relation to lung function are illustrated in Table 5
. Active smoking, the presence of comorbidities, and treatment with inhaled corticosteroids had no association with the sputum bacteriology, NPA culture, and paired serology results.
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Discussion
To the best of our knowledge, this has been the first study conducted in Asia of bacteriology and virology in patients who had been admitted to the hospital with AECOPD. Previous studies mainly focused on the investigation of either bacterial pathogens817181920 or viral pathogens2122 alone. The strength of our study was its prospective nature, with a relatively large sample size, and the inclusion of the results of paired serology tests for the detection of atypical organisms.
Potentially pathogenic bacteria were found in 32.3% of episodes of AECOPD, based on sputum culture findings. The result was similar to that of our previous retrospective study8 of the sputum bacteriology of patients who had been admitted to the hospital with AECOPD, in which positive sputum culture results were recorded in 37.8% of hospital admissions. Our rate of positive sputum culture was higher than that reported by Sethi et al17 in the United States (23.6%), but was lower than the rates reported by Groenewegen and Wouters18 (50%) in the Netherlands and Papi et al23 (57%) in Italy. Similar to other studies, the most common bacteria found in sputum were H influenzae, Pseudomonas aeruginosa, and S pneumoniae.1718 We noted that patients with very severe airflow obstruction (ie, FEV1 < 30% predicted) had a higher rate of positive sputum culture growth of potential pathogenic organisms (40.4% vs 28.2%, respectively; p = 0.006). A similar finding was observed by Miravitlles et al19 in Spain that patients with AECOPDs whose FEV1 was < 50% predicted had a greater chance of having P aeruginosa or H influenzae isolated from samples of their sputum. Active tobacco smoking was also associated with a higher probability of P aeruginosa or H influenzae isolation from sputum samples.19 It is possible that COPD patients with more severe airflow obstruction or active tobacco smoking have more severe airway inflammation and decreased airway mucosal defense, predisposing them to increased colonization or infection of the airway by bacteria. A previous study10 has shown that the presence of bacteria in sputum in stable patients was associated with a higher frequency of AECOPD. In addition, sputum interleukin-8 levels correlated with the sputum bacterial count.10 A recent study23 has found that AECOPDs associated with infection (bacterial or viral) were more severe than those with no pathogens identified. The severity of AECOPD was measured by the length of hospital stay and changes in lung function.23 It is thus possible that bacteria in the airway lead to more airway inflammation, more AECOPDs, and a more rapid decline in lung function.2
In this study, we found that in those subjects with poorer lung function (ie, FEV1 < 30% predicted), the rate of positive findings for bacteria from cultures of sputum samples was higher. However, overall patients with positive bacterial culture results had a lower rate of hospital readmission. The reason behind this paradox was not entirely clear. One possibility was that patients with positive sputum culture findings were treated with appropriate antibiotics and thus had fewer hospital readmissions. Previous trials24 on antibiotic therapy in patients with AECOPDs seldom have looked at hospital readmissions over a long period (eg, in 12 months, as was done in this study). This study was not powered or designed to study the effect of antibiotic therapy on the rate of hospital readmissions for AECOPDs. Further studies are needed to look at the relationship among sputum culture results, the type of treatment given, and hospital readmissions.
In this study, we have noted a high prevalence of penicillin resistance in the S pneumoniae isolates, with 69.9% showing at least intermediate resistance to penicillin. Intermediate penicillin resistance is defined as a minimal inhibitory concentration of 0.12 to 1.0 µg/mL, whereas penicillin-resistant strains had a minimal inhibitory concentration of 2.0 µg/mL.25 In Hong Kong, the prevalence of S pneumoniae with reduced penicillin susceptibility rose rapidly from 10% in 1993 to 50.0% in 1997.26 It had further risen to 65% by year 2000.27 These rates had been attributed to the spread of variants of the Spain23F-1 and Spain6B-2 clones,28 and these clones were also characterized by multidrug resistance to erythromycin, tetracycline, and chloramphenicol.26 The high percentage of penicillin resistance in our S pneumoniae isolates among our COPD cases was thus not unexpected.
In this study, approximately 10% of the AECOPD patients had NPA culture findings that were positive for virus. Previous studies21 had reported a higher rate (approximately 30%) of culture findings positive for virus using more sensitive techniques like polymerase chain reaction. Interestingly, the yield of viruses from induced sputum samples was higher than that from nasal lavage fluid, and this may be due to direct viral involvement of the lower airways.21 Our lower rate of virus detection by both NPA culture and serology might be the result of the lower sensitivity of the laboratory tests used. When compared to other studies using similar methods of viral detection (eg, viral cell culture from NPA and serology),2930 similar rates of hospitalization for acute viral respiratory tract infection (Greenberg et al,29 12% hospitalization) and RSV infection (Walsh et al,30 4.3 per 100 person-winters) were observed.
We noted two peaks of viral infection (as shown in Fig 3) in our COPD patients over a period of 1 year. The first peak occurred in spring (ie, March and April), whereas another peak was noted in summer. The observation of influenza season in the spring/winter period was consistent with other overseas studies729 and another local study.31 A second peak of influenza-like illness in summer that was noted in this current study of AECOPD patients requiring hospitalization was also in line with the seasonality of influenza for the general community in Hong Kong.32
There are several limitations to this study. First, we assessed COPD patients with AECOPDs without comparing them with either stable control subjects with COPD or with healthy control subjects. Previous studies1721 have identified bacteria in the sputum samples and virus in the NPA samples of stable patients with COPD. It is thus difficult for us to be certain whether the bacteria or viruses identified in these AECOPD patients were genuine pathogens or just the result of colonization. As the identification of a new strain of bacteria was associated with an AECOPD,17 the identification of the potential pathogen in the respiratory secretions of COPD patients is likely to reflect some degree of infection and thus still provide a useful guide to antimicrobial treatment. Second, sputum, NPA, and serology specimens were not available in every case. Third, rhinovirus is an important causative agent for the common cold, but our study did not assess this virus, which has fastidious growth requirements and > 100 serotypes, making detection by culture or serologic methods very difficult.4 Without using very sensitive polymerase chain reaction testing, other studies2933 have shown little evidence that rhinovirus was related to AECOPDs. However, a 2003 study by Rohde et al21 showed that approximately 20% of patients experiencing AECOPDs have rhinovirus isolated from sputum or nasal lavage fluid. Last, our study included hospital-based patients, with the majority having moderate-to-severe COPD, and the results might not reflect the etiology of ambulatory exacerbations.
In conclusion, H influenzae, P aeruginosa, and S pneumoniae were the most common bacteria identified, whereas influenza A, RSV, and influenza B were the most common viruses detected in patients who were hospitalized with AECOPDs. Very severe airflow obstruction was associated with a higher chance of positive sputum culture results, but there was no significant reduction in laboratory-confirmed influenza A and B infection despite influenza vaccination over the past 12 months. The sputum bacteriology results and the antibiotic resistance pattern could provide some guidance for the choice of empirical antibiotic treatment for COPD patients admitted to the hospital with clinical evidence of airway infection such as fever, and increased sputum volume and purulence.
Footnotes
Abbreviations: AECOPD = acute exacerbation of COPD; CXR = chest radiograph; IMV = invasive mechanical ventilation; NPA = nasopharyngeal aspirate; NPPV = noninvasive positive-pressure ventilation; RSV = respiratory syncytial virus
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication May 29, 2006. Accepted for publication August 3, 2006.
References
This article has been cited by other articles:
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  M. A. Campos, S. Alazemi, G. Zhang, R. A. Sandhaus, and A. Wanner Influenza Vaccination in Subjects With {alpha}1-Antitrypsin Deficiency Chest, January 1, 2008; 133(1): 49 - 55. [Abstract] [Full Text] [PDF]
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F. W. S. Ko, M. Ip, P. K. S. Chan, M. C. H. Chan, K.-W. To, S. S. S. Ng, S. S. L. Chau, J. W. Tang, and D. S. C. Hui Viral Etiology of Acute Exacerbations of COPD in Hong Kong Chest, September 1, 2007; 132(3): 900 - 908. [Abstract] [Full Text] [PDF]
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