| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
* From the Department of Veterans Affairs Western New York Healthcare System, Division of Pulmonary and Critical Care Medicine and Division of Infectious Diseases of the Department of Medicine, State University of New York at Buffalo, Buffalo, NY.
Correspondence to: Sanjay Sethi, MD, Department of Veterans Affairs Western New York Healthcare System (151), 3495 Bailey Ave, Buffalo, NY 14215
 |
Abstract |
|---|
 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Design: This hypothesis was tested by
comparing levels of interleukin (IL)-8, tumor necrosis factor
(TNF)-
, and neutrophil elastase (NE) in 81 sputum samples obtained
from 45 patients with AECB. Four groups were compared. In the first
three groups, nontypeable Haemophilus influenzae
(n = 20), Haemophilus parainfluenzae (n = 27), and
Moraxella catarrhalis (n = 14) were isolated as sole
pathogens, respectively. In the fourth group, only normal flora was
isolated (n = 20). Paired samples, obtained from individual patients
at different times, that differed in their culture results were also
compared.
Setting: An outpatient research clinic at a Veterans Affairs Medical Center.
Patients: These patients were participating in a prospective, longitudinal study of the dynamics of bacterial infection in chronic bronchitis, for which they were seen in the study clinic on a monthly basis as well as when they were experiencing symptoms suggestive of AECB.
Interventions: None.
Measurements and
results: H influenzae exacerbations were
associated with significantly higher sputum IL-8, TNF-, and NE.
M catarrhalis exacerbations demonstrated significantly
higher sputum TNF- and NE when compared to pathogen-negative
exacerbations. H parainfluenzae-associated exacerbations
had an inflammatory profile similar to pathogen-negative exacerbations.
Sputum elastase level distinguished bacterial from nonbacterial AECB
and correlated with clinical severity of the AECB.
Conclusions: Increased airway inflammation associated with isolation of H influenzae and M catarrhalis supports an etiologic role of these pathogens in AECB.
Key Words: airway inflammation • chronic bronchitis • exacerbation • Haemophilus moraxella
|
Introduction |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The role of bacterial pathogens as a cause of AECB is controversial for several reasons.8 9 10 11 Bacterial pathogens can be isolated from sputum during stable chronic bronchitis at the same frequency as during exacerbations. Serologic studies examining antibodies to common bacterial pathogens and placebo-controlled antibiotic trials in AECB have yielded confusing and contradictory results. Though alternative explanations exist for these observations, many authors have interpreted them to show that bacterial pathogens play no role in AECB.8 11 This view holds that isolation of bacteria during AECB represents chronic colonization and is a mere epiphenomenon.
If bacterial pathogens were playing a role in AECB, one would expect a neutrophilic inflammatory response in the airways to the acute infection. Therefore, one would expect that airway inflammation during AECB should be related to sputum culture results. We therefore hypothesized that sputum collected during bacterial AECB exhibits neutrophilic inflammation to a greater degree than sputum collected during pathogen-negative AECB, which are of a viral or other etiology.
We tested this hypothesis by measuring markers of inflammation in a
collection of sputum samples obtained during AECB observed during a
prospective, longitudinal study of bacterial infection in chronic
bronchitis. Pathogen-negative AECB were those in which only normal
flora was isolated from sputum obtained at the time of diagnosis.
Normal flora was defined as the absence of the following pathogens in
sputum culture: Haemophilus spp., M catarrhalis, S
pneumoniae, Staphylococcus aureus, Pseudomonas spp.,
and Gram-negative bacilli. Bacterial AECB were those in which any of
these pathogens were isolated from sputum culture. The bacterial AECB
included in this study were specifically those in which either H
influenzae or M catarrhalis was the sole pathogen
isolated from sputum obtained at the time of diagnosis. To examine the
role of Haemophilus parainfluenzae as a pathogen in AECB, we
included a group of exacerbations in which H parainfluenzae
was the sole "pathogen" isolated. We measured neutrophilic
inflammation by quantifying interleukin (IL)-8, tumor necrosis factor
(TNF)-, and neutrophil elastase (NE) in the sputum
supernatants.12
13
14
Pathogen-positive sputum samples were
compared with pathogen-negative samples.
|
Materials and Methods |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
At each visit, clinical information, sputum, and serum samples were collected. Of a total of 1,503 clinic visits, the subject’s COPD was clinically stable in 1,227 of these visits (81.6%), while in 276 visits (17.4%), the subject was experiencing an AECB. Whether a patient was stable or experiencing an exacerbation was determined as follows. At each visit, the subject was questioned about the status of his chronic respiratory symptoms (dyspnea; cough; sputum production, viscosity, and purulence), and the responses were graded as same as baseline or worse than baseline. If the symptom was reported to be worse than baseline, the subject was asked to grade it as somewhat worse or much worse than baseline. If there was minor (somewhat worse) worsening of two or more symptoms or a major (much worse) worsening of one or more symptoms, a clinical assessment was made as to the cause. If necessary, a chest radiograph was obtained. If no other cause, such as pneumonia, upper-respiratory infection, or congestive heart failure, was identified, the patient was determined to be experiencing an exacerbation.
We also calculated an overall clinical score at each visit, which served as a measure of clinical severity of the AECB episode. At each clinic visit in our longitudinal study, we assessed 10 clinical parameters (overall well-being; dyspnea; cough; sputum production, viscosity, and purulence; overall appearance, respiratory rate, wheezing, and rales) and graded each of these from 1 to 3 as described above. A score of 10 represented baseline, and a score of 30 represented the sickest patient.
Sputa collected were spontaneous morning samples. The whole sputum sample was weighed, graded macroscopically for purulence and viscosity, and homogenized by incubation at 37°C for 15 min with an equal volume of 0.1% dithiothreitol (Sputolysin; Calbiochem; San Diego, CA). Serial dilutions of homogenized sputum were prepared in phosphate-buffered saline solution and plated on blood, chocolate, and MacConkey agar plates. Bacterial identification was performed by standard techniques. If H influenzae, M catarrhalis, or S pneumoniae was present, we attempted to isolate and characterize 10 individual colonies of each bacterial species. Single colonies of other potential pathogens, including H parainfluenzae, S aureus, Pseudomonas spp., and Gram-negative bacilli were also isolated and characterized. Bacterial titers were measured by counting the number of colonies in the dilution plates and multiplying the count by the appropriate dilution factor. The remainder of the sputum sample was centrifuged at 25,000g for 45 min at 4°C, and the resultant supernatant was stored at - 70°C.
Of the 276 episodes of AECB, sputum samples were obtained for culture in 267 episodes. Normal flora was isolated in 83 of these samples (pathogen-negative AECB), while one or more potential pathogens (Haemophilus spp., M catarrhalis, S pneumoniae, S aureus, Pseudomonas spp., and Gram-negative bacilli) were isolated in 184 episodes (bacterial AECB). Sputum supernatant obtained in 81 exacerbations in 45 patients was selected to be included in this study, as shown in Figure 1 . These selection criteria allowed us to avoid overrepresentation by patients who had frequent exacerbations.
|
|
Sputum Inflammation Measurement
In all of the assays described below, Immulon-4 microtiter
plates (Dynatech; Chantilly, VA) were used. All sputum supernatants and
standards were tested in duplicate, and mean values were used.
Intra-assay coefficient of variation of < 10% and interassay
coefficient of variation of < 15% were accepted. Because of limited
volume of sputum supernatant available for a small number of samples,
all measurements were not performed on all samples (see "Results"
section).
IL-8 Assay
A sandwich ELISA was developed. All cytokine reagents were
obtained from R&D Systems, Minneapolis, MN. All intermediate washes
were done with plate wash buffer ([PWB], phosphate-buffered saline
solution with 0.05% Tween-20). Microtiter wells were coated with 50
µL of goat antihuman IL-8 antibody diluted to 4 µg/mL in
carbonate-bicarbonate buffer (0.1M sodium carbonate, 0.1M sodium
bicarbonate, pH 9.6) overnight at room temperature. The coating
antibody was aspirated, and the wells were blocked with 300 µL of 3%
nonfat dried milk in PWB for 1 h. The wells were washed, dried,
and then coated with 50 µL of immunoassay stabilizer (Stabilcoat;
Surmodics; Eden Prairie, MN) for 45 min. After removing the
Stabilcoat, the plates were dried overnight at room temperature and
stored at 4°C.
Serial dilutions of recombinant IL-8 and 1:10 dilution of sputum supernatants in 1% nonfat dried milk in PWB were prepared. Fifty microliters of the standard or sample was added to the wells and incubated at 37°C for 2 h. After washing, 50 µL of biotinylated antihuman IL-8 diluted to 200 ng/mL in 1% nonfat dried milk in PWB was added to the wells for 1 h at 37°C. After washing, bound biotinylated antibody was detected with streptavidin-horseradish-peroxidase, and the optical density of the wells was read at 450 nm. A standard curve was constructed from the wells containing recombinant IL-8, and the amount of IL-8 in the samples was read from this curve. The lower limit of detection of IL-8 in this assay was 5 pg/mL, and the linear range was 20 to 12,500 pg/mL.
TNF- Assay
A sandwich ELISA similar to the IL-8 ELISA was developed with
the appropriate reagents obtained from R&D Systems. Homogenized sputum
supernatants were tested without further dilution. The lower limit of
detection of TNF- was 10 pg/mL, and the linear range was 80 to 5,000
pg/mL.
NE Assay
Free elastase activity in undiluted sputum supernatants was
determined with a colorimetric assay with a synthetic substrate,
N-methoxysuccinyl-ala-ala-pro-val p-nitroanilide, as described
previously.12
Standard elastase was site-titrated enzyme
purified from sputum obtained from Elastin Productions (Owensville,
MO). The minimum elastase activity detectable was 41 MU/mL, and
the linear range was 94 to 3,200 MU/mL.
Data Analysis
Nonparametric statistical methods were used for all data with
Statview 5.0 software. For unpaired data, the Kruskall-Wallis
and Mann-Whitney U rank tests were used; for paired data,
the Wilcoxon signed-rank test was used. Correlation was tested with the
Spearman coefficient. A p < 0.05 was considered significant.
|
Results |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
|
IL-8 was detectable in all 81 sputa tested, TNF- in 40 of the 79
sputa tested, and free NE activity in 66 of the 80 sputa tested. Figure 2
depicts the results obtained. H influenzae exacerbations
were associated with significantly higher sputum IL-8, TNF-, and NE
when compared to pathogen-negative (normal flora only) exacerbations.
M catarrhalis exacerbations were associated with
significantly higher sputum TNF- and NE when compared to
pathogen-negative (normal flora only) exacerbations. Except for a
significantly higher sputum NE, airway inflammation in H
parainfluenzae exacerbations was similar to pathogen-negative
(normal flora only) exacerbations. There were differences in the
intensity and nature of inflammation among the different pathogens.
H influenzae exacerbations were associated with
significantly greater sputum IL-8, TNF-, and NE, while M
catarrhalis exacerbations were associated with significantly
greater sputum TNF- when compared to H parainfluenzae
exacerbations. The H influenzae and M
catarrhalis groups did not differ in any of the sputum
inflammatory parameters.
|
There is overlap between groups in the values obtained of the various inflammatory molecules measured; however, 16 of 19 pathogen-negative (normal flora only) sputa (84.2%) have a NE level < 350 MU/mL, while only 10 of 34 H influenzae and M catarrhalis sputa (29.4%) have a level below this value. In the H parainfluenzae group, 12 of 27 sputa (44.4%) have sputum NE < 350 MU/mL.
Comparison of Sputum Inflammation Within Patients
Sputum samples used in this study were collected on a longitudinal
basis, with individual patients contributing from one to four samples.
Comparison of sputum inflammation in pairs of samples obtained from
individual patients during two exacerbations, which differ only in the
presence or absence of pulmonary pathogens, is a more rigorous test of
our hypothesis. Such an analysis accounts for the variability among
patients in the baseline level of airway inflammation, and the
differences seen within a patient should reflect the presence of
pathogens in the airways.
All possible pairs of samples available were included in this analysis. In order to obtain at least 10 pairs for analysis, we combined H influenzae and M catarrhalis into a single pathogen-positive group. To further elucidate the role of H parainfluenzae as a pathogen, we treated it in this analysis both as a nonpathogen and as a pathogen by comparing it with pathogen-positive exacerbations and with pathogen-negative exacerbations (Table 4 ).
|
, and NE than pathogen-negative AECB (Table 4 , Fig 3
). When compared to H parainfluenzae exacerbations, sputum
IL-8, TNF-, and NE were significantly increased in pathogen-positive
AECB. H parainfluenzae exacerbations did not differ in any
of the sputum inflammatory parameters from the pathogen-negative
(normal flora only) AECB (Table 4)
.
|
Correlation Between Symptoms and Sputum Inflammation
Clinical scores for the exacerbations included in this study
ranged from 12 to 26, with a mean score of 17.5. There was no
difference in clinical score among the groups of exacerbations defined
by culture results (Kruskal-Wallis, p = not significant). There was a
significant correlation between clinical score with sputum NE
(
= 0.449; p < 0.001; Fig 4
). This correlation was unaffected by exclusion of the four outliers
with clinical scores > 24. However, none of the other inflammatory
markers measured showed such a relationship. This observation
demonstrates that sputum elastase is a marker of the clinical severity
of an AECB and could reflect a cause-effect relationship between the
two parameters.
|
values of
0.504 for IL-8 and TNF- (p < 0.001), 0.396 for IL-8 and NE
(p < 0.001), and 0.571 for TNF- and NE (p < 0.001).
Bacterial titers per gram of sputum (mean ± 1 SEM) of H
influenzae (4.89 ± 1.03 x 108) and
M catarrhalis
(4.71 ± 1.13 x 108) did not differ from
each other but were significantly greater than H
parainfluenzae (4.35 ± 3.69 x 107)
with a p value < 0.001 for both comparisons. There was significant
correlation between bacterial titers and sputum IL-8 ( = 0.382;
p = 0.003), TNF- ( = 0.437; p < 0.001), and NE
( = 0.381; p = 0.003). These results suggest that bacterial
infection is acting as an inflammatory stimulus, and as the stimulus
increases, there is a corresponding increase in the airway inflammatory
response.
|
Discussion |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
S pneumoniae was isolated in 10 of the 276 episodes of AECB observed in our longitudinal study. In only four of these episodes (in three subjects), S pneumoniae was a sole pathogen (Fig 1) . This low rate of infection by S pneumoniae could be related to almost all our subjects having received the pneumococcal vaccine. In addition, the pneumococcus appears to be more prevalent in the earlier stages of COPD, while 85% of our subjects had moderate or severe obstructive disease.22 23
The present study demonstrates a strong association between recovering
H influenzae and M catarrhalis in sputa
during exacerbations and neutrophilic airway inflammation. We did not
enumerate neutrophils in sputa; however, previous studies have shown
excellent correlation between measured levels of IL-8 and NE levels and
sputum or BAL neutrophil counts.12
24
Both H
influenzae and M catarrhalis are clearly
associated with mucosal infections at other airway sites, such as the
middle ear and sinuses. H influenzae and its products reduce
mucociliary clearance, increase mucus secretion, and cause bronchial
epithelial damage in vitro.25
26
Lipo-oligosaccharide of H influenzae induces IL-8, IL-6, and
TNF- secretion from bronchial epithelial cells in
vitro.27
It is therefore likely that a similar
inflammatory process is being engendered by these mucosal pathogens
during AECB. An alternative explanation of our findings is that the
pathogens recovered are actually oropharyngeal isolates and were
isolated in the sputum from salivary contamination. Several
bronchoscopic studies of distal airway bacterial flora in AECB
have shown that H influenzae and M
catarrhalis are often present in concentrations of
> 103/mL in the distal airways during
AECB.18
19
20
Laurenzi et al28
and Haas et
al29
have shown that in patients with COPD, H
influenzae is simultaneously recovered in the upper and the lower
airways. These studies would support the notion that most, if not all,
of the sputum isolates of H influenzae and M
catarrhalis in the present study reflect bronchial infection
rather than oropharyngeal colonization.
Measuring inflammatory molecules in sputum as done in this study is now a widely accepted method of studying airway inflammation, but is associated with significant limitations. Contamination with oropharyngeal flora has been discussed above. Contamination with saliva could variably dilute the inflammatory markers present in sputum and could have influenced our results. Microscopic evaluation was not performed in the 81 samples included in this study; however, macroscopic evaluation revealed that only four of these samples were mucoid (three in the H parainfluenzae group and one in the normal flora-only group). Seventy-seven of the 81 samples were either entirely purulent or contained multiple flecks of pus, indicating their predominantly lower-respiratory origin. Another major limitation of sputum is that it represents secretions from all levels of the bronchial tree. Therefore, it is not possible to determine from this study if the neutrophilic inflammation in bacterial AECB is confined to the large airways or involves the small airways also. Future studies examining distal airway inflammation in bacterial AECB are needed to extend our observations.
Though H parainfluenzae is frequently isolated in sputum obtained during stable and unstable COPD, its role of as an airway pathogen in COPD is ill defined.30 31 Whether this sputum isolation is from oropharyngeal contamination or from the lower respiratory tract is unclear because H parainfluenzae is a common constituent of normal oropharyngeal flora.32 Furthermore, little evidence exists to suggest that H parainfluenzae is a mucosal pathogen in other respiratory tract sites, most notably the middle ear and the sinus cavity. Bronchoscopic studies of AECB have added to the confusion. In the three published studies, H parainfluenzae was the most common pathogen isolated in the study by Fagon et al,18 while it was completely absent in the other two studies.19 20 In this study, sputa that contained H parainfluenzae resembled pathogen-negative sputa. However, unlike the pathogen-negative sputa, the H parainfluenzae sputa are a heterogeneous group. For example, while only 3 of 19 normal flora-only sputa (15.8%) have free neutrophil elastase activity of > 350 MU/mL, 15 of 27 H parainfluenzae sputa (55.6%) have elastase levels exceeding this value. Some of these sputa had elastase values resembling pathogen-positive exacerbations.
This heterogeneity among the H parainfluenzae sputa can be explained in two possible ways. It is possible that H parainfluenzae sputa with an inflammatory profile that resembles pathogen-positive samples are actually harboring H influenzae that was missed because of sampling error, in spite of our efforts to isolate and characterize multiple Haemophilus colonies. Another potential explanation is that a proportion of H parainfluenzae strains are more virulent and cause mucosal infections associated with significant neutrophilic airway inflammation. Further study of the virulence of H parainfluenzae strains and the immune response to these strains is needed to arrive at definitive conclusions regarding their role in AECB.
The abundant NE activity found in our sputa during bacterial AECB suggests that these exacerbations could increase the airway elastase burden and cause airway epithelial injury and remodeling. Such a process in the distal small airways could contribute to progressive airway obstruction.33 34 How does one reconcile our data that bacterial AECB are associated with free elastase and could therefore contribute to progression of COPD with epidemiologic evidence that the number of exacerbations is not predictive of decline in lung function over time?35 36 37 There are several reasons to question the conclusions of these epidemiologic studies. These studies were generally conducted in cohorts of middle-aged men with either no lung disease or mild chronic bronchitis, rather than cohorts of patients with established COPD. The impact of AECB on lung function may be quite different in these two populations. These studies measured occurrence of AECB by patient recall in questionnaires administered every 6 months to 1 year. This can be a major potential source of error. These studies did not define the etiology of the recorded AECB; therefore, the actual number of bacterial AECB was not measured. If only bacterial AECB contribute to loss of lung function, definitive conclusions about their role in progression of COPD cannot be drawn from these studies. Finally, two epidemiologic studies38 39 that studied patients with established COPD and had closer follow-up showed a significant relationship between the decline of lung function and the occurrence of AECB.
Clinical features cannot readily distinguish bacterial from nonbacterial AECB. Sputum purulence has often been described as a marker for bacterial exacerbations, but sputum was mucoid on gross examination in only 4 of the 81 exacerbations included in this study. On the other hand, a sputum elastase (NE) level of 350 MU/mL had a sensitivity of 70.6%, specificity of 84.2%, positive predictive value of 88.9%, and negative predictive value of 61.5% in distinguishing bacterial (H influenzae or M catarrhalis) from nonbacterial (normal flora-only) AECB. This suggests that a semiquantitative method of measuring free sputum elastase, possibly as a "dipstick," could be used in clinical practice to distinguish bacterial from nonbacterial AECB, which would be extremely useful in identifying patients who would benefit from antibiotics.
In summary, this study demonstrates that H influenzae and Mcatarrhalis are associated with a neutrophilic inflammatory response in the airways in AECB. Furthermore, it shows that when H parainfluenzae is isolated from sputum during AECB, in most instances it is not the etiologic agent. Whether free elastase in the sputum can be used as a clinical marker to distinguish bacterial from nonbacterial AECB and to estimate the severity of an AECB is an interesting proposition that needs to be explored further. The extent to which bacterial AECB involves the small airways of the lung and contributes to progressive airway obstruction needs to be investigated.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Financial support provided by the Department of Veterans Affairs Merit Review.
Received for publication February 7, 2000. Accepted for publication July 6, 2000.
|
References |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153,530-534[Abstract]
1-antitrypsin in sputum of asthmatic patients. Am J Respir Crit Care Med 157,505-511 and expression of ICAM-1. Eur Respir J 7,2109-2116[Abstract]
This article has been cited by other articles:
|
|
 |
|
  P. Mallia and S. L. Johnston How viral infections cause exacerbation of airway diseases. Chest, October 1, 2006; 130(4): 1203 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. West-Barnette, A. Rockel, and W. E. Swords Biofilm Growth Increases Phosphorylcholine Content and Decreases Potency of Nontypeable Haemophilus influenzae Endotoxins Infect. Immun., March 1, 2006; 74(3): 1828 - 1836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sethi Coinfection in Exacerbations of COPD: A New Frontier. Chest, February 1, 2006; 129(2): 223 - 224. [Full Text] [PDF]
|
|
|
|
 |
|
 P. Mallia and S. L. Johnston Mechanisms and Experimental Models of Chronic Obstructive Pulmonary Disease Exacerbations Proceedings of the ATS, November 1, 2005; 2(4): 361 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Berenson, T. F. Murphy, C. T. Wrona, and S. Sethi Outer Membrane Protein P6 of Nontypeable Haemophilus influenzae Is a Potent and Selective Inducer of Human Macrophage Proinflammatory Cytokines Infect. Immun., May 1, 2005; 73(5): 2728 - 2735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Morris, F. C. Sciurba, I. P. Lebedeva, A. Githaiga, W. M. Elliott, J. C. Hogg, L. Huang, and K. A. Norris Association of Chronic Obstructive Pulmonary Disease Severity and Pneumocystis Colonization Am. J. Respir. Crit. Care Med., August 15, 2004; 170(4): 408 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. Murphy, A. L. Brauer, A. T. Schiffmacher, and S. Sethi Persistent Colonization by Haemophilus influenzae in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 266 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rial, D. Lens, L. Betancor, H. Benkiel, J. S. Silva, and J. A. Chabalgoity Intranasal Immunization with a Colloid-Formulated Bacterial Extract Induces an Acute Inflammatory Response in the Lungs and Elicits Specific Immune Responses Infect. Immun., May 1, 2004; 72(5): 2679 - 2688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sethi Bacteria in Exacerbations of Chronic Obstructive Pulmonary Disease: Phenomenon or Epiphenomenon? Proceedings of the ATS, April 1, 2004; 1(2): 109 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Buhl and S. G. Farmer Current and Future Pharmacologic Therapy of Exacerbations in Chronic Obstructive Pulmonary Disease and Asthma Proceedings of the ATS, April 1, 2004; 1(2): 136 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sethi, C. Wrona, B. J. B. Grant, and T. F. Murphy Strain-specific Immune Response to Haemophilus influenzae in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 15, 2004; 169(4): 448 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Wang, P. P. Cleary, H. Xu, and J.-D. Li Up-Regulation of Interleukin-8 by Novel Small Cytoplasmic Molecules of Nontypeable Haemophilus influenzae via p38 and Extracellular Signal-Regulated Kinase Pathways Infect. Immun., October 1, 2003; 71(10): 5523 - 5530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. Murphy, C. Kirkham, D.-F. Liu, and S. Sethi Human Immune Response to Outer Membrane Protein CD of Moraxella catarrhalis in Adults with Chronic Obstructive Pulmonary Disease Infect. Immun., March 1, 2003; 71(3): 1288 - 1294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A J White, S Gompertz, and R A Stockley Chronic obstructive pulmonary disease * 6: The aetiology of exacerbations of chronic obstructive pulmonary disease Thorax, January 1, 2003; 58(1): 73 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Dewan COPD Exacerbations : To X-ray or Not To X-ray Chest, October 1, 2002; 122(4): 1118 - 1121. [Full Text] [PDF]
|
|
|
|
|
|
I S Patel, T A R Seemungal, M Wilks, S J Lloyd-Owen, G C Donaldson, and J A Wedzicha Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations Thorax, September 1, 2002; 57(9): 759 - 764. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sethi, N. Evans, B. J.B. Grant, and T. F. Murphy New Strains of Bacteria and Exacerbations of Chronic Obstructive Pulmonary Disease N. Engl. J. Med., August 15, 2002; 347(7): 465 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Miravitlles Exacerbations of chronic obstructive pulmonary disease: when are bacteria important? Eur. Respir. J., July 1, 2002; 20(36_suppl): 9S - 19s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sohy, C. Pilette, M.S. Niederman, and Y. Sibille Acute exacerbation of chronic obstructive pulmonary disease and antibiotics: what studies are still needed? Eur. Respir. J., May 1, 2002; 19(5): 966 - 975. [Abstract] [Full Text] [PDF]
|
< |
