(Chest. 2000;117:286S-291S.)
© 2000
American College of Chest Physicians
Bacterial Infection and the Pathogenesis of COPD*
Sanjay Sethi, MD
*
From the VA Western New York Healthcare System and Department of Medicine, Division of Pulmonary and Critical Care, State University of New York at Buffalo, Buffalo, NY.
Correspondence to: Sanjay Sethi, MD, VA Western New York Healthcare System (151), 3495 Bailey Ave, Buffalo, NY 14215; e-mail: SETHI.SANJAY{at}Buffalo.VA.Gov
 |
Abstract
|
|---|
Bacterial infection of the lower respiratory tract
can impact on the etiology, pathogenesis, and the clinical course of
COPD in several ways. Several recent cohort studies suggest that lung
growth is impaired by childhood lower respiratory tract infection,
making these individuals more vulnerable to developing COPD on exposure
to additional injurious agents. Impairment of mucociliary clearance and
local immune defense in smokers allows bacterial pathogens to gain a
foothold in the lower respiratory tract. These pathogens and their
products can cause further impairment of mucociliary clearance due to
enhanced mucus secretion, disruption of normal ciliary activity, and
airway epithelial injury, and thus persist in the lower respiratory
tract. This chronic colonization of the lower respiratory tract by
bacterial pathogens could induce a chronic inflammatory response with
lung damage. Nontypeable Haemophilus influenzae, usually
regarded as an extracellular mucosal pathogen, has been demonstrated to
cause intracellular infections of the upper and lower respiratory tract
respiratory tissue. Increased incidence of chronic Chlamydia
pneumoniae infection of the respiratory tract has been
associated with COPD. These chronic infections of respiratory tissues
could contribute to the pathogenesis of COPD by altering the host
response to cigarette smoke or by inducing a chronic inflammatory
response. Application of newer molecular and immunologic research
techniques is helping us define precisely the role of bacterial
infection in COPD.
Key Words: bacterial infection • COPD • Haemophilus influenzae • pathogenesis
|
Introduction
|
|---|
Abbreviations: CF = cystic fibrosis;
IL = interleukin; LOS = lipo-oligosaccharide;
NTHI = nontypeable Haemophilus influenzae;
PCR = polymerase chain reaction
The
precise role of bacterial infection in COPD has been a source of
controversy for several decades.1
2
Several putative roles
of bacterial infection in the etiology, pathogenesis, and the clinical
course of COPD can be identified.1
These include the
following: (1) childhood lower respiratory tract infection impairs lung
growth reflected in a lower FEV1 in adulthood;
(2) chronic colonization of the lower respiratory tract by bacterial
pathogens induces a chronic inflammatory response with lung damage (the
vicious circle hypothesis); (3) chronic infection of respiratory
tissues by bacterial pathogens contributes to the pathogenesis of COPD
by altering the host response to cigarette smoke or by inducing a
chronic inflammatory response; (4) bacteria cause acute exacerbations
of chronic bronchitis, which contribute significantly to the morbidity
and mortality of COPD; and (5) bacterial antigens in the lower airway
induce hypersensitivity that enhances airway hyperreactivity. With the
availability of newer molecular and immunologic research techniques,
the role of bacterial infection in COPD is being reevaluated. In this
article, the first three putative roles of bacterial infection in
either predisposing to COPD or contributing to its pathogenesis by
causing a chronic infection of the lower airways will be discussed.
|
Childhood Infection and Adult Lung Function
|
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Several recent studies have reported lung function (by spirometry)
in cohorts of adult patients for whom reliable information is available
regarding the incidence of lower respiratory tract infection
(bronchitis, pneumonia, whooping cough) in childhood (< 14 years of
age; Table 1
).3
4
5
6
All of these studies have shown a lower
FEV1 and often a lower FVC among adults who
experienced childhood lower respiratory tract
infection.3
4
5
6
This association is seen after controlling
for confounding factors such as tobacco exposure. The magnitude of this
defect in FEV1 has varied among the studies and
is greater in older cohorts. The defect in lung function is not
obstructive with preservation of the FEV1/FVC
ratio, but is consistent with "smaller lungs," suggesting impaired
lung growth. The extent of decrease in FEV1 is
unlikely to cause symptomatic pulmonary disease on its own, but could
make the individual susceptible to the effects of additional injurious
agents such as tobacco smoke.
Although the association between childhood lower respiratory tract
infection and impaired lung function in adulthood is now well
established, there is ongoing debate as to whether this association
reflects a cause-effect relationship in which the infectious process
damages a vulnerable lung undergoing rapid postnatal growth and
maturation. If this was the case, then the effect of the infection on
lung function should be seen only in the first 2 years of life during
postnatal lung growth but not in later childhood (3 to 14 years).
However, this has not been observed consistently in the studies to
date.3
4
5
6
An alternative explanation for the observed
association is that an undetermined genetic factor predisposes these
individuals to lower respiratory tract infections in childhood as well
as a lower FEV1 in adulthood. This explanation
implies that impaired lung growth antedates the respiratory tract
infection.
The etiology of childhood pneumonia and bronchitis was not established
in these studies. Bacterial infection, especially by
Streptococcus pneumoniae and Haemophilus
influenzae is a common cause of severe pneumonia in
children.7
The impact of childhood bacterial lower
respiratory tract infection on the prevalence of COPD is likely to be
greater in developing countries where there is a high incidence and
inadequate treatment of these infections.
|
Vicious Circle Hypothesis
|
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Tobacco smoking cannot be the sole factor responsible for the
pathogenesis of COPD, as only a small proportion (15%) of smokers
develop chronic bronchitis and an even smaller proportion go on to
develop COPD. In the absence of underlying lung disease, the
tracheobronchial tree is sterile. In patients with COPD, the
tracheobronchial tree is chronically colonized with potential
respiratory pathogens, predominantly nontypeable H
influenzae (NTHI), S pneumoniae, and Moraxella
(Branhamella) catarrhalis.8
9
Several years ago, we
proposed a vicious circle hypothesis to explain how chronic bacterial
colonization of the lower airways in patients with COPD can perpetuate
inflammation and contribute to progression of the disease (Fig 1
).1
10
Substantial supporting evidence for this hypothesis,
both in vitro and in vivo, has now accumulated
and is discussed below.
|
Vicious Circle Hypothesis Supporting Evidence
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Central to the vicious circle hypothesis is the notion that once
bacterial pathogens have gained a foothold in the lower respiratory
tract from impaired mucociliary clearance due to tobacco smoking, they
persist by further impairing mucociliary clearance (Fig 1)
. This
impairment of mucociliary clearance can be due to enhanced mucus
secretion, disruption of normal ciliary activity, and airway epithelial
injury. Experimental evidence demonstrates that respiratory tract
pathogens and their products can cause all of these effects in
vitro.
|
Bacterial Infection and Chronic Mucus Hypersecretion
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Adler et al11
examined the effect of cell free
filtrates of broth cultures of NTHI, S pneumoniae, and
Pseudomonas aeruginosa on the secretion of mucous
glycoproteins by explanted guinea pig airway tissue. Seven of 28
strains (25%) of NTHI, 10 of 26 strains (34%) of S
pneumoniae, and 12 of 18 strains (66%) of P aeruginosa
stimulated mucin secretion. This stimulation was a true secretory
effect and not passive release of preformed intracellular
macromolecules due to cellular damage, as ultrastructural assessment
(by light, transmission, and scanning electron microscopy) demonstrated
an absence of cytotoxicity. The Pseudomonas stimulatory products were
60- to 100-kd proteases. The NTHI and pneumococcal stimulatory
exoproducts were 50 to 300 kd in size and did not possess proteolytic
activity.
|
Bacterial Infection and Mucociliary Clearance
|
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The tracheobronchial ciliary escalator is of paramount importance
in maintaining sterility of the lower respiratory tract by transporting
bacteria trapped in mucus toward the pharynx.12
Disruption
of this ciliary activity is therefore likely to be very important in
the establishment of a chronic colonization in the tracheobronchial
tree. Wilson et al13
measured using photometry the effect
of cell-free supernatants of NTHI, P aeruginosa, and
Staphylococcus aureus on ciliary beat frequency of strips of
human nasal ciliary epithelium. Rapid inhibition of ciliary beat
frequency was seen with NTHI and P aeruginosa but not with
S aureus. On direct examination, ciliary dyskinesia and
ciliostasis were seen. Human neutrophil elastase inhibits ciliary
activity and damages respiratory epithelium.14
15
Bacterial products in the airways may be a potent stimulus for
neutrophil migration into the airways, and elastase released from these
neutrophils can act synergistically with bacterial products and cause
further inhibition of tracheobronchial ciliary function.
|
Bacterial Infection and Airway Epithelial Injury
|
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An important component of the vicious circle hypothesis is the
potentially damaging effects of bacteria and bacterial products on
airway epithelial lining cells. Such epithelial injury in the large
airways would contribute to bacterial persistence, and in the small
airways could contribute to the respiratory bronchiolitis that causes
progressive airways obstruction. In an in vitro tissue
culture model of nasal turbinate epithelium, Read et al16
have demonstrated that NTHI is capable of causing airway epithelial
injury. They studied these epithelia after 30 min, 14 h, and
24 h of incubation with a NTHI strain. At 30 min, the airway
epithelium and cilia were intact and the bacteria were found associated
with the overlying mucus layer. At 14 h, patchy injury developed
to the airway epithelium, with bacterial cells now associating with
these damaged epithelial cells but not with intact epithelium. At
24 h, detached epithelial cells with adherent bacteria were seen.
The studies discussed above demonstrate that bacteria that colonize and
infect the lower respiratory tract in COPD are capable of fostering in
the tracheobronchial tree an environment in which they can persist,
supporting the central tenet of the vicious circle hypothesis (Fig 1)
.
Recently, more attention is being directed toward another portion of
the vicious circle, the possible effects of bacterial products and the
chronic inflammatory response it engenders on the
elastase-anti-elastase balance in the lung. If bacterial products in
the tracheobronchial tree could cause neutrophil influx and
degranulation in the airways and lung parenchyma, they could contribute
to chronic inflammation, parenchymal lung damage, and progressive small
airway obstruction seen in COPD. Evidence to support the occurrence of
such an effect of bacterial products in the lower respiratory tract is
presented below.
|
Bacterial Infection and Airway Inflammation
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The presence of bacteria in the lower airways in patients with
stable COPD has been labeled colonization. However, this
bacterial presence is definitely abnormal, as the lower respiratory
tract in the absence of lung disease is normally
sterile.8
9
This abnormal colonization of the
tracheobronchial tree is not confined to the large airways. It has been
shown to extend to the peripheral airways by bronchoscopic protected
specimen brushings culture.17
Even during colonization,
bacteria in these airways are likely to be in a constant state of
turnover, releasing extracellular products, undergoing lysis with
release of a variety of proteins, lipo-oligosaccharide (LOS) and
peptidoglycan. LOS is a potent inflammatory stimulus; in fact, repeated
instillation of LOS can lead to development of emphysema in
hamsters.18
It is therefore quite likely that this
colonization actually is a low-grade smoldering infection that induces
chronic airway inflammation. In the large airways, such inflammation
would contribute to mucus production; in the small airways, it could
contribute to respiratory bronchiolitis and progressive airway
obstruction. Direct evidence from patients with COPD that colonization
of the airways induces inflammation is forthcoming.19
20
Indirect evidence includes in vitro experiments with NTHI
LOS and from patients with cystic fibrosis (CF), another disease
associated with airway bacterial colonization.
Khair et al21
incubated explant cultures of human
bronchial epithelium with NTHI LOS at two different concentrations, 10
µg/mL and 100 µg/mL. Epithelial permeability and intracellular
adhesion molecule-1 expression, and release of interleukin (IL)-6,
IL-8, and tumor necrosis factor-
into the culture medium were
measured. IL-6 and tumor necrosis factor- secretion and
intracellular adhesion molecule-1 expression by the bronchial
epithelial cells was significantly increased by only the higher
concentration of LOS (100 µg/mL), while IL-8 expression was
stimulated by both 10 µg/mL and 100 µg/mL LOS. The levels of
inflammatory mediators attained in the culture medium were adequate to
increase neutrophil chemotaxis and adherence in vitro. There
was no increase in epithelial permeability.
Konstan et al22
compared airway inflammation in 18
adolescents or adults with mild CF (FEV1 of
79 ± 4% predicted) with 23 healthy control subjects. The CF
patients were free of symptoms of acute infection and were therefore
presumed to be have mucosal bacterial colonization with little
inflammatory response or ongoing lung destruction. BAL was obtained in
these subjects for quantitative bacterial culture, cell counts, Ig, and
elastase measurement. P aeruginosa was isolated from the BAL
in 16 patients, S aureus and NTHI in 6 patients each, while
all the samples from the healthy control subjects were sterile. A
marked inflammatory response was seen in the CF patients, with total
(mean ± SEM) cell counts in the BAL of epithelial lining fluid of
68 ± 32 x 106 cells/µL vs
5 ± 1x106 cells/µL in healthy control
subjects; differential cell count in the CF patients revealed an
intense neutrophilia (57%) vs 3% in control subjects. IgG, IgA, and
IgM were elevated 2.5- to sixfold in the patients demonstrating an
active local immune response. Fifteen of 18 patients had free elastase
in BAL, while none was present in the control subjects, and the
concentrations measured were greatly in excess of the nanomolar
quantity required to interfere with local host defenses, cause mucin
secretion, and stimulate IL-8 release, etc. This shows that in CF there
is an active inflammatory response in the lower airways to bacterial
colonization.
|
Chronic Bacterial Infection of Respiratory Tissues
|
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Bacterial pathogens implicated in COPD such as NTHI have always
been regarded as extracellular pathogens that infect the airway lumen.
Recently, NTHI infection of the respiratory tissue by has been
demonstrated in both upper and lower respiratory
tract.23
24
Whether chronic Chlamydia
pneumoniae infection of the respiratory tract is associated with
COPD has also been recently investigated.25
These studies
have used detection techniques more sensitive than bacterial cultures
for determining the presence of bacterial organisms in tissue and have
made some very interesting and somewhat surprising observations.
|
Intracellular NTHI Infection of Respiratory Tissues
|
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Forsgren et al23
examined hypertrophied adenoid
tissue removed at adenoidectomy from 10 children with nasal obstruction
for the presence of intracellular NTHI. Three complementary techniques
were used: in situ hybridization with a fluorescent-labeled
probe specific for 16s ribosomal RNA of NTHI, transmission electron
microscopy, and culture of the adenoid tissues after treatment with an
aminoglycoside to kill extracellular bacteria. They detected NTHI in
the adenoids of all 10 patients with in situ hybridization,
mostly in the reticular crypt epithelium and in subepithelial
locations. Transmission electron microscopy confirmed these findings,
and culture techniques showed that these intracellular bacteria were
viable. The reservoir for these bacteria appeared to be large
subepithelial mononuclear cells, likely macrophages, which contained up
to 200 viable and actively dividing intracellular NTHI per cell. This
was confirmed by enriching macrophages from the adenoid cell suspension
and demonstrating high titers of bacteria on culture in these enriched
cells.
Forty-nine explanted lungs from patients undergoing lung
transplantation were examined for the presence of NTHI by Möller
et al.24
The underlying lung disease was COPD in 16, CF in
16, bronchiectasis in 5, and noninfectious pulmonary diseases in 12
patients. The presence of NTHI was determined by staining tissue
sections with a monoclonal antibody that binds to an epitope on the
outer membrane protein P6 of NTHI and with polymerase chain reaction
(PCR) for the same outer membrane protein with DNA extracted from the
lung tissue as a template. NTHI was present in tissue sections by
immunostaining and PCR in 24 of 49 (49%) patients overall. When
classified by underlying disease, lung explants were positive for NTHI
in 10 of 16 CF (62%), 8 of 16 COPD (50%), 2 of 5 bronchiectasis
(40%), and 4 of 12 noninfectious diseases (33%) specimens.
NTHI was present in a significantly greater proportion of tissue
sections from patients with COPD and CF than from patients with
bronchiectasis and noninfectious diseases (58% and 47% vs 33% and
29%, respectively; p < 0.0001). NTHI was found in subepithelial
tissues and in macrophages, and were found with equal frequency in all
parts of the lung, central and peripheral airways, and in the
parenchyma.
These two studies demonstrate that NTHI resides intracellularly,
especially in macrophages, and in the subepithelial zone in human
respiratory tissues. These bacteria are protected from antibiotics and
bactericidal antibodies, and may act as reservoirs of
infection.26
Tissue infection by NTHI could also
contribute to the pathogenesis of COPD directly or indirectly. Chronic
low-grade infection could directly induce a chronic inflammatory
response in the parenchyma and the airways of the lung that could be
additive or synergistic to the inflammatory effects of tobacco smoke.
Indirectly, such an infection could enhance the damaging effects of
tobacco smoke on respiratory tissues. On the other hand, it is possible
that this tissue infection is simply a marker of compromised local
immunity. Whether tissue infection by NTHI is seen in early COPD and
the effect of this infection in tissue models needs to be investigated.
|
Chronic C pneumoniae infection in COPD
|
|---|
C pneumoniae is an obligate intracellular atypical
bacterial pathogen. Acute C pneumoniae infection can cause
bronchitis and pneumonia. Chronic infection with C
pneumoniae is being actively investigated as a cause of several
systemic diseases, especially coronary artery disease.27
von Hertzen et al25
studied whether the incidence of
chronic C pneumoniae infection is increased in COPD.
Presence of chronic C pneumoniae infection was determined by
three different methods: serum antibodies to C pneumoniae
(IgG and IgA and circulating immune complexes), sputum IgA antibodies
to C pneumoniae, and PCR of sputum for C
pneumoniae DNA. Two of the three methods had to yield positive
results in a patient to conclude that he or she had a chronic C
pneumoniae infection. Thirty-four patients with severe COPD, and
13 patients with mild to moderate COPD were compared with 23 patients
with community-acquired pneumonia who served as control subjects. The
incidence of chronic C pneumoniae infection (as defined
above) was 71% in patients with severe COPD, 46% in mild to moderate
COPD, and 0% in the control group. Whether this chronic infection
contributes to the pathogenesis of COPD as discussed above or is a
reflection of compromised local immunity warrants further
investigation.
|
Summary
|
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Figure 2
summarizes the known and proposed mechanisms by which bacterial
infection of the tracheobronchial tree can produce the symptom complex,
pathologic features, and pathophysiology of COPD. This model parallels
in many respects the mechanisms by which tobacco smoking causes chronic
bronchitis and airway obstruction. This proposed mechanism therefore
emphasizes how tobacco smoking and tracheobronchial infection can
synergistically induce this chronic disabling disease.
Future Directions
There are several unanswered questions regarding bacterial
infection in COPD that can be exciting areas of investigation. Which
bacterial products (eg, LOS, outer membrane proteins)
are present in the lower airways in chronic bronchitis and at what
concentration? What are the mechanisms by which these bacteria and
their components incite airway inflammation? Is this airway
inflammation correlated with progression of airway obstruction in these
patients?
Answering such questions will enable us to place the role of
bacteria in this chronic disabling disease in the correct perspective.
If bacteria do play a role in progression of obstruction, then
important new areas of therapeutic intervention open up,
including vaccines and antimicrobial therapy to prevent persistent
bacterial colonization.
|
Acknowledgements
|
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The author thanks Adeline Thurston for secretarial
assistance.
|
Footnotes
|
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Supported by VA Merit Review.
|
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TOP
Abstract
Introduction
