Sunteți pe pagina 1din 16

PDF

Volume November Numb PDA Full Text


359:2355-2365 27, 2008 er 22
PowerPoint Slide Set
Infection in the Pathogenesis and CME Exam
Course of Chronic Obstructive Supplementary Material
Pulmonary Disease
Sanjay Sethi, M.D., and Timothy F. Murphy, M.D.

Historical Perspective

In the 1950s and 1960s, according to a theory known as the British Add to Personal Archive
hypothesis, repeated airway infection and hypersecretion of mucus Add to Citation Manager
were thought to be the causes of chronic obstructive pulmonary Notify a Friend
disease (COPD). Subsequently, exposure to tobacco smoke was
E-mail When Cited
identified as the predominant cause. Researchers were still unable to
relate the frequency of exacerbations acute increases in the E-mail When Letters
Appear
respiratory symptoms of COPD that require medical intervention
and hypersecretion of mucus to the progression of airflow
obstruction.1

Instead, the frequency of bacterial


isolation from sputum was found to be PubMed Citation
similar in stable COPD and during
exacerbations. On the basis of these observations, a seminal
review in 1975 indicated that there was insufficient evidence to
support a role of bacterial infection in chronic bronchitis.2
Subsequently, infection, especially bacterial infection, came to
be regarded as an epiphenomenon of little pathogenic
significance in COPD. In the past two decades, our
understanding of the pathogenesis of infections has increased
substantially. New molecular, cellular, and immunologic
techniques used to study the hostpathogen interaction have
been applied in a reexamination of the role of infection in
COPD, and there is considerable new evidence that infection is
the predominant cause of exacerbations and is a likely
contributor to the pathogenesis of COPD.
Exacerbations

Exacerbations are characteristic of the course of COPD. The average frequency is one to two
exacerbations annually, and the frequency generally increases as the disease progresses. Most
exacerbations of COPD are caused by viral or bacterial infection (Table 1 and the Supplementary
Appendix). The clinical manifestations of exacerbations result from the direct effects of viruses and
bacteria and from the host response. Air pollution and other environmental conditions that increase
airway inflammation or bronchomotor tone probably account for 15 to 20% of exacerbations.
Increased respiratory symptoms resulting from coexisting conditions such as congestive heart failure
and pulmonary emboli should be clinically ruled out in the evaluation of exacerbations.
View this table: Table 1. Microbial Pathogens in COPD.
[in this window]
[in a new window]

Bacteria as a Cause of Exacerbations

The controversy regarding the role of bacteria in exacerbations stemmed from numerous reports in
the literature that relied on data gleaned from sputum cultures in point-prevalence studies, serologic
studies using laboratory strains rather than homologous strains, and antibiotic trials with design
flaws. Studies
with improved design and modern methods have
now established that approximately 50% of exacerbations are
caused by bacterial infection.
Bronchoscopic sampling with the use of a protected specimen brush yields reliable specimens from
the lower airways. A pooled
analysis of studies relying on this
technique revealed that bacteria were present in clinically
significant concentrations in the airways of 4% of healthy
adults, 29% of adults with stable COPD, and 54% of adults
with exacerbated COPD. One study reported the presence of
3
intracellular Haemophilus influenzae in bronchial mucosal
biopsy specimens from 87% of patients who were intubated
because of exacerbations as compared with 33% of patients
with stable COPD and 0% of healthy controls. Purulent sputum during 4

an exacerbation is highly correlated with the presence of bacteria in the lower respiratory tract,
providing an additional line of evidence for the pathogenic role of bacteria.5

Older models proposed that increases in the concentration of bacteria (the bacterial load) that
chronically colonize the airways in stable COPD account for exacerbations. However, a
comprehensive analysis of the relationship between bacterial concentrations in sputum, new
pathogen acquisition, and clinical symptoms showed that a change in the bacterial load is an
improbable independent mechanism of exacerbation.6 Rather, bacterial infection of the lower
respiratory tract represents a dynamic, complex process, and acquisition of new bacterial strains
plays a central role in the pathogenesis of exacerbations (Figure 1). Acquisition of a new strain of H.
influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, or Pseudomonas aeruginosa is
strongly associated with the occurrence of an exacerbation.6,7,8,9,10 It has not been determined whether
this association extends to other bacteria isolated from sputum during exacerbations, such as
Staphylococcus aureus and Enterobacteriaceae.

Figure 1. Proposed Model of the Pathogenesis of Bacterial


Exacerbations in COPD.

View larger version


(21K):
[in this window]
[in a new window]

Both pathogenic and host factors determine the outcome of acquisition of a bacterial strain. Not all
acquisitions of pathogenic bacteria are followed by exacerbations. Genomic differences between
strains account in part for differences in the outcome of an encounter with H. influenzae.11 Strains of
H. influenzae that cause exacerbations show increased adherence to epithelial cells, increased
induction of interleukin-8, and increased neutrophil recruitment, as compared with colonizing
strains.12

Host factors are also key determinants in the pathogenesis of an exacerbation. A failure of innate
immune mechanisms in COPD allows bacteria to proliferate and persist in the airways. However,
adults with COPD do have adaptive immune responses to bacteria, and some of these responses
mediate partial protection.9,13 A mucosal IgA response is associated with a reduced likelihood of
exacerbation after acquisition of M. catarrhalis.9 A T-cell response to the P6 protein of H. influenzae
is associated with relative protection from exacerbation caused by this pathogen.14 Collectively, the
degree of impairment of innate immunity, a patient's previous immunologic experience with the
pathogenic strain, and the nature of the adaptive immune response all affect the clinical
manifestation of an acquired bacterial pathogen.

Most exacerbations of COPD are inflammatory events. As


compared with nonbacterial exacerbations, bacterial
exacerbations result in increased airway and systemic
inflammation. 15,16,17
The level of inflammation is highest during exacerbations associated
with acquisition of new bacterial pathogens.17 Persistence of bacteria after antimicrobial therapy is
associated with persistent inflammation, further establishing the role of bacteria in the inflammation
observed in exacerbations.18 The clinical courses of exacerbation and inflammation are closely
linked.17 Bacteria slough highly inflammatory cell-wall antigens, including endotoxin,
peptidoglycan fragments, and outer-membrane proteins, which are deposited in the airways. The
pattern of inflammation is most likely determined by the specific pathogen.

Analysis of immune responses to bacteria is instructive in understanding the mechanisms of


recurrent infections, provided appropriate methods are used. It is important to use the homologous
infecting strain rather than laboratory strains because adults with COPD have strain-specific immune
responses.9,13 Furthermore, immunoassays that are specific for antibodies to epitopes on the bacterial
surface are more likely to detect potentially protective responses. Finally, mucosal immune
responses may play a role in protection.9 When exacerbations develop at the same time that a new
strain of H. influenzae or M. catarrhalis is acquired, new antibody responses develop9,13 an
observation that supports the view that bacteria play a pathogenic role in exacerbations. The strain-
specific immune response leaves the host susceptible to infection by other pathogenic bacterial
strains, accounting in part for the pattern of recurrent exacerbations that characterizes COPD (Figure
1).

Viruses as a Cause of Exacerbations

Studies using a combination of cultures, serologic tests, and


polymerase-chain-reaction (PCR) assays reveal that viruses
can be detected in one third to two thirds of exacerbations.
However, it is difficult to define precisely the proportion of
exacerbations caused by viruses because studies that rely on
culture alone underestimate the role of viruses and studies that
rely on PCR alone overestimate the role. Caution must be exercised before
concluding that the detection of viral RNA in a sputum sample by means of sensitive PCR assays
identifies that virus as the cause of an exacerbation, because viral RNA can be detected in up to 15%
of sputum samples during stable COPD.19,20,21 Quantification of viral RNA by PCR, analysis of
samples collected sequentially during exacerbations and stable periods, characterization of immune
responses, and further study of inflammation will help to define more precisely the proportion of
exacerbations caused by viruses. This uncertainty notwithstanding, viral respiratory tract infections
have substantial clinical consequences in COPD, especially in cases of moderate or severe disease,
with infections sometimes precipitating emergency room visits and hospitalization.22
The mechanisms by which viruses induce exacerbations have been partially elucidated. A key
question is whether viruses that infect the upper respiratory tract infect the lower airways as well.
Rhinovirus infects airway epithelial cells, indicating that viral infection of the lower airways
probably occurs in exacerbations.23,24 Viral infection also induces inflammatory mediators, including
cytokines and chemokines. The association of airway eosinophilia with viral exacerbations
highlights the role of the host in determining the severity of inflammation and symptoms.21

A range of respiratory viruses has been shown to cause exacerbations19,20,21,22 (Table 1). It is not
possible to identify a specific viral cause on the basis of clinical manifestations. The
most
common viruses associated with exacerbations of COPD are
rhinoviruses, but in more severe exacerbations requiring
hospitalization, influenza is more common. Respiratory syncytial virus and
human metapneumovirus have recently been recognized as causes of exacerbations.25,26

Interaction of Viruses and Bacteria

Exacerbations caused by both viruses and bacteria are more


severe and are associated with higher levels of inflammatory
markers than infection caused by viruses or bacteria
alone.16,21 Viruses alter the expression of receptor molecules
on respiratory epithelial cells, allowing increased adherence
and invasion by bacteria.27 Similarly, antecedent bacterial
infection may increase the susceptibility to viral infection by
increasing expression of host-cell molecules that bind
viruses.28 These scenarios represent potential mechanisms
whereby a preceding infection potentiates secondary
infections.
Chronic Infection in COPD

In contrast to the sterile airways of a healthy lung, in stable


COPD, the presence of respiratory pathogens in the airways is
a common occurrence (Table 1). Pathogens are detected in sputum, bronchial
brushings, bronchoalveolar lavage, and bronchial biopsy specimens by culture techniques and by
nonculture-based methods in 25 to 50% of adults with stable COPD, and this rate increases with
worsening airflow obstruction.3,4,29,30 Such
isolation of pathogens has been
regarded as colonization, primarily because of the absence of
acute symptoms of infection. However, the appropriate
definition of colonization is the presence of a pathogen that
does not cause damaging effects to the host or elicit a host
response. Several recent studies show that in stable COPD,
bacterial pathogens are associated with host inflammatory and
immune responses.
Bacterial Colonization and Inflammation
Levels of sputum cytokines or chemokines, such as tumor necrosis factor (TNF- ), interleukin-8,
and leukotriene B4, and levels of sputum neutrophil degradation products, such as myeloperoxidase
and neutrophil elastase, are elevated in patients with COPD whose sputum is colonized with
bacterial pathogens as compared with patients without such pathogens.31,32 However, sputum mainly
reflects the milieu of the larger airways. Bronchoscopy samples the peripheral tracheobronchial tree,
the major site of airway obstruction in COPD. Two bronchoalveolar-lavage studies showed
increased levels of neutrophils, TNF- , interleukin-8, and matrix metalloproteinase 9 in association
with bacterial colonization in COPD.30,33

Bacterial colonization and associated inflammation develop


early in the course of the disease in smokers with
nonobstructive chronic bronchitis and persist in former
smokers with COPD. Airway inflammation related to bacterial colonization is
30,33

neutrophilic, with interleukin-8 as a major mediator. Interleukin-8 and neutrophils play a key role in
the development of COPD. Both interleukin-8 production and airway neutrophilia have been
associated with emphysema in asymptomatic smokers as well as with increased sputum production,
worsening airflow obstruction, and peripheral airway dysfunction in COPD.34,35,36 Therefore,
colonization-induced inflammation probably contributes to the development of COPD throughout its
course.

Other Evidence of Chronic Infection

Development of specific adaptive immune responses to colonizing bacteria would support the
paradigm that in COPD this colonization is actually a smoldering infection. Indeed, serum IgG
antibody responses to the infecting strains after colonization by M. catarrhalis, P. aeruginosa, H.
influenzae, and S. pneumoniae have been observed in COPD.9,10

Pathological and radiologic evidence of chronic infection in COPD has also emerged. Lymphoid
follicles rich in B lymphocytes are present in the small airways when airway obstruction in COPD is
worsening, and their presence probably represents a tissue response to chronic local infection.37
High-resolution computed tomographic scans show that mild bronchiectasis is common in advanced
COPD.38 Chronic infection is an important mediator of cystic
fibrosis and of bronchiectasis that is not related to cystic
fibrosis. These varied observations support the idea that
prolonged, low-grade infection in COPD may worsen the
disease, possibly by damaging airways and inducing
bronchiectasis.
Other Chronic Infections

As the severity of airflow obstruction increases in COPD, colonization by Chlamydophila


pneumoniae and Pneumocystis jiroveci becomes more prevalent.39,40 The significance of this
observation is under investigation. Patients infected with the human immunodeficiency virus are
more susceptible to emphysema than are uninfected persons, and pneumocystis infection represents
an intriguing link between the two diseases.41 Latent adenoviral infection, which is more frequent in
patients with COPD than in people with healthy lungs, could contribute to the pathogenesis of
COPD by enhancing the inflammatory response to tobacco smoke.42

Mechanisms of Chronic Infection in COPD

The results of routine cultures of sputum or bronchoscopic bronchoalveolar-lavage specimens may


considerably underestimate the incidence of chronic infection in COPD.10,29 Nonculture-based
detection techniques have identified H. influenzae in the airway lumen (sputum), in the bronchial
epithelium, and inside subepithelial macrophages.4,29 Whether H. influenzae and P. aeruginosa form
biofilms in COPD, as they do in cystic fibrosis, is not known.43

Innate Lung Defense

Maintenance of a pathogen-free environment in a healthy lung is dependent on an efficient innate


lung defense system, which is multifaceted and redundant (Figure 2). Several
disruptions of innate lung defense occur in COPD. Probably
most important is impairment of mucociliary clearance, which
is universal though variable in moderate-to-heavy smokers. The
airway surface liquid is rich in endogenous antimicrobial polypeptides, including cationic
polypeptides and collectins. Several of these molecules also have important immunoregulatory
functions. Concentrations of surfactant proteins A and D are decreased in smokers, with even lower
levels associated with emphysema.44 Deficiency in salivary lysozyme and sputum secretory
leukocyte protease inhibitor has been related to more frequent exacerbations.45,46

Figure 2. Overview of Innate Defense in the Human Respiratory Tract.


Predominant defense mechanisms for large airways, for both large and small
airways, and for alveoli are depicted; some mechanisms are operative at
multiple sites. Cells that participate in innate immunity include ciliated
epithelial cells, goblet cells, dendritic cells, airway macrophages, alveolar
macrophages, neutrophils, and pneumocytes. Secreted products that
contribute to innate immunity include antimicrobial peptides, inflammatory
View larger version mediators, mucin, and secretory IgA.
(86K):
[in this window]
[in a new window]
The alveolar macrophage is a key defense against inhaled
particulate matter and pathogens. In COPD, alveolar
macrophages show impaired phagocytosis for H. influenzae
and are hyporesponsive to H. influenzae antigens. Airway epithelial 47,48

cells serve important roles in innate lung defense, not only as a physical barrier but also as
orchestrators of host defense, along with lung macrophages. Increased adherence of bacterial
pathogens to oropharyngeal cells has been described in smokers and in patients with COPD who are
prone to exacerbations.49 Whether such a propensity extends to the lower respiratory tract is not
known.

The presence of a bacterium in the respiratory tract is initially sensed by the innate immune system.
A set of diverse host receptor molecules, called pattern-recognition receptors, coordinate an innate
inflammatory response to microbial pathogens by distinguishing molecules that are exclusive to
microbes (Table 2). Toll-like receptors (TLRs), nucleotide-binding oligomerization domain proteins,
and other receptors play critical roles in host protection against microbial infection of the respiratory
tract by activating multiple signaling pathways.50,51 Decreased TLR-2 expression on alveolar
macrophages has been observed in smokers and in patients with COPD, and decrements in TLR-4
expression in nasal and tracheal epithelium have been noted in severe COPD.52,53 Nuclear factor B
(NF- B) is one of several transcriptional regulators of a large number of genes including those
coding for cytokines, chemokines, and other mediators of inflammation whose expression is
increased in COPD.54,55 In addition to NF- B, other signaling pathways are activated by bacterial
molecules in the respiratory tract, including transforming growth factor , Smad, p38 mitogen-
activated protein kinase, and phosphoinositide 3-kinase56 (Table 2).
View this table: Table 2. Bacterial Ligands That Trigger Signal-Transduction Pathways in the
[in this window] Respiratory Tract through Pattern-Recognition Receptors.
[in a new
window]

In addition to triggering signaling pathways that induce innate inflammatory responses, bacterial
ligands, such as P6 of H. influenzae, trigger pathways that mediate up-regulation of mucin
transcription.57 Thus, bacterial ligands initiate signaling pathways that both mediate protective
inflammatory responses and contribute to the pathogenesis of COPD by inducing airway
inflammation and increasing mucin production.

The Vicious Circle

The failure of innate lung defense allows the establishment of infection in the lower airway. In turn,
respiratory pathogens, by further disrupting innate lung defense, perpetuate chronic infection, setting
up what many believe to be a vicious circle (Figure 3). H.
influenzae and P.
aeruginosa, which are the most prevalent chronic bacterial
pathogens in COPD, enhance mucus secretion, disrupt normal
ciliary activity, and cause airway epithelial injury, thereby
further impairing mucociliary clearance. Components of H. influenzae,
58

including lipo-oligosaccharide and the P6 protein, are potent inducers of inflammatory mediators
from airway epithelia and alveolar macrophages (Table 2).12,59,60 H. influenzae induces neutrophil
necrosis, and repeated exposure of mice to H. influenzae lysate leads to pathologic changes that are
consistent with COPD.61,62
Figure 3. The Vicious-Circle Hypothesis of Infection and Inflammation in
COPD.
After the initial insult impairs innate lung defense, microbial colonization
perpetuates a cyclical sequence of events that contributes to the persistent
View larger version inflammation and infection that are characteristic of COPD.
(16K):
[in this window]
[in a new window]

Several impairments in innate lung defense and hostpathogen interactions that facilitate acute and
chronic infection in COPD are becoming evident and support the hypothesis of the vicious circle.
However, definitive evidence that progression of COPD results from infection-induced
inflammation is still lacking.

Antibiotics in COPD

Antibiotics are beneficial in the treatment of moderate and


severe exacerbations, especially when purulent sputum is one
of the presenting symptoms. Observational studies have
63

identified advanced age, severe airflow obstruction, recurrent


exacerbations, and coexisting cardiac disease as predictive
factors for poor clinical outcomes after an exacerbation. We, like 64

others, advocate a stratified approach to antibiotic choice based on these risk factors.65,66 Though not
prospectively validated, such an approach can promote judicious use of antibiotics, and it also
addresses concerns about antibiotic resistance and suboptimal clinical outcomes. An approach using
these principles is shown in Figure 4.

Figure 4. Algorithm for Antibiotic Treatment in Patients with Acute


Exacerbations of COPD.
FEV1 denotes forced expiratory volume in 1 second.
View larger version
(30K):
[in this window]
[in a new window]

Trials performed before 1970 showed a small benefit of antibiotics provided as prophylaxis against
exacerbations.67 However, this benefit was outweighed by concerns about antibiotic resistance and
adverse effects associated with prolonged use of antibiotics. Ongoing trials are reexamining the
question of whether intermittent pulsed treatment with antibiotics or the antiinflammatory action of
antibiotics such as macrolides can be useful in preventing exacerbations (see ClinicalTrials.gov
numbers NCT00739648 [ClinicalTrials.gov] , NCT00473460 [ClinicalTrials.gov] , and
NCT00325897 [ClinicalTrials.gov] ). The results of these trials will indicate whether selected
patients with COPD should be candidates for such prophylaxis.

Future Directions

The interaction of environmental factors, viruses, and bacteria in the pathogenesis of COPD
exacerbations deserves investigation. Development of suitable animal models and additional
translational and basic research on the mechanisms and implications of the so-called vicious circle
will provide a better understanding of the importance of infection in COPD. Exciting new
therapeutic approaches to COPD, such as augmentation or modulation of innate and adaptive
immunity and specific antimicrobial treatments, are on the horizon.

Supported by grants from the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious
Diseases, and the Department of Veterans Affairs Merit Review Award Program.

Dr. Sethi reports receiving consulting fees from Bayer, Sanofi-Aventis, ScheringPlough, Transave and Mpex, lecture
fees from Pfizer and Sanofi-Aventis, and grant support from Bayer and GlaxoSmithKline and holding a patent for a
vaccine antigen for M. catarrhalis and a patent for a diagnostic test for bacterial infection in sputum. Dr. Murphy reports
receiving consulting fees from GlaxoSmithKline, Merck, and Mpex and grant support from Sanofi-Aventis, having a
licensing agreement with Wyeth for vaccine antigens, and holding patents related to bacterial vaccines. No other
potential conflict of interest relevant to this article was reported.

Source Information
From the Divisions of Pulmonary and Critical Medicine (S.S.) and the Division of Infectious Diseases (T.F.M.),
Department of Medicine, University at Buffalo, State University of New York, Buffalo; and the Department of Veterans
Affairs Western New York Healthcare System, Buffalo (S.S., T.F.M.).

Address reprint requests to Dr. Sethi at Veterans Affairs Western New York Healthcare System (151), 3495 Bailey Ave.,
Buffalo, NY 14215, or at ssethi@buffalo.edu .

References

1. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645-
1648. [ISI][Medline]

2. Tager I, Speizer FE. Role of infection in chronic bronchitis. N Engl J Med 1975;292:563-
571. [ISI][Medline]

3. Rosell A, Mons E, Soler N, et al. Microbiologic determinants of exacerbation in chronic


obstructive pulmonary disease. Arch Intern Med 2005;165:891-897. [Free Full Text]

4. Bandi V, Apicella MA, Mason E, et al. Nontypeable Haemophilus influenzae in the lower
respiratory tract of patients with chronic bronchitis. Am J Respir Crit Care Med
2001;164:2114-2119. [Free Full Text]

5. Soler N, Agusti C, Angrill J, Puig De la Bellacasa J, Torres A. Bronchoscopic validation of


the significance of sputum purulence in severe exacerbations of chronic obstructive
pulmonary disease. Thorax 2007;62:29-35. [Free Full Text]

6. Sethi S, Sethi R, Eschberger K, et al. Airway bacterial concentrations and exacerbations of


chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:356-
361. [Free Full Text]

7. Sethi S, Evans N, Grant BJB, Murphy TF. New strains of bacteria and exacerbations of
chronic obstructive pulmonary disease. N Engl J Med 2002;347:465-471. [Free Full Text]

8. Murphy TF, Brauer AL, Sethi S, Kilian M, Cai X, Lesse AJ. Haemophilus haemolyticus: a
human respiratory tract commensal to be distinguished from Haemophilus influenzae. J
Infect Dis 2007;195:81-89. [CrossRef][Medline]
9. Murphy TF, Brauer AL, Grant BJ, Sethi S. Moraxella catarrhalis in chronic obstructive
pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med
2005;172:195-199. [Free Full Text]

10. Murphy TF, Brauer AL, Eschberger K, et al. Pseudomonas aeruginosa in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2008;177:853-860. [Free Full Text]

11. Fernaays MM, Lesse AJ, Sethi S, Cai X, Murphy TF. Differential genome contents of
nontypeable Haemophilus influenzae strains from adults with chronic obstructive pulmonary
disease. Infect Immun 2006;74:3366-3374. [Free Full Text]

12. Chin CL, Manzel LJ, Lehman EE, et al. Haemophilus influenzae from patients with chronic
obstructive pulmonary disease exacerbation induce more inflammation than colonizers. Am
J Respir Crit Care Med 2005;172:85-91. [Free Full Text]

13. Sethi S, Wrona C, Grant BJB, Murphy TF. Strain specific immune response to Haemophilus
influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2004;169:448-453. [Free Full Text]

14. Abe Y, Murphy TF, Sethi S, et al. Lymphocyte proliferative response to P6 of Haemophilus
influenzae is associated with relative protection from exacerbations of chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2002;165:967-971. [Free Full Text]

15. Gompertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in bronchial
inflammation during acute exacerbations of chronic bronchitis. Eur Respir J 2001;17:1112-
1119. [Free Full Text]

16. Wilkinson TM, Hurst JR, Perera WR, Wilks M, Donaldson GC, Wedzicha JA. Effect of
interactions between lower airway bacterial and rhinoviral infection in exacerbations of
COPD. Chest 2006;129:317-324. [CrossRef][ISI][Medline]

17. Sethi S, Wrona C, Eschberger K, Lobbins P, Cai X, Murphy TF. Inflammatory profile of new
bacterial strain exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 2008;177:491-497. [Free Full Text]

18. White AJ, Gompertz S, Bayley DL, et al. Resolution of bronchial inflammation is related to
bacterial eradication following treatment of exacerbations of chronic bronchitis. Thorax
2003;58:680-685. [Free Full Text]

19. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and


inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 2001;164:1618-1623. [Free Full Text]

20. Rohde G, Wiethege A, Borg I, et al. Respiratory viruses in exacerbations of chronic


obstructive pulmonary disease requiring hospitalisation: a case-control study. Thorax
2003;58:37-42. [Free Full Text]

21. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic
obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med
2006;173:1114-1121. [Free Full Text]

22. Greenberg SB, Allen M, Wilson J, Atmar RL. Respiratory viral infections in adults with and
without chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:167-
173. [Free Full Text]

23. Papadopoulos NG, Bates PJ, Bardin PG, et al. Rhinoviruses infect the lower airways. J
Infect Dis 2000;181:1875-1884. [CrossRef][ISI][Medline]
24. Mallia P, Johnston SL. How viral infections cause exacerbation of airway diseases. Chest
2006;130:1203-1210. [CrossRef][ISI][Medline]

25. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus
infection in elderly and high-risk adults. N Engl J Med 2005;352:1749-
1759. [Free Full Text]

26. Hamelin ME, Ct S, Laforge J, et al. Human metapneumovirus infection in adults with
community-acquired pneumonia and exacerbation of chronic obstructive pulmonary disease.
Clin Infect Dis 2005;41:498-502. [CrossRef][Medline]

27. Avadhanula V, Rodriguez CA, Devincenzo JP, et al. Respiratory viruses augment the
adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-
dependent manner. J Virol 2006;80:1629-1636. [Free Full Text]

28. Sajjan US, Jia Y, Newcomb DC, et al. H. influenzae potentiates airway epithelial cell
responses to rhinovirus by increasing ICAM-1 and TLR3 expression. FASEB J
2006;20:2121-2123. [Free Full Text]

29. Murphy TF, Brauer AL, Schiffmacher AT, Sethi S. Persistent colonization by Haemophilus
influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2004;170:266-272. [Free Full Text]

30. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway inflammation and bronchial
bacterial colonization in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2006;173:991-998. [Free Full Text]

31. Bresser P, Out TA, van Alphen L, Jansen HM, Lutter R. Airway inflammation in
nonobstructive and obstructive chronic bronchitis with chronic Haemophilus influenzae
airway infection: comparison with noninfected patients with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 2000;162:947-952. [Free Full Text]

32. Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation
and health status in clinical stable COPD. Eur Respir J 2004;23:685-691. [Free Full Text]

33. Soler N, Ewig S, Torres A, Filella X, Gonzalez J, Zaubet A. Airway inflammation and
bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease.
Eur Respir J 1999;14:1015-1022. [Abstract]

34. Tanino M, Betsuyaku T, Takeyabu K, et al. Increased levels of interleukin-8 in BAL fluid
from smokers susceptible to pulmonary emphysema. Thorax 2002;57:405-
411. [Free Full Text]

35. O'Donnell RA, Peebles C, Ward JA, et al. Relationship between peripheral airway
dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax
2004;59:837-842. [Free Full Text]

36. Fuke S, Betsuyaku T, Nasuhara Y, Morikawa T, Katoh H, Nishimura M. Chemokines in


bronchiolar epithelium in the development of chronic obstructive pulmonary disease. Am J
Respir Cell Mol Biol 2004;31:405-412. [Free Full Text]

37. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic
obstructive pulmonary disease. N Engl J Med 2004;350:2645-2653. [Free Full Text]

38. Patel IS, Vlahos I, Wilkinson TM, et al. Bronchiectasis, exacerbation indices, and
inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2004;170:400-407. [Free Full Text]
39. Morris A, Sciurba FC, Lebedeva IP, et al. Association of chronic obstructive pulmonary
disease severity and Pneumocystis colonization. Am J Respir Crit Care Med 2004;170:408-
413. [Free Full Text]

40. Blasi F, Damato S, Cosentini R, et al. Chlamydia pneumoniae and chronic bronchitis:
association with severity and bacterial clearance following treatment. Thorax 2002;57:672-
676. [Free Full Text]

41. Diaz PT, King MA, Pacht ER, et al. Increased susceptibility to pulmonary emphysema
among HIV-seropositive smokers. Ann Intern Med 2000;132:369-372. [Free Full Text]

42. Retamales I, Elliott WM, Meshi B, et al. Amplification of inflammation in emphysema and
its association with latent adenoviral infection. Am J Respir Crit Care Med 2001;164:469-
473. [Free Full Text]

43. Starner TD, Zhang N, Kim G, Apicella MA, McCray PB Jr. Haemophilus influenzae forms
biofilms on airway epithelia: implications in cystic fibrosis. Am J Respir Crit Care Med
2006;174:213-220. [Free Full Text]

44. Betsuyaku T, Kuroki Y, Nagai K, Nasuhara Y, Nishimura M. Effects of ageing and smoking
on SP-A and SP-D levels in bronchoalveolar lavage fluid. Eur Respir J 2004;24:964-
970. [Free Full Text]

45. Taylor DC, Cripps AW, Clancy RL. A possible role for lysozyme in determining acute
exacerbation in chronic bronchitis. Clin Exp Immunol 1995;102:406-416. [ISI][Medline]

46. Gompertz S, Bayley DL, Hill SL, Stockley RA. Relationship between airway inflammation
and the frequency of exacerbations in patients with smoking related COPD. Thorax
2001;56:36-41. [Free Full Text]

47. Berenson CS, Wrona CT, Grove LJ, et al. Impaired alveolar macrophage response to
Haemophilus antigens in chronic obstructive lung disease. Am J Respir Crit Care Med
2006;174:31-40. [Free Full Text]

48. Berenson CS, Garlipp MA, Grove LJ, Maloney J, Sethi S. Impaired phagocytosis of
nontypeable Haemophilus influenzae by human alveolar macrophages in chronic obstructive
pulmonary disease. J Infect Dis 2006;194:1375-1384. [CrossRef][ISI][Medline]

49. Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med 2004;164:2206-
2216. [Free Full Text]

50. Malley R, Henneke P, Morse SC, et al. Recognition of pneumolysin by Toll-like receptor 4
confers resistance to pneumococcal infection. Proc Natl Acad Sci U S A 2003;100:1966-
1971. [Free Full Text]

51. Ratner AJ, Aguilar JL, Shchepetov M, Lysenko ES, Weiser JN. Nod1 mediates cytoplasmic
sensing of combinations of extracellular bacteria. Cell Microbiol 2007;9:1343-
1351. [Medline]

52. Droemann D, Goldmann T, Tiedje T, Zabel P, Dalhoff K, Schaaf B. Toll-like receptor 2


expression is decreased on alveolar macrophages in cigarette smokers and COPD patients.
Respir Res 2005;6:68-68. [CrossRef][Medline]

53. MacRedmond RE, Greene CM, Dorscheid DR, McElvaney NG, O'Neill SJ. Epithelial
expression of TLR4 is modulated in COPD and by steroids, salmeterol and cigarette smoke.
Respir Res 2007;8:84-84. [Medline]

54. Shuto T, Xu H, Wang B, et al. Activation of NF-kappa B by nontypeable Hemophilus


influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha/beta-I kappa
B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proc Natl
Acad Sci U S A 2001;98:8774-8779. [Free Full Text]

55. Di Stefano A, Caramori G, Oates T, et al. Increased expression of nuclear factor-kappaB in


bronchial biopsies from smokers and patients with COPD. Eur Respir J 2002;20:556-
563. [Free Full Text]

56. Mikami F, Gu H, Jono H, Andalibi A, Kai H, Li JD. Epidermal growth factor receptor acts
as a negative regulator for bacterium nontypeable Haemophilus influenzae-induced Toll-like
receptor 2 expression via an Src-dependent p38 mitogen-activated protein kinase signaling
pathway. J Biol Chem 2005;280:36185-36194. [Free Full Text]

57. Ha U, Lim JH, Jono H, et al. A novel role for IkappaB kinase (IKK) alpha and IKKbeta in
ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus
pneumoniae. J Immunol 2007;178:1736-1747. [Free Full Text]

58. Chen R, Lim JH, Jono H, et al. Nontypeable Haemophilus influenzae lipoprotein P6 induces
MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-
IkappaBalpha-NF-kappaB signaling pathways. Biochem Biophys Res Commun
2004;324:1087-1094. [CrossRef][ISI][Medline]

59. Berenson CS, Murphy TF, Wrona CT, Sethi S. Outer membrane protein P6 of nontypeable
Haemophilus influenzae is a potent and selective inducer of human macrophage
proinflammatory cytokines. Infect Immun 2005;73:2728-2735. [Free Full Text]

60. Clemans DL, Bauer RJ, Hanson JA, et al. Induction of proinflammatory cytokines by human
respiratory epithelial cells after stimulation by nontypeable Haemophilus influenzae. Infect
Immun 2000;68:4430-4440. [Free Full Text]

61. Naylor EJ, Bakstad D, Biffen M, et al. Haemophilus influenzae induces neutrophil necrosis:
a role in chronic obstructive pulmonary disease? Am J Respir Cell Mol Biol 2007;37:135-
143. [Free Full Text]

62. Moghaddam SJ, Clement CG, De la Garza MM, et al. Haemophilus influenzae lysate
induces aspects of the chronic obstructive pulmonary disease phenotype. Am J Respir Cell
Mol Biol 2008;38:629-638. [Free Full Text]

63. Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, Garcia-Aymerich J, Barnes NC.


Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database
Syst Rev 2006;2:CD004403-CD004403. [Medline]

64. Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory
treatment of acute exacerbations of chronic bronchitis. Eur Respir J 2001;17:928-
933. [Free Full Text]

65. The Global Initiative for Obstructive Lung Disease home page. (Accessed November 3,
2008, at http://www.goldcopd.com.)

66. Balter MS, La Forge J, Low DE, Mandell L, Grossman RF. Canadian guidelines for the
management of acute exacerbations of chronic bronchitis. Can Respir J 2003;10:Suppl
B:3B-32B. [Medline]

67. Black P, Staykova T, Chacko E, Ram FS, Poole P. Prophylactic antibiotic therapy for chronic
bronchitis. Cochrane Database Syst Rev 2003;1:CD004105-CD004105.