Download Infectious Etiology of Acute Exacerbations of Chronic Bronchitis*

Infectious Etiology of Acute
Exacerbations of Chronic Bronchitis*
Sanjay Sethi, MD
Infectious agents are a major cause of acute exacerbations of chronic bronchitis (AECB) and
COPD. Several respiratory viruses are associated with 30% of exacerbations, with or without a
superimposed bacterial infection. Atypical bacteria, mostly Chlamydia pneumoniae, have been
implicated in < 10% of AECB. The role of bacterial pathogens when isolated from the respiratory
tract during AECB has become better defined by application of several newer investigative
techniques. Bacterial pathogens can be isolated in significant concentrations from distal airways
in 50% of AECB. Specific immune responses to surface exposed antigens of the infecting
pathogen have been shown to develop after an exacerbation. Emerging evidence from molecular
epidemiology and measurement of airway inflammation further support the role of bacteria in
AECB. When properly defined, 80% of AECB are likely to be infectious in origin.
(CHEST 2000; 117:380S–385S)
Key words: chronic bronchitis; COPD; exacerbation; infection
Abbreviations: AECB ⫽ acute exacerbations of chronic bronchitis; NTHI ⫽ nontypeable Haemophilus influenzae;
OMP ⫽ outer membrane protein; PSB ⫽ protected specimen brush
OPD is a chronic disabling disease. It is characC terized
by intermittent acute exacerbations of
chronic bronchitis (AECB) associated with worsening symptoms and lung function. These acute exacerbations contribute considerably to the morbidity
and the diminished quality of life experienced by
people afflicted with COPD.1 AECB are an important cause of mortality, and in a longitudinal study of
a cohort of patients with moderate to severe COPD,
lower respiratory tract infection was the most common identified cause of death.2
Several etiologic factors alone or in combination
cause exacerbations of COPD.3 One major etiologic
factor discussed in this article is infection of the lower
respiratory tract. Although recognized for several decades, several new lines of evidence utilizing newer
research techniques have improved our understanding
of the role of infection in acute exacerbations.
Definition and Diagnosis
The most commonly used definition of an acute
exacerbation of chronic bronchitis is a subjective
*From the Department of Medicine, Division of Pulmonary and
Critical Care Medicine, State University of New York at Buffalo
and Department of Veterans Affairs Western New York Healthcare System, Buffalo, NY.
Supported by VA Merit Review.
Correspondence to: Sanjay Sethi, MD, Veterans Affairs Western
New York Healthcare System (151), 3495 Bailey Ave, Buffalo, NY
14215; e-mail: [email protected]
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increase from baseline of one or more chronic
symptoms. These symptoms include shortness of
breath, cough, sputum production, sputum purulence, and sputum tenacity. Several other disorders
can cause such an increase in symptoms and need to
be excluded with reasonable certainty by the evaluating clinician. Differential diagnoses include pneumonia, congestive heart failure, myocardial ischemia,
upper respiratory tract infection, pulmonary embolism, recurrent aspiration, and noncompliance with
medications.3 In most circumstances, a thorough
history and examination are adequate to make the
diagnosis. Occasionally, a chest radiograph or ECG is
required. Sputum studies are not useful in most
episodes of AECB except in certain circumstances,
such as recurrent AECB, inadequate response to
therapy, and before starting treatment with prophylactic antibiotics.
Infectious Etiologies of AECB
Three classes of pathogens have been implicated
as causing acute exacerbation of COPD by infecting
the lower respiratory tract: respiratory viruses, atypical
bacteria, and aerobic Gram-positive and Gramnegative bacteria.4 The relative contributions of these
three different classes of pathogens may change depending on the severity of the underlying obstructive
airway disease. Such changes may also happen within a
class, especially for bacterial pathogens.
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Respiratory Viruses
Several longitudinal studies of groups of COPD
patients in the 1970s examined the role of viruses in
causing acute exacerbations of COPD.5–7 Viral infection in these studies was usually documented by
serology and occasionally by culture. In these studies, about 30% of the episodes of AECB were
associated with viral infection. Asymptomatic viral
infections (diagnosed by fourfold rise in specific
antibody titers) were also seen, but the incidence of
viral infection in association with exacerbations was
significantly greater than during stable periods.5
Figure 1 is a composite of incidence data for specific
viral pathogens from three longitudinal studies.5–7
Significant incidence of influenza virus as a cause of
AECB stresses the importance of yearly influenza
immunization in patients with COPD.
In a more recent cross-sectional study, Soler et al8
studied 50 episodes of severe AECB requiring ICU
admission and mechanical ventilation. In 38 episodes, adequate paired serologic samples were available for analysis. Viral infection was present in six of
these episodes (15.8%), influenza in five episodes,
and respiratory syncytial virus in one episode. Interestingly, in three of the five influenza infections, a
concomitant pathogen was present. This study would
suggest that viral infection decreases in importance
in the most severe end of the spectrum of AECB,
and is often complicated by concomitant bacterial
infection.
Atypical Bacteria
In recent years, we have seen an increasing recognition of the role of atypical bacterial pathogens in
acute bronchitis and community-acquired pneumonia. However, in AECB, several older studies and a
few recent studies have implicated atypical bacteria
in only 5 to 10% of episodes. Legionella does not
appear to cause an isolated bronchial infection, with
pneumonic infiltrates invariably associated with its
isolation from the lower respiratory tract. Mycoplasma pneumoniae infection has been shown to be
a rare cause of AECB.5– 8 Chlamydia pneumoniae
has been associated with AECB in 5 to 10% of
cases.9,10 In the study of severe exacerbations requiring intensive care by Soler et al,8 C pneumoniae
infection was present in 7 of 38 evaluable cases
(18%), but a concomitant bacterial pathogen was
present in two of these patients. No Mycoplasma
infection was documented in these patients.
Bacteria
Bacteria are isolated from sputum in 40 to 60% of
AECB. The three predominant bacterial species isolated are nontypeable Haemophilus influenzae (NTHI),
Moraxella catarrhalis, and Streptococcus pneumoniae.
Whether this isolation represents infection of the
lower airway causing AECB has been a controversial
issue for several decades. In the 1950s and 1960s, the
British hypothesis included bacterial exacerbations
along with mucus hypersecretion as major contributors to the pathogenesis of COPD. With the realization of the central role of tobacco smoke exposure
and the emergence of evidence that mucus hypersecretion and worsening airway obstruction were not
linked, this hypothesis fell into disfavor. Several
longitudinal studies in the 1960s and 1970s demonstrated that the incidence of bacterial isolation during exacerbations of COPD was not different from
the incidence during stable COPD. Serologic studies
conducted in the same time period compared serum
antibody titers to airway bacterial pathogens such as
NTHI in COPD patients to titers in control subjects.
These studies yielded confusing and contradictory
results (reviewed in Murphy and Sethi11).
As a consequence of these observations, bacterial
infection was discounted as a cause of AECB, with
the supposition that isolation of bacteria from sputum represents chronic colonization, an “innocent
bystander” role.12 In the last decade, several new
lines of evidence have emerged that have reexamined this issue using either new diagnostic modalities
or research techniques (Table 1). These new lines of
Table 1—New Approaches to Understanding the Role
of Bacteria in COPD Exacerbations
Figure 1. Viral pathogens that cause acute exacerbations of
COPD. RSV ⫽ respiratory syncytial virus. Reprinted with permission from Sethi.4
Bronchoscopic sampling of the lower respiratory tract
Immune response to bacterial pathogens in AECB
Molecular epidemiology of bacterial pathogens
Airway inflammation measurement and correlation with
bacteriology
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evidence support the role of bacterial infection as a
cause of AECB and will be discussed below.
Bronchoscopic Sampling of Lower Respiratory
Tract in AECB
An attractive approach to understanding the role
of bacterial infection in AECB is sampling of distal
airway secretions for quantitative culture by protected specimen brush (PSB) or by BAL to determine bacterial concentrations in the distal airways.
Such an approach has contributed tremendously to
our understanding of nosocomial pneumonia. Four
studies have been published that have used this
methodology, and all of them have shown significant
bacterial infection of the distal airways in approximately 50% of patients (Table 2).8,13–15 The bacterial
species isolated in these studies represent the same
spectrum of pathogens commonly isolated from sputum cultures of patients with AECB.
The study of Monso et al13 is especially informative, as it included a control group of 29 patients with
stable COPD. Figure 2 demonstrates that AECB was
associated twice as often with distal airway infection
with ⱖ 103 cfu/mL of pathogenic bacteria, and four
times as often with ⱖ 104 cfu/mL of pathogenic
bacteria. Soler et al8 examined a more severe population of 50 patients, who received mechanical ventilation for an AECB, and obtained lower airway
Figure 2. Culture results of PSB samples from patients with
stable COPD or with acute exacerbations. Reprinted with permission from Sethi.4
secretions for culture by bronchoscopy with PSB,
BAL, and endotracheal aspirates. A major drawback
of their study was that 21 of their 50 patients had
received antibiotics prior to the samples being obtained for bacterial cultures. In spite of that, bacterial
infection was demonstrated alone in 21 of 50 patients
(42%) and with a viral or atypical pathogen in 7 patients
(14%). The distribution of the bacterial pathogens
isolated in their study is remarkable for the high
Table 2—Bronchoscopic Studies in AECB
Study
Subjects
Diagnostic Methods
% Bacterial
Pathogen Positive
Bacterial Pathogens
Isolated, No.
Haemophilus parainfluenzae, 11
S pneumoniae, 7
H influenzae, 6
M catarrhalis, 3
P aeruginosa, 3
Other Gram-negative, 5
Other Gram-positive, 9
H influenzae, 10
S pneumoniae, 3
P aeruginosa, 2
M catarrhalis, 2
H influenzae, 11
P aeruginosa, 9
S pneumoniae, 4
M catarrhalis, 4
Other Gram-negative, 6
S pneumoniae, 10
Alpha-hemolytic streptococci, 6
M catarrhalis, 2
H influenzae, 1
P aeruginosa, 1
Other Gram-negative, 1
Other Gram-positive, 1
Fagon et al14
50 ICU patients receiving
mechanical ventilation
PSB
50*
Monso et al13
29 outpatients
PSB
51.7
Soler et al8
50 ICU patients receiving
mechanical ventilation†
PSB, BAL, endotracheal
aspirate
46
Pela et al15
40 outpatients
PSB
52.5
*ⱖ102 cfu/mL was used to define a positive culture, instead of the usual ⱖ103 cfu/mL.
†Twenty-one patients had antimicrobial therapy in the 24 h prior to admission to the ICU.
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incidence of Pseudomonas aeruginosa and other Gramnegative bacilli (14 of 50 patients; 28%). Another study,
by Eller et al,16 utilizing sputum cultures has also
demonstrated an increasing frequency of isolation of
these groups of pathogens in exacerbations of severe
COPD. Whether this is due to environmental factors
(such as antibiotic selection pressure or exposure to
hospital flora from frequent exacerbations) or is related
to a greater degree of host immune compromise is not
clear.
The remarkably consistent results of these four
studies and the increased rate of isolation of pathogenic bacteria in AECB than in stable COPD support the pathogenic role of bacteria in a proportion
of AECB.
Immune Responses to Bacterial Pathogens in
AECB
Demonstration of the development of an immune
response to an infecting pathogen satisfies one of the
Koch postulates. Several studies in the 1950s and
1960s attempted to demonstrate that patients with
COPD have increased serum antibody titers to NTHI
as compared to control subjects without COPD. These
studies yielded confusing and contradictory results
that could be attributed to the limitation of the
methods in these studies, such as using a single
laboratory strain of NTHI and measuring antibody
levels to whole bacteria.11
We recently studied the immune response to
NTHI in two patients who had experienced an
AECB with methods that would avoid the shortcomings of earlier studies.17 NTHI strains used in these
studies were homologous infecting strains, and the
immunoassays used were specific for antibodies to
surface-exposed epitopes. In addition, as these patients are part of a longitudinal study, we were able
to study paired sera collected 1 month prior to the
exacerbation (preserum) and sera collected a month
after the onset of the AECB (postserum). In both
patients, the postserum demonstrated bactericidal
activity to the homologous strain that was absent in
the preserum. Immunoblots with purified outer
membrane proteins (OMPs) of the homologous
NTHI strains did not reveal significant differences
between the presera and postsera indicating development of new antibodies. However, in a radioimmunoprecipitation assay, an immunoassay specific
for antibodies to surface-exposed epitopes, the postsera demonstrated development of new antibodies to
surface-exposed epitopes of OMP P2 and a high
molecular weight OMP of the homologous strains.
We were able to demonstrate further that the new
antibodies to OMP P2 were responsible for a substantial proportion of the bactericidal activity in the
postsera. OMP P2 of NTHI has been shown to have
several hypervariable regions on the surface of the
bacteria.18 This explains why these bactericidal antibodies were strain-specific for the homologous infecting strain.
Development of a specific immune response to
the infecting strain of NTHI in this study supports
the role of bacterial infection in AECB. Similar
evidence with other bacterial species implicated in
AECB (see Table 2) would help us better define
their role in acute exacerbations.
Molecular Epidemiology of Bacterial Pathogens
There is increasing recognition that strains of a
bacterial species differ considerably in their surface
antigenic structure. Earlier reports in which the
incidence of bacterial infection during stable and
periods of exacerbation of COPD have been compared assumed that all strains of a bacterial species
are the same, and that bacterial infection of the
lower respiratory tract in COPD is a static process.5
In preliminary studies, we have performed strain
typing for NTHI in patients with COPD.19 What has
become apparent is that there is a dynamic turnover
in these patients of NTHI strains, and there appears
to be an association between this dynamic process
and the occurrence of AECB. Therefore, a simple
comparison of the frequency of isolation of a bacterial species in these patients is inadequate, and
application of molecular epidemiology to bacterial
isolates from COPD patients is necessary to further
elucidate the role of bacterial infection.
Airway Inflammation Measurement and
Correlation With Bacteriology
Bacterial infection of the lower airways during an
episode of AECB should be associated with neutrophilic inflammation, as is seen in other mucosal sites
such as the middle ear and sinuses. One would
therefore expect bacterial exacerbations to be associated with significantly greater neutrophilic airway
inflammation than nonbacterial exacerbations.
Therefore, sputum culture results should correlate
with measures of airway inflammation in AECB.
Preliminary data from our laboratory support this
hypothesis, with pathogen-positive AECB having
substantially increased measures of airway inflammation in expectorated sputum than pathogen-negative
AECB.20
Model of Recurrent NTHI Infection in
COPD
Patients with COPD have recurrent infections
with NTHI, which clinically manifest as associated
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with increasing symptoms (exacerbation), or without
an acute change in symptoms (colonization). Based
on emerging evidence that NTHI infection in COPD
is a dynamic process and the immune response to
infecting strains is predominantly strain specific, we
can hypothesize a model to explain recurrent NTHI
infections in patients with COPD (Fig 3). The factors
that determine the clinical manifestations of an acquisition of a new NTHI strain by a patient with COPD
are unknown. In this model, virulence of the infecting
strain and the presence of preexisting protective antibody are assumed to be important factors. Absence or
a low level of protective antibodies and/or a virulent
strain predisposes to development of increased symptoms, ie, an exacerbation, with the opposite predisposing to an acquisition without increased symptoms, ie, a
colonization. Exacerbation (and possibly colonization)
leads to development of antibodies to the infecting
strain, which, with or without antibiotics, successfully
clear it from the lower respiratory tract. However, as a
substantial proportion of these antibodies are directed
to hypervariable regions of OMPs (such as P2), these
antibodies are strain specific and do not protect the
host from NTHI strains that are antigenically different
(Fig 3). Such strains then replace the previous strain in
a repetitive manner.
This model would suggest that identifying virulence factors in NTHI strains and identifying antigens on the surface of NTHI that are shared among
several strains and can elicit a protective antibody
response are important areas of research.
Conclusion
When strictly defined as suggested above, it is
likely that 80% of AECB are infectious in origin, with
Figure 3. Model of recurrent infection by NTHI in patients with
COPD.
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40 to 50% caused by bacteria, 30% by viruses, and 5
to 10% by atypical bacteria. Concomitant infections
by more than one infectious pathogen appear to occur
in 10 to 20% of patients. Several lines of evidence
demonstrate bacterial infection to be a cause of AECB.
Tracheobronchial airway infection in COPD is a complex dynamic process. Understanding this process and
the host immune response to it should lead to new ways
of abrogating these infections.
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