Title

Author(s)

Sputum bacteriology in patients with severe chronic lung

diseases

Lam, Siu-pui;

Citation

Issued Date

URL

Rights

2011

http://hdl.handle.net/10722/144854

Creative Commons: Attribution 3.0 Hong Kong License

Sputum bacteriology in patients with severe chronic lung diseases

By

Dr LAM Siu Pui

This work is submitted to

Faculty of Medicine of The University of Hong Kong
In partial fulfillment of the requirements for
The Postgraduate Diploma in Infectious Diseases, PDipID (HK)

Date: 31 May 2011

Supervisor: Dr PL Ho

Declaration
I, Dr. Lam Siu Pui, declare that this manuscript represents my own work and that it
has not been submitted to this or other institutions in application for a degree, diploma
or any other qualifications.
I, Dr. Lam Siu Pui, also declare that I have read and understand the guideline on
What is plagiarism? published by The University of Hong Kong and that all parts of
this work complies with the guideline.

31 May 2011

Content

1.

Introduction

2.

Design and methods

3.

Results

4.

Discussion

5.

Conclusions

Total word count: 5547

ABSTRACT

Background: Exacerbations are common in patients with chronic lung diseases and
are associated with decline in lung function, poor nutritional status, impaired
functional and quality of life outcomes. Bacterial infections are common etiologies
leading to exacerbations but the role of antimicrobial treatment is not well defined.
The present study is to review the sputum bacteriology and to examine the
characteristics and outcomes of infective exacerbations in patients with chronic lung
diseases.
Methods: A retrospective study was performed in patients with chronic lung diseases
who received pulmonary rehabilitation (PR) in a local hospital in Hong Kong. The
clinical, radiological and microbiological profiles were examined. The episodes of
infective exacerbations and the antimicrobial treatment prescribed were reviewed. The
baseline characteristics and rehabilitation outcomes in the exacerbation and stable
groups were compared.
Results: 84 patients (18 female 64 male) with chronic lung diseases who joined PR
between April 2009 and March 2010 were included. The mean age of the group was
75.1 (55-99) and the mean FEV1 (SD) and mean FVC (SD) were 0.62 (0.27) and 1.2
(0.48) liter respectively. The majority of patients suffered from COPD (92.8%) and in
4

severe or very severe stages (84.5%) with associated co-morbidities (80%). 37

patients developed infective exacerbation during the course of training with
antibiotics prescribed. Sputum samples were available in 65 (77.5%) of patients and
31 of which showed positive bacterial cultures. Haemophilus influenza was the
commonest organism detected in the sputum samples (17.9%), followed by Moraxella
catarrhalis (8.3%), Pseudomonas aeruginosa (8.3%) and Streptococcus pneumonia
(3.6%). Augmentin, quninolones and sulperaonze were the common antibiotics
chosen. Clinical response was observed in 25 (67.6%) but treatment failure (addition
or step up of antibiotics, clinical or radiological deterioration or acute respiratory
failure) in 12 (32.4%) subjects. In the 65 sputum samples sent for AFB smears and
culture, all were negative for mycobacterium tuberculosis but two were positive for
atypical mycobacteria. Both patients were asymptomatic and received no treatment.
Patients with infective exacerbation (IE) during the rehabilitation training were found
to have lower baseline lung function, nutritional and physical function parameters as
compared with patients with stable disease. In the IE group, the length of the program
was significantly longer (45.8 14.7 vs. 33.6 12, p < 0.001) and the physical
function as measured by the six minute walking test (6MWT) distance was
significantly lower at baseline (130 + 87 vs. 173 + 96 meters, p < 0.05) and at 6
months after program (165 + 101 vs. 241 + 106 meters, p = 0.01).
5

Conclusion: Infective exacerbations were common in patients with chronic lung

diseases in stable state and associated with adverse physiological variables and
impaired rehabilitation outcomes.

BACKGROUND
Chronic lung diseases (CLD), predominately chronic obstructive pulmonary
disease (COPD), are the leading causes of morbidity and mortality worldwide.
Chronic lung diseases are characterized by obstructive or restrictive defects leading to
reduced capacity for functional activities such as leisure, activities of daily living and
impaired health related quality of life (HRQoL) (1). Pulmonary rehabilitation (PR) is
receiving increasing recognition as an important component in the overall
management of pulmonary disabled patients with improvement noted in multiple
outcome measurements (2).
Exacerbations in COPD carry important clinical and health cost implications as
associated with deterioration of clinical symptoms, lung function, physical function,
health related quality of life and acceleration in disease progression (3-5). Infective
exacerbations may or may not associated with bronchopneumonia which contribute to
further morbidities and mortalities (6).
The majority of etiologies of exacerbations are believed to be infective (bacterial
and / or viral) in origin (7-9), though the definition of exacerbations and the exact
mechanisms are yet to be defined (10). The management of exacerbations of COPD is
challenging and poses high demand of utilization of health resources. Bronchodilators
and corticosteroids are commonly prescribed, but the routine use of antibiotics in the
7

treatment and prevention of exacerbations remain controversial.

Systemic and airway inflammation is present in COPD in chronic stable state but
the degree of inflammation is further enhanced by infective exacerbation (11-12).
New strains of bacteria may contribute to the increased airway inflammatory
responses. A number of inflammatory markers such as neutrophils, interleukin 8
(IL-8), tumour necrosis factor a (TNFa), neutrophil elastase (NE), C-reactive proteins
had been extensively studied in recent years as to document the relationship of
bacterial infection, airway inflammation and the disease progression in COPD related
to exacerbations (11-13).
The present study was designed to study the sputum bacteriology in a group of
patients with chronic lung diseases in stable states who had received pulmonary
rehabilitation program at a local hospital in Hong Kong.

METHODS

Objectives
The present study aimed to (1) evaluate the sputum bacteriology profiles in
patients with chronic lung diseases and (2) review the episodes of infective
exacerbations and antimicrobial treatment (3) compare the demographic features in
the groups of infective exacerbations and stable diseases (4) examine the effects of the
infective exacerbation on the functional, physical and HRQoL outcomes in a group of
patients with chronic lung diseases CLD.

Study Design
The principal component of the study is a cross sectional study of the sputum
bacteriology profiles in a cohort of patients with chronic lung diseases. Chronic lung
diseases referred to the lung diseases enlisted in the position statement of the
American Thoracic Society in 2006 (1).
The study was a retrospective one conducted in a local hospital with the
population studied being subjects mostly with COPD who had received in-patient
pulmonary rehabilitation (PR) at Wong Tai Sin Hospital (WTSH) between April 2009
and March 2010. Hospital records, discharge summaries, laboratory and radiological
9

results were retrieved. The detailed information on clinical characteristics, nutritional,

functional, HRQoL parameters in addition to the sputum bacteriology results and the
prescribed antimicrobial treatment were analysed.
The physiological measurements include the physiological status (including
SaO2, heart rate and respiratory rate), arterial blood gases measurement and lung
function testing. Spirometry tests with bronchodilator response were performed
during the stable phase of the diseases under standard laboratory settings. Nutritional
assessment included body mass index, body fat percentages, serum haemoglobin and
albumin. The physical function of the studied subjects was evaluated by the six
minute walking tests (6MWT) performed by the physiotherapists according to the
standard protocol. Health related quality of life measurements included the St.
Georges Respiratory Questionnaires (SGRQ) and the Short Form-36 (Hong Kong)
was also administered.
Episodes of infective exacerbations which occurred during the four to five week
course of in-patient pulmonary rehabilitation program at WTSH were reviewed. The
occurrence of infective exacerbations with associated clinical, radiological and
microbiological abnormalities and the anti-microbial treatment was reviewed.
Infective exacerbation of COPD (or other CLD) was considered when patient
developed at least two of the major symptoms (increased dyspnoea, increased sputum
10

purulence, increased sputum amount) that necessitated antimicrobial treatment.

Chest radiographies (CXRs) were reviewed by respiratory specialists. Subjects
with new pulmonary infiltrates on CXRs were diagnosed as bronchopneumonia. The
clinical and radiological response to antibiotics treatment was reviewed.
Microbiological results included sputum bacterial cultures, sputum AFB smears
and cultures, blood cultures and relevant laboratory investigations were examined.
The antimicrobial susceptibility to the potential pathogenic micro-organisms (PPMs)
was also examined.

Statistics
The principal component is a cross-sectional study on the sputum bacteriology
profiles in patients with CLD. Descriptive statistics (proportions, means and standard
deviations) was used to describe the study population at baseline. The demographics
and clinical outcomes in exacerbation and stable groups were compared for difference
using student t test or chi-square test whichever appropriate. For comparison of
baseline and post rehabilitation outcomes, paired sample t test or Mann-Whitney U
tests was applied if appropriate. A p value of less than 0.05 was considered to be
significant.

11

RESULTS
Demographics
The baseline characteristics of the study population are shown on table 1. The
group included 84 patients (18 female and 64 male) with the diagnoses of chronic
lung diseases who received pulmonary rehabilitation program at WTSH between
April 2009 and March 2010. The mean age of the study population was 75.1 (SD 8.6,
range 55-99) with the mean age in female group being 77.4 (SD 10.48) and male
being 74.5 (SD 8.1). The mean FEV1 (SD) and mean FVC (SD) were 0.62 (0.27) and
1.2 (0.48) liter respectively.
The respiratory diagnoses included COPD in 78 patient (92.8%), pulmonary
tuberculosis (clinical or radiological, inactive) in 26 patients (30.9%), bronchiectasis
in 14 patients (16.7%), restrictive (pulmonary and extra-pulmonary) lung diseases
(11.9%), sleep apnoea (2.4%), chronic asthma (1.2%) occupational lung disease
(1.2%) and pulmonary embolism (1.2%).
The majority of patients studied had at least one co-morbid condition (N=70,
83.3%) and 50% of patients had two or more associated comorbid conditions. The
common comorbidities included hypertension (33.3%), benign prostate hypertrophy
(23.8%), ischaemic heart disease (15.5%), gastro-intestinal disorders (13.1%),
congestive heart failure (9.5%), cerebrovascular or CNS disorders (8.3%) and
12

diabetes mellitus (7.2%).

The severity of COPD based on the GOLD classification (2) showed that the
majority of our patients had stage IV (FEV1 < 30% predicted) (51.9%) and stage III
(FEV1 < 50% - > 30% predicted) diseases (38%). Very severe and severe obstructive
airway defects occurred in nearly 90% of the patients studied.
The baseline physiological, nutritional, functional and HRQoL parameters were
illustrated on table 2. The mean PaO2 and SaO2 were lowish with a relatively high
PaCO2 (9.8 kPa, 90% and 5.9 kPa respectively). The mean body mass index (BMI)
was 18.6 (SD 3.5) kg/m2 with a lowish albumin level (31.1 + 4) suggested impaired
nutritional status was common in COPD subjects. The mean six minute walking
distance (6MWD) was only 155 (SD 94), reflecting poor exercise capacity. The
general health status as measured by the SF-36 (Hong Kong) Physical Component
Summary (mean 33.6 + 6.9) and Mental Component Summary (mean 42.2 + 13.6)
was markedly lower than the population norms. Both the domain and total scores of
the St. Georges Respiratory Questionnaires (SGRQ) were markedly increased
suggesting significant impairment in respiratory health status.
Clinical & microbiology results
47 (56%) patients remained exacerbation free during the rehabilitation period, 37
(44%) patients developed 44 episodes of exacerbations with clinical, radiological or
13

bacteriological evidence. Among the 37 patients with infective exacerbations,

potential pathogenic micro-organisms (PPMs) were identified in the sputum samples
in 31 (83.8%) patients and were negative in 6 (16.2%) patients. In the study cohort,
radiological

appearance

of

newer

pulmonary

infiltrates

suggestive

of

bronchopneumonia was present in 24 (64.9%) subjects in the exacerbation group.

Sputum samples were collected from 65 (77.5%) subjects and bacterial
pathogens were found in the sputum samples from 31 patients and atypical
mycobacteria from 2 patients. The sputum bacteriology profile is shown on Table 3.
The predominant organisms were Haemophilus influenzae, which were found in
the sputum samples of 15 patients (17.9%). Other predominant bacteria included
Moraxella catrrhalis (N=7, 8.3%) and Pseudomonas aeuroginosa (N=7, 8.3%).
Haemophilus influenzae were found in 40.5% patients with infective exacerbations,
moraxella catarrhalis in 18.9% and pseudomonas aeuroginosa in 18.9%. The three
commonest microorganisms accounted for 34.5% of PPMs in our study population
and 78.4% in patients with infective exacerbations. Other PPMs identified in the
sputum samples from our study included Streptococcus pneumonia (3.6%),
Acinetobacter and Klebsiella species, gram-negative species including ICBL strains
and MRSA.
The antimicrobial susceptibility to the three common pathogens in our study is
14

shown on table 4. In our local laboratory, Haemophilus influenza showed significant

resistance to ampicillin and sulfamethoxazole /trimethoprim (Septrin) and remained
sensitive to augmentin, cefuroxime and levofloxacin. Beta-lactamase activities were
present in 11 patients (73.3%) and negative in 4 (26.7%). Similarly, Moraxella
catarrhalis showed absolute resistance to ampicillin in sputum samples. However,
Moraxella showed full sensitivity to augmentin, cefuroxime (oral and parental),
levofloxacin, septrin. Beta-lactamase was positive in 6 (85.7%) and negative in 1
(14.3%). For the antimicrobial susceptibility pattern of Pseudomonas aeuroginosa,
resistance to ciprofloxacin and aminoglycosides was seen in one of the seven samples
while sensitivity to piperacillin remained in all pseudomonas samples. Streptococcus
pneumoniae species (moderate to heavy growth) were found in 3 samples. The
organisms were mostly resistant to oral penicillin and erythromycin but sensitive to
parental penicillin. The MIC was reported only one of these cases. 2 cases responded
to an oral course of augmentin, augmentin and amoxil but the third case failed to
respond despite parenteral antibiotics and required acute respiratory support.
Sputum samples for AFB smears and cultures were performed in 65 patients. All
the samples were negative for mycobacterium tuberculosis but atypical mycobacteria
(M. kanasaii and M. avium complex) were identified. Both patients were
asymptomatic and specific anti-mycobacterial treatment had not been given.
15

Antimicrobials
The antimicrobial treatment received by the study population was illustrated on
figure 1. The common antibiotics prescribed for infective exacerbations for our group
of patients were augmentin (23), quinolones (12) and sulperazone (8). The routes of
antibiotics administration distributed as oral 17 (46%), parenteral 4 (10.8%) and both
oral and parenteral 16 (43.2%). The clinical response rate among the patients who had
received antibiotics treatment was 67.6% and the treatment failure rate was 32.4%.
In the 25 patients who showed clinical response to initial antibiotics treatment,
17 (68%) patients received oral antibiotics alone, 3 (12%) patients received parenteral
antibiotics alone and 5 (20%) patients received both oral and parenteral antibiotics
either as step down or pathogen direct regimens. The most common antibiotics
included augmentin (17), quinolones (8), sulperazone (3) and tazocin (2).
In the 12 patients who showed treatment failure (addition or step up of
antibiotics treatment, worsening of clinical or radiological conditions, or progression
to respiratory failure), parental antibiotics had been given with variable outcomes.
Rrecurrent infections were common which necessitated another course of antibiotics
in a short period of time. This group of patients had poor general state and associated
with acute on chronic respiratory failure.
Pseudomonas aeuroginosa were identified from 7 patients in the studied group.
16

One patient belonged to the stable group and no antibiotics had been given. Specific
anti-pseudomonal treatment was given in 4 out of 6 cases with infective exacerbations
and the treatment failure rate was 25%.
Exacerbation versus stable groups
The baseline characteristics and demographics between the infective
exacerbation (IE) and stable group were compared (table 5). There was no significant
difference in age and baseline lung function parameters. The mean age + SD in the IE
and stable group was 74.7 + 37 and 75.4 + 47 respectively. The smoking pack years in
IE and stable groups were 49.7 + 33 and 46.6 + 35 respectively. The difference in
FEV1 between the two groups was not significant at baseline (IE 0.58 + 0.24 vs.
stable 0.65 + 0.28 L., p =NS), though the difference became significant on completion
of the rehabilitation program (IE 0.57 + 0.21 vs. stable 0.71 + 0.33 L., p= 0.03).
Patients with CLD who developed infective exacerbations were associated with
poor physiological parameters, poorer nutritional status, lower exercise capacity,
impaired health related quality of life measures and prolonged hospitalization.
Patients in the IE group tended to have lower SaO2 (88.1% + 5.1 vs. 91.5 + 4.2 p
= 0.001) and higher heart rate (89.2 + 13 vs. 82.0 + 14, p = 0.023) at rest though the
respiratory rates were similar.
The baseline nutritional profiles were measured by the body mass index, % of
17

body fat composition, blood haemoglobin and alumin levels. The baseline BMI and %
fat were similar between the two groups (BMI 17.8 + 3.3 vs 19.2 + 3.5 kg/m2, p = NS,
Fat 15.6 + 5.9 vs 17.7 + 9.2 %, p = NS) but the BMI level in IE group was
significantly lower than the stable group after the rehabilitation program. The baseline
haemoglobin and albumin levels were both lower in the IE group as compared with
the stable group (Hb 12.2 + 2.0 vs. 13.0 + 1.7 g/dL, p < 0.05, albumin 29.5 + 3.8 vs.
32.5 + 3.7 g/L, p < 0.01).
The baseline physical function as measured by the total six minute walking test
(6WDT) distance was significantly lower in the IE group as compared with the stable
group (130 + 87 vs. 173 + 96 meters, p < 0.05). The six minute walking test distance
at one goal was also lower in the IE group when compared with the stable group (105
+ 88 vs. 151 + 105 meters, p = 0.041)
Respiratory specific HRQoL measurement showed that subjects in the IE group
had greater impairment in the total score domain (IE 70.3 + 13.9 vs. 63.5 + 14.8, p =
0.039). The SGRQ scores in other domains and the SF-36 (Hong Kong) were similar
between the two groups.
Outcomes of rehabilitation
Patients with infective exacerbations prolonged the length of the rehabilitation
program with as compared than with patients with stable diseases (45.9 + 14.7 vs.
18

33.6 + 12.0 days, p < 0.001). There was no mortality during the in-patient program
but two patients were transferred to acute hospital for intensive respiratory support.
The clinical outcomes between the two groups were compared at the end of the
rehabilitation program. Patients with exacerbations were found to have higher heart
rate (90 + 10 vs. 83 + 10, p=0.002), lower BMI (17.95 + 3.22 vs. 19.54 + 3.52 kg/m2,
p =0.036) and lower serum albumin level (31.1 + 4.53 vs. 33.8 + 3.3 g/L, p = 0.002).
The exercise capacity as measured by the 6MWT distance was lower in exacerbation
group (130 + 87 vs. 173 + 96) though the difference failed to reach statistically
significant. There was no significant difference in other clinical outcome parameters.
The mortality data at six months showed 8 (21.6%) patients from the
exacerbation group and 5 (10.6%) patients from the stable group died at 6 months but
the difference was not significant.
54 (64.3%) patients attended reassessment at 6 months. Patients in the
exacerbation groups (N=23), as compared with stable group (N=31) showed higher
baseline heart rate (90.7 + 13.9 vs. 83.3+ 12, p=0.04) and lower exercise capacity as
measured by the 6MWD (165 + 101 vs. 241 + 106 meters, p = 0.01). Other
physiological, nutritional and HRQoL parameters were not significantly different at 6
months.

19

DISCUSSION
There is no consensus to the definition of COPD exacerbation and GOLD
accepted a general definition as an acute event in the natural course of disease
characterized by a change in the patients baseline symptoms (dyspnoea, cough and/or
sputum) that warranted changes in regular medical medications (2). The most
important cause of COPD exacerbation is bacterial infection of the tracheobronchial
tree with or without concomitant bronchopneumonia.
The severity of COPD according to GOLD classification (2) showed our cohort
had predominantly very severe (stage IV, 51.9%) and severe (stage III, 38%)
obstructive lung defects. This group of COPD patients carried high risks of infective
exacerbation and bacterial pneumonitis and was associated with adverse clinical
outcomes and high demand of healthcare resources (14).
In our study, positive sputum cultures were found in 36.9% of patients and
positive mycobacterial cultures in 2.4% of patients. The sputum bacteriology profiles
in our group of patients showed similar patterns to both local and overseas reports.
The predominant organism identified was Haemophilus influenzae which occurred in
17.9% of the study group and 40.5% of those with infective exacerbations.

Together

with Moraxella catrrhalis and Pseudomonas aeuroginosa, the three commonest

microorganisms accounted for 34.5% of PPMs in our study population and 78.4% in
20

patients with infective exacerbations. Other PPMs identified in the sputum samples
from our study included Streptococcus pneumonia (3.6%), Acinetobacter and
Klebsiella species, gram negative species including ICBL strains and MRSA.
Although the proportion of resistant micro-organisms was relatively low in our
sputum results, rational use of antimicrobial treatment must be followed.
A one year prospective study of the etiologies of infective exacerbations in a
cohort of hospitalized moderately severe COPD patients (mean age 75 years, mean
FEV1 40% predicted) was done by Ko in Hong Kong (7). Bacterial infection was
found in 32.3% among the 530 episodes and mycobacterial infection was found in
1.8%.

Haemophilus

influenza

(13%),

Pseudomonas

aeruginosa

(6%)

and

Streptococcus pneumonia (5.5%) were the commonest PPMs detected. The viral
yields from nasopharyngeal aspirates (NPA) was 9.8% mostly influenza A, B and
respiratory syncytial virus (RSV). Stage IV COPD disease with FEV1 < 30% was
associated with positive sputum cultures as compared with better lung function
measurement (40.4% vs. 28.2%, p = 0.006). In another study by the same author on
the infectious etiology in 71 patients hospitalized with AECOPD with concomitant
pneumonia, 40.8% showed positive bacterial sputum cultures (8). Streptococcus
pneumonia, Pseudomonas aeruginosa and Haemophilus influenzae were the
commonest bacteria identified (11.3%, 9.9% and 9.9% respectively); and Influenza A
21

and rhinovirus (6.1%, 3.0% respectively) were detected by PCR of the NPA
specimens. In Kos studies, positive sputum was associated with high dose inhaled
steroid (>1000 micrograms of beclomethasone equivalent daily) and stage IV disease
(FEV1 < 30%). In an earlier retrospective study by Ko on infective COPD
exacerbations without concomitant pneumonia, Haemophilus influenzae were positive
in 23.1% of the sputum samples while Pseudomonas aeruginosa, Streptococcus
pneumoniae and Mycobacterium tuberculosis were positive in 6.3%, 4.0% and 1.1%
of the sputum samples respectively (9).
In Lodis study in 2004, potential pathogenic micro-organisms (PPMs) were
isolated in 50% - 52.6% in patients with AECOPD (16). The most frequency isolated
strains were Haemophilus influenzae (23.9-25.8%), Streptococcus Pneumoniae
(14.5-16.6%) and Morxella (13.8-10.4%). In a Taiwan study on AECOPD, Klebsiella
pneumonia,

Pseudomonas aeuroginosa and Haemophilus influenzae were the most

common pathogens (19.6%, 16.8% and 7.5%) respectively (17). In Papis study on 64
COPD subjects, bacterial or viral infection was evidenced in 78% exacerbations as
compared with stable disease (bacteria 54.7%, virus 48.4% vs. 6.2% and 37.5%
respectively). Infective exacerbation was associated with increased sputum neutrophil
concentration, lengthened hospital stay and increased lung function impairment (18).
The role of atypical pathogens had not been examined in this study because of
22

diagnostic limitations. But the role of atypical pathogens in infective COPD

exacerbations remained uncertain. In an Indian study, the diagnosis of Mycoplasma
pneumoniae was based on sputum culture, paired serology, detection of specific
antigen and PCR. Evidence of M pneumonia was seen in 16% of patients (19). In
Diederens study, 284 sputum samples from 104 COPD patients were examined by
standard cultures and PCR. All sputum cultures from both stable and exacerbated
groups were negative for atypical pathogens (Mycoplamsa pneumonia and Chlamydia
pneumonia) and hence they were thought to have not played any role in AECOPD
(20). In a local study by Lui among patients hospitalizd with community acquired
pneumonia (CAP), atypical pathogens (Mycoplamsa pneumonia and Chlamydophila
pneumonia) were identified in 28.6% either as single pathogen or co-existed with
bacteria or viruses (21). As no reliable clinical predictors are available and empirical
coverage of atypical pathogens in patients hospitalized for CAP should be considered.
As exacerbations are significant contributor to the morbidity, mortality and
health related QOL in patients with COPD, the relationship of bacterial exacerbations
and airway inflammation had been extensively studied. The observations of bacterial
infection of the lower airways of COPD subjects included (1) increase in sputum
neutrophil concentration and airway and systemic inflammatory responses (2)
elevations of bacterial and viral loads in the exacerbation stage as compared with
23

stable disease (3) eradication of colonized bacteria with anti-microbial may only have
short lasting and doubtful effects.
Marin examined the relationships between bacterial colonisation and
inflammation and serial lung function measurement in COPD subjects (22). Bacterial
colonisation was observed in 71% of patients with common organisms being
Haemophilus influenzae, Pseudomonas aeruginosa and enterobacteria . The PPMs
was associated with sputum neutrophilia with dose response relation observed in
Haemophilus influenza (IL-1 beta, IL-12) and was associated with major lung
function decline. In this study, persistent strains were mostly P. aeruginosa or
enterobacteria. In Sethis study, the acquisition of new strain of bacterial pathogen
was associated with an increase chance of exacerbation (relative risk 2.15) (12). He
also found that neutrophilic airway and systemic inflammation responses (sputum
IL-8, TNFa, neutrophil elastase, sputum C-reactive protein) were more intense with
new bacterial strains than pre-existing strains and non-bacterial exacerbations. The
resolution of the inflammatory responses correlated with the clinical resolution while
persistent inflammation was associated with continued symptoms (13).
Rosell examined the bronchial bacterial profiles and their relations with COPD
exacerbations in 337 subjects (23). The bacterial colonization (> 102 CFU/ml) was
found in 29% stable patients as compared with 54% in exacerbated patients. H.
24

influenzae and P. aeruginosa predominated and exacerbations were significantly

associated with higher bacterial loads and the detection of Pseudomonas aeruginosa in
the bronchial sampling. Another study was performed in 39 COPD patients who had
acquired 76 new strains of Moraxella catrarrhalis over 6 years (24). The acquistion of
Moraxella catarrhalis enhanced airway inflammation with significant elevation of the
post-acquisition sputum levels of IL-8, TNFa and neutrophil elastase and secretory
leucocyte protease inhibitor as compared with baseline. The protease-antiprotease
balance was disrupted both in exacerbated and colonized states and might contribute
to the disease progression in COPD. More recently, the effect of exacerbation on
airway antimicrobial proteins and peptides (AMPs) was studied (25). The results
showed that acquisition of non-typable haemophilus influenzae (NTHI) and M.
catarrhalis are associated with significant changes in sputum levels of AMPs, with
larger changes in exacerbations. The author suggested that AMPs might have role in
disease progression after bacterial infection.
Miravitlles had studied the effectiveness of moxifloxacin in the eradication of
bacterial colonization in a double blinded randomized controlled trial (26). Potentially
pathogenic microorganisms (PPMs) were found in 33.6% of stable subjects with
moderate to severe COPD. Moxifloxacin carried higher PPM eradication rates when
compared with placebo (75% vs. 30%, p = 0.01) but no difference was noted in the
25

acquisition of new PPM and exacerbation rates in 5 months. Antimicrobial should be

effective in eradication of colonizied organisms but the long term effect is doubtful.
Groenwegen studied the physiological and inflammatory parameters in COPD
exacerbations and showed that independent predictors of COPD exacerbations
included decreased FEV1,, increased fibrinogen level, frequent previous exacerbations
and decreased DLCO (27). Therapeutic strategies which attenuate the systemic
inflammation remain the area of further research.
Our studied cohort was mostly elderly patients with severe or very severe airflow
obstruction and multiple co-morbidities. They belonged to the high risk group for
acute respiratory failure with substantial morbidities and mortalities. The majority of
patients who developed symptoms of infective exacerbations received antibiotics
treatment.
Debates had been going on for years for the prescription of antibiotics in the
acute exacerbations of COPD. The question had been addressed in a number of
clinical trials and systemic reviews. In the Cochranes review on the use of antibiotics
for AECOPD published in 2006, 917 COPD subjects from 11 randomised controlled
trials were included (28). In most studies, the clinical diagnostic criteria (increase in
cough, sputum volume and/or purulence) were used for AECOPD. Anti-microbial
therapies produced significant reduction in mortality (relative risk 0.23), treatment
26

failure (RR 0.47) and sputum purulence (RR 0.56). Antimicrobial treatment was
associated with increased risk of dirarrhoea (RR 2.86%). The review provided
evidence that antimicrobial treatment should be given in exacerbations episodes of
moderate to severe COPD subjects. Another systemic review by Puhan also supported
the use of antibiotics in severe COPD exacerbations (29). His systemic review of 13
trials on 1557 COPD subjects suggested that antibiotics were beneficial in patients
with severe exacerbations who required hospitalization but not in outpatients with
mild to moderate exacerbations. Antibiotics were recommended as significantly
decreased the treatment failure rates (odd ratio 0.25) and mortality (OR 0.20) in
severely exacerbated COPD subjects. The addition of antibiotics to systemic steroids
in exacerbation management was examined in a historical general practice-based
cohort. Antibiotic was associated with risk reduction in subsequent exacerbation and
all-cause mortality (30-31).
The clinical effectiveness of the choice of antibiotics in the treatment of
AECOPD had been evaluated in a number of clinical studies. Lode compared the
efficacy of levofloxacin with clarithromycin in 511 patients with AECOPD.
Levofloxacin was found to have higher bacterial eradication rates (96 vs. 81.7% p <
0.0001) though the clinical success rates (82.8% vs. 79.8%) were similar to
clarithromycin. In addition, the exacerbation free interval (100.5 vs. 95 days) and the
27

frequency of exacerbations in one year were similar in both treatment groups (16). In
a retrospective cohort study involving 375 acute care hospitals and 19, 608 patients
across U.S., the efficacy of macrolides and quinolones in AECOPD was compared
(32). The results showed that treatment failure rate was higher for initial quinolones
than macrolide treatment (6.8% vs. 8.1%; P < 0.01) but the difference was
insignificant after group treatment analysis. The utilization of hospital resources was
similar but more diarrheoa was noted in the quinolones groups (1.2%).
In Martinezs study, patients with AECOPD were stratified into uncomplicated
and complicated groups and randomized to receive different antibiotics regimens (33).
Complicated subjects were patients with FEV1 < 50% or FEV1 50-65% with
significant co-morbidities or > 4 exacerbation per year. In uncomplicated patients,
levofloxacin for three days or azithromycin for five days produced similar clinical
success rates (93.0% vs. 90.1%) but levofloxacin showed superiority in
microbiological eradication (93.8% vs. 82.8%). In complicated patients, levofloxacin
for five days or amoxicillin / clavulante for 10 days produced similar clinical success
rates (79.2% vs. 81.7%) and similar microbiological eradication rates (81.4 vs.
79.8%). Another review involved 19 RCTs on the clinical and microbiological
efficacy of amoxicillin/clavulanate, macrolides and quinolones in the treatment of
infective AECOPD (34). Macrolides were found to have lower bacterial eradication
28

rates (odd rate 0.47) and more recurrence of AECOPD when compared with
quinolones while Augmentin was associated more diarrhoea when compared with
quinolones (odd ratio 1.36%). However, the short term efficacy of the antibiotics in
AECOPD was considered to be similar by the author. Recently, a pulse moxifloxacin
courses (400mg daily for 5 days once every 2 months for 6 courses) had been
described by Sethi in 323 stable COPD patients and treatment decreased the odds of
exacerbations by 25% in protocol subjects and by 45% in subjects with purulent or
mucopurulent sputum. The treatment was well tolerated and resistance was not
problematic (35).
The decision to administer antibiotics in AECOPD is multifactorial, which
included the severity of COPD, clinical symptoms (dyspnoea, sputum volume and
purulence, fever), radiological evidence of pneumonia, respiratory failure and
complications and associated comorbidities. In our study population, the clinical
response rates to the empirical antibiotics treatment was 67.6%. In the 25 patients
who showed clinical response to initial antibiotics treatment, 17 (68%) patients
received oral antibiotics alone, 3 (12%) patients received parenteral antibiotics and 5
(20%) patients received both oral and parenteral antibiotics either as step down or
pathogen direct regimens. The most common antibiotics included augmentin (17),
quinolones (8), sulperazone (3) and tazocin (2). In the 12 patients who showed
29

treatment failure (addition or step up of antibiotics treatment, worsening of clinical or

radiological conditions, or progression to respiratory failure), parenteral antibiotics
had been given with variable outcomes.
As most of the studied subjects were frail elderly with mean age of 75.1, mean
FEV1 predicted 32.4% and 2 or more comorbidities, antibiotics treatment were
administered readily if patients presented with worsening dyspnea, increased sputum
volume and purulence. The treatment regimens included coverage for Hemophilus
influenzae, Streptococcus pneumoniae and Moraxella catarrhalis in all cases, and
additional coverage based on the clinical and microbiological findings.
The antimicrobial susceptibility of haemophilus influenzae and moraxella
catarrhalis suggested that ampicillin resistance were common in our locality. The
choice of antibiotics should be augmentin, quinolones (moxifloxacin, levofloxacin) or
macrolides. Macrolides are alternative treatments for infective AECOPD, and have
the advantage of atypical pathogen coverage. Moxifloxacin had been studied in a
number of randomized controlled trials and clinical and microbiological efficacy
demonstrated with good tolerance. However, macrolides are not commonly included
in the antimicrobial susceptibility testing in our sample. Quinolones should be used
with caution as tuberculosis is endemic in our locality. According to Changs study,
quinolones can delay the diagnosis of mycobacterium tuberculosis (36).
30

Pseudomonas species are associated with severe and advanced lung diseases and
two distinct patterns (short-term colonization and long-term persistence) were
described (37). Pseudomonas aeruoginosa was found in six sputum samples from the
exacerbation group and one from the stable disease group. Specific anti-pseudomonal
treatment was given in three cases with variable success.
Prompt administration of appropriate antibiotics in severe COPD patients when
symptomatic of exacerbations may shorten the clinical course and prevent severe
deterioration. For the in-patient management of infective COPD exacerbation and
community acquired pneumonia, major guidelines should be followed (2-38).
Long-term erythromycin therapy is associated with decreased chronic obstructive
pulmonary disease exacerbations. Seemungal evaluated the efficacy of long term
erythromycin (250 mg BD for one year) in 109 moderate severe COPD patients (39).
Macrolide therapy was associated with significant decrease in the frequency of
exacerbation. The number of moderate or severe exacerbations that required
antibiotics, or steroids or hospitalization was lower in the erythromycin arm as
compared with placebo with rate ratio of exacerbation 0.648 (95% CI 0.489-0.859, p
= 0.003). The duration of exacerbation was also lower in erythromycin group but no
difference existed in lung function, sputum inflammatory markers (IL6, IL8,
myeloperoxidase) and bacterial flora, serum C-reactive protein and serum IL-6. In a
31

Chinese study, 36 COPD patients were randomized to receive erythromycin or

placebo for 6 months (40). The results showed that the sputum neutrophil , total cell
counts and neutrophil elastase were significantly decreased in the erythromycin group
together with less exacerbations (relative risk = 0.554) and longer exacerbation free
interval.
Infection of the tracheobronchial tree is the most important cause of COPD
exacerbation and adverse effects on the multiple health related outcomes as measured
by the FEV1, MMRC dyspnoea scores, 6MWD in the BODE index, predicting
mortality, hospitalization and disease progression (4).
Patients with adverse physiological variables had higher chance of infective
exacerbation in our study. The exacerbation group had poorer lung function
parameters, higher baseline heart rate and lower oximetery oxygen saturation. Patients
with poorer nutritional status as reflected by the BMI, proportion of body fat, lowish
serum haemoglobin and albumin level were more susceptible to infective
exacerbations. Poorer exercise performance as reflected by the six minute walking
distance and impaired respiratory specific quality of life measure were also found to
be associated with higher chance of infective exacerbations. Both BMI and exercise
capacity are the key components of the BODE index which predicts the survival rates
and hospital admission rates in COPD subjects (4, 41).
32

COPD patients with exacerbations and concomitant pneumonia were associated

with poorer clinical outcomes with significantly higher in-patient mortality (11 vs. 7%)
and 90 day mortality (17 vs. 13%) than non-pneumonic patients, together with a more
prolonged length of hospital stay (6). In the study cohort, radiological evidence of
pneumonia was present in 24 (64.9%) subjects in the exacerbation group. However,
there was no difference in the baseline characteristics, clinical outcomes and 6 month
mortality as compared with exacerbated patients without pneumonia.
Exacerbations are frequent in patients with severe stages of COPD. In Hursts
study on the susceptibility to exacerbation in 2138 COPD patients, frequent
exacerbations ( > 2 per year) was present in 22%, 33%, 47% of stage II, III and IV
diseases respectively. A history of exacerbation was the strongest predictor of
exacerbations and may reflect a susceptible phenotype (42). In our studied cohort,
exacerbation rates were even higher, infective exacerbations occurred in 37.7%, 33.3
% and 51.2 % of stage II, III and IV COPD patients within the training period
respectively.
Limitations of the study include a retrospective one with small sample size in a
selected group of COPD who were in stable state of the disease. The role of viral and
atypical microorganisms had not been examined because of diagnostic limitations in
routine clinical practice. Systemic and airway inflammatory markers had not been
33

studied in this review. A prospective study should be designed to examine the role of
bacterial, viral and atypical pathogens on the infective exacerbations of COPD. In
clinical practice, molecular techniques may help to provide rapid and accurate
diagnosis and may improve treatment outcomes.

34

CONCLUSIONS
The present study showed that infective exacerbation were common in patients
with chronic lung diseases in stable state. H. influenzae were the most common
bacteria isolated from sputum samples in our cohort. Antibiotic treatment was
prescribed for patients with clinical symptoms and augmentin was the commonest
antibiotic chosen.

Patients with infective exacerbation were associated with lower

baseline SaO2 and higher resting heart rate; and impaired nutritional status and
HRQoL. The exercise capacity of the exacerbation group was lower at baseline and at
6 months, but the difference in mortality was not significant.

35

Table 1.

Baseline characteristics in patients with chronic lung diseases (N = 84)

Variables

Number /
Mean + SD

%/
(Range)

66

78.6 %

75.1 + 8.6
0.62 + 0.27
1.2 + 0.48
32.4 + 13.5
37
44
72

(55 99)
(0.21-1.52)
(0.21 2.62)
(10.2- 80)
44.1 %
85.7 %

78
26
14
9
2
1
1
1

92.8 %
30.9 %
16.7 %
11.9 %
2.4 %
1.2 %
1.2 %
1.2 %

Hypertension
Benign Prostate Hypertrophy
Ischaemic heart diseases
Gastrointestinal disorders
Congestive heart failure

28
20
13
11
8

33.3 %
23.8 %
15.5 %
13.1 %
9.5 %

CNS disorders
Diabetes mellitus
Liver disorders
Orthopaedics diseases
Renal diseases
Cancer

7
6
4
3
1
1

8.3 %
7.2 %
4.8 %
3.6 %
1.2. %
1.2 %

I: Mild

1.2 %

II: Moderate
III: Severe

7
30

8.9 %
38 %

Male
Age (years)
FEV1 (L)
FVC (L)
FEV1 % of predicted
Patients with infective exacerbations
Number of exacerbation episodes
Current / ex-smokers
Respiratory diagnoses (n=84)
COPD
Pulmonary tuberculosis
Bronchiecatsis
Restrictive lung disease
Sleep apnoea
Chronic asthma
Occupational lung disease
Pulmonary embolism
Co-morbidity (n=84)

COPD Staging (GOLD) N = 79

36

IV: Very severe

41

51.9 %

Table 2.Physiological, nutritional, functional and HRQoL parameters of patients

(N = 84)
Variables

Mean + SD

Range

PaO2 (kPa)

9.8 (2.3)

4.7 16.4

PaCO2 (kPa)

5.9 (1.2)

3.6 9.8

SaO2 (%)
Respiratory rate (per minute)
Heart rate (per minute)

90 (4.9)
18.3 (1.1)
85.2 (14.4)

78 - 98
16-20
50-120

Body Mass Index (BMI)

18.6 (3.5)

12.4 - 28

Body Fat (%)

16.4 (8.1).

2.1 -50.8

Haemogoblin (g/dl)

12.68 (1.9)

7.1-18.8

Albumin

31.1 (4)

23-40

6MWT distance (meters)

155 + 94

5-376

Length of program (days)

39 + 14.5

10 - 73

SF-36 (HK) PCS

33.6 + 6.9

18.7 53.8

SF-36 (HK) MCS

42.2 + 13.6

7.8 63.5

SGRQ Symptom

61.8 + 16.4

14.4 96

SGRQ Activity

89.8 + 12.5

41.7 - 100

SGRQ Impact
SGRQ Total

54.4 + 19.6
66.5 + 14.7

18.5 100
30.6 96.5

PaO2: Arterial oxygen tension, PaCO2: Arterial CO2 tension, SaO2: Saturation of
arterial oxygen, 6MWT: six minute walking test, SF-36 (HK) PCS: Short Form 36
(HK) Physical Component Summary, SF-36 (HK) PCS: Short Form 36 (HK) Physical
Component Summary, SRGQ: St. Georges Respiratory Questionnaires

37

Table 3

Sputum bacteriology in patients with chronic lung diseases (N=84)

Pathogens

Number

Percentages (%)

Haemophilus influenzae

15

17.9

Moraxella catarrhalis

8.3

Pseudomonas aeruginosa
Streptococcus pneumonia
Acinetobacter species

7
3
3

8.3
3.6
3.6

Atypical mycobacterium

2.4

Achromobacter xylosoxidans

1.2

Klebsiella species

1.2

Morganella morganii (ICBL)

1.2

Serratia species (ICBL)

1.2

MRSA

1.2

Corynebacterium striatum

1.2

38

Figure 1.

Antimicrobial treatment for patients with infective exacerbations

Duration of anti-microbial treatment (days)

39

Table 4: Antimicrobial susceptibility of common pathogens

Sensitive (%)

Resistant (%)

Intermediate
(%)

Haemophilus influenza (N=15)

Ampicillin

4 (26.7)

11 (73.3)

Augmentin

11

Cefuroxime (oral)
Cefuroxime (parental)
Clarithromycin

11
15 (100)
1

0
0

Levofloxacin

15 (100)

Sulpha/Trimeth

(40)

B-lactamase

Positive

9 (60)
11

Negative

Moraxella catarrhalis (N = 7)
Ampicillin

0 (0)

7 (100)

Augmentin

7 (100)

Cefuroxime (oral)

7 (100)

Cefuroxime (parental)

7 (100)

Levofloxacin

7 (100)

Sulpha/Trimeth
B-lactamase

(100)

Positive

0
6

Negative

Pseudomonas aeuroginosa (N=7)

Amikacin

1 (14.3)

Ciprofloxacin

6 (85.7)

1 (14.3)

Gentamicin
Piperacillin

(85.7)
7 (100)

40

Table 5.

Characteristics According to Exacerbation Status

Exacerbation
group
Mean + SD

Stable group

37

47

Age (years)

74.7 8.4

75.4 8.8

NS

Length of program (days)

Smoke pack years

45.8 14.7
49.7 38.2

33.6 12
46.6 27.7

P < 0.001
NS

FEV1 (L)

0.58 0.24

0.65 0.28

NS

FEV1 (% Predicted)

29.9 12.1

34.4 14.3

NS

FVC (L)

1.18 0.43

1.24 0.49

NS

PaO2 (KPa)

9.56 2.47

10.07 2.27

NS

PaCO2 (KPa)

6.15 1.26

5.7 1.22

NS

SaO2 (%)

88.1 5.1

91.5 4.2

P = 0.001

Respiratory rate (/minute)

18.5 1.1

18.1 1

NS

Heart rate (/ minute)

89.2 13.8

82 14.1

P = 0.023

BMI (kg/ m2)

17.8 3.2

19.2 3.5

NS

Fat (%)

14.9 6.3

17.7 9.2

NS

12.2 2

13 1.7

P = 0.014

25.5 3.8

32.5 3.7

P = 0.001

SF-36 (HK) PCS

33.7 6.3

33.5 7.4

NS

SF 36 (HK) MCS

41.9 15

42.4 12.5

NS

SGRQ symptom

65.3 14.9

59.1 17.1

NS

SGRQ Activity

92.5 10.2

87.7 13.9

NS

SGRQ Impact

59.1 19.5

50.7 19.1

NS

SGRQ Total

70.3 13.9

63.5 14.8

P = 0.039

6MWT distance (meters)

130 87

173 96

P = 0.043

6MWT distance at 1 goal (m)

105 88

151 105

P = 0.041

Number

Mean + SD

Test of
significance

Physiological

Nutritional

Haemoglobin (g/dL)
Albumin (g/L)
HRQoL

Exercise Capacity

PaO2: Arterial oxygen tension, PaCO2: Arterial CO2 tension, SaO2: Saturation of
arterial oxygen, 6MWT: six minute walking test, SF-36 (HK) PCS: Short Form 36
(HK) Physical Component Summary, SF-36 (HK) PCS: Short Form 36 (HK) Physical
Component Summary, SRGQ: St. Georges Respiratory Questionnaires
41

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