| 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 Respiratory Medicine, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK.
Correspondence to: Robert A. Stockley, MD, DSc, Department of Medicine, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK
 |
Abstract |
|---|
 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
|---|
Design: Open, longitudinal study of sputum characteristics and acute-phase proteins.
Setting: Patients presenting to primary-care physicians in the United Kingdom. Patients were followed up as outpatients in specialist clinic.
Patients: One hundred twenty-one patients with acute exacerbations of COPD were assessed together with a single sputum sample on the day of presentation (89 of whom produced a satisfactory sputum sample for analysis). One hundred nine patients were assessed 2 months later when they had returned to their stable clinical state.
Interventions: The expectoration of green, purulent sputum was taken as the primary indication for antibiotic therapy, whereas white or clear sputum was not considered representative of a bacterial episode and the need for antibiotic therapy.
Results: A positive bacterial culture was obtained from 84% of patients sputum if it was purulent on presentation compared with only 38% if it was mucoid (p < 0.0001). When restudied in the stable clinical state, the incidence of a positive bacterial culture was similar for both groups (38% and 41%, respectively). C-reactive protein concentrations were significantly raised (p < 0.0001) if the sputum was purulent (median, 4.5 mg/L; interquartile range [IQR], 6.2 to 35.8). In the stable clinical state, sputum color improved significantly in the group who presented with purulent sputum from a median color number of 4.0 (IQR, 4.0 to 5.0) to 3.0 (IQR, 2.0 to 4.0; p < 0.0001), and this was associated with a fall in median C-reactive protein level to 2.7 mg/L (IQR, 1.0 to 6.6; p < 0.0001).
Conclusions: The presence of green (purulent) sputum was 94.4% sensitive and 77.0% specific for the yield of a high bacterial load and indicates a clear subset of patient episodes identified at presentation that is likely to benefit most from antibiotic therapy. All patients who produced white (mucoid) sputum during the acute exacerbation improved without antibiotic therapy, and sputum characteristics remained the same even when the patients had returned to their stable clinical state.
Key Words: bacteria • COPD • exacerbations • myeloperoxidase • sputum
|
Introduction |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
|---|
However, despite the publication of such guidelines, their validity depends on the quality of the published literature that forms the evidence for their basis, and often the indicators for antibiotic therapy in exacerbations are vague. For instance, in the British Thoracic Society guidelines,5 the management of acute exacerbations of COPD in primary care was summarized in box 10. This included empirically adding or increasing bronchodilators (which would be expected to reduce airflow obstruction) and giving antibiotics to treat bacterial infections and oral corticosteroids to reduce inflammation. However, if such treatments are to be used wisely and appropriately, particularly given the sensitivity regarding the use of antibiotic therapy, it is imperative to classify and treat the exacerbations according to their features.
Antibiotic therapy is widely used in the treatment of acute exacerbations, but evidence of efficacy is debatable, with some controlled studies showing a clear benefit,6 7 whereas others do not.8 9 Such results are to be expected as the nature of the exacerbation is rarely defined. Although sputum culture may be expected to clarify the role of antibiotics, the results can also be confusing because, in the stable clinical state, some patients have a sputum culture that is positive for bacteria.10 11 Madison and Irwin12 highlighted the lack of a widely accepted definition of an exacerbation and emphasized that this created difficulties in the interpretation of studies and was not helpful for the clinician. This view was also promoted by Wilson and Wilson,13 who stated that future studies required defined populations but that placebo-controlled studies were probably no longer ethically justified. However, in 1987, Anthonisen and colleagues14 published what remains the most widely referenced controlled trial, which indicated some clinical features related to a significant benefit of antibiotic therapy. These authors classified exacerbations into three groups depending on the number of clinical features present. Subjects with increased breathlessness, sputum volume, and sputum purulence showed a significant advantage of antibiotic therapy, whereas those with only one or two of these three features showed none.14 Nevertheless, the results of this study have been incorporated specifically into the British Thoracic Society guidelines; antibiotic therapy is recommended if two of the three clinical criteria, outlined above, are present, and, therefore, the production of purulent sputum is not mandatory.5 Other guidelines, however, are less clear, suggesting the decision should be made clinically1 or when sputum becomes purulent.4
In view of this relatively loose guidance, we decided to embark on a prospective study of acute exacerbations of COPD in an attempt to determine whether a subgroup existed in which antibiotic therapy was likely to play a more important role. In an editorial review on the relationship of bacteria to lung host defenses, it was suggested that it should be possible to separate the presence of bacteria as commensals in the airway from those causing an infection.15 The latter would be expected to be accompanied by activation of secondary host defenses, which include increased neutrophil recruitment to the airways. This neutrophil influx should be associated with a change in secretions from mucoid to purulent (because the myeloperoxidase from the neutrophils is green), and the process would reverse after antibiotic therapy that reduced or eliminated the bacterial load, thereby leading to resolution of the secondary host response. Such a concept is consistent with the classic study of Anthonisen and colleagues,14 because sputum purulence was one of the three clinical features in the group that showed a significant response to antibiotics. In addition, the presence of sputum purulence would be consistent with the reported increase in neutrophils seen microscopically by other workers in an assumed bacterial exacerbation.16 17
We therefore decided to differentiate acute exacerbations at presentation into those with or without purulent sputum assessed clinically. The microscopic and bacteriologic characterization of these secretions was also recorded, and data were compared with samples obtained some 2 months later in the stable clinical state. In addition, we measured serum C-reactive protein as an independent marker of the systemic effect related to the activation of host defenses.
|
Materials and Methods |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
|---|
Patients were seen on the day of the consultation by a respiratory research nurse. Demographic details were noted and a postbronchodilator FEV1 was obtained when possible using a bellows spirometer. A fresh sample of sputum was collected into a sterile container during a 1-h period, as free from saliva as possible. Samples containing more than minimal salivary contamination were discarded, and the remainder were sent to the Respiratory Research Laboratory. The sample was assessed by one of three laboratory staff, and the macroscopic appearance of the majority of the sample was allocated a sputum number by reference to a standard color chart. This chart was based on the principle that neutrophil myeloperoxidase concentrations in the sputum reflect the number of neutrophils present and that this would relate to the degree of yellow-green coloration of the sample. Values of 1 and 2 reflected the nature of mucoid sputum (opaque or milky), whereas values of 3 to 8 reflected increasing yellow-green coloration up to the darkest color observed in sputum from cystic fibrosis patients. Intrasubject assessment demonstrated that individuals differed by no more than one number category but that mucoid (grade 2) and mucopurulent (grade 3) sputum were always identified correctly.
After macroscopic assessment, a sputum smear was prepared for Gram’s stain. This was examined for the presence of a predominant bacterial type under high-power microscopy. In addition, the smear was examined under low-power microscopy (x 100) for the presence of neutrophils. These were counted in a semiquantitative way, and the sample was classified as containing < 25, 25 to 50, 50 to 100, or > 100 neutrophils/low-power field.
After classification of the nature of the sputum, those patients with macroscopically mucoid samples did not receive antibiotic therapy. However, for the purpose of the current study, the ethics committee believed that antibiotic therapy was mandatory for those with clearly purulent sputum on the basis of the arguments presented in the introduction.
Quantitative sputum culture was then performed on an aliquot of the
sample as described previously.18
Finally, 10 mL of blood
was obtained from the patient, and the serum was collected and stored
at -70°C for subsequent measurement of the C-reactive protein
concentrations by radial immunodiffusion using commercially available
prepoured plates and standards (Binding Site; Birmingham, UK). In
addition, repeat serum samples were obtained 
14 days after the
presentation with symptoms and assessed for a rise in or positive
complement fixation titer to viral agents or atypical organisms.
When patients were reviewed in the stable clinical state, sputum was again collected, when possible, and subjected to the above procedure, and a final blood sample was drawn for further measurement of C-reactive protein.
The study was approved by the University Hospital Birmingham NHS Trust Ethical Review Board. Statistical differences of sputum sample characteristics between groups were determined by Fisher’s Exact Test. Differences in C-reactive protein and its change with resolution, together with sputum color change, were assessed by Wilcoxon rank sum test for unpaired and paired data, respectively. A p value of < 0.05 was taken as an indicator of a difference in the data.
|
Results |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
|---|
|
There was no difference between the two groups with respect to inhaled therapy (ß2-agonists or anticholinergic agents). Only 6 patients were receiving regular nonsteroidal anti-inflammatory drugs, and 21 were receiving prophylactic low-dose aspirin.
The sputum samples from the 121 patients entered into the study were graded as mucoid (grade 1 or 2) for 34 patients, grade 3 for 12 patients, grade 4 for 42 patients, grade 5 for 29 patients, and grade 6 for 4 patients by the laboratory research staff.
Of the 121 samples assessed at the start of the study, 112 (92.6%) had > 25 neutrophils/low-power field seen on the sputum smear. Seventy-nine samples (65.3%) contained a predominant bacterial type seen on Gram’s stain, but a viable bacterial species was cultured from 86 samples (71.1%). In 71 of the samples, the number of the bacterial species cultured was > 107 cfu/mL.
Sputum Characteristics
Mucoid Exacerbations (n = 34): At presentation,
the Gram’s stain appearance of samples showed > 25
neutrophils/low-power field in 26 samples and the presence of a
predominant bacterial type in 3 samples (Fig 1
). Thirteen samples (38.2%) subsequently grew a putative pathogen on
quantitative sputum culture, which included 38.5% Haemophilus
influenzae, 38.5% Haemophilus parainfluenzae, 15.4%
Moraxella catarrhalis, and 6.7% Neisseria
meningitidis. The median bacterial culture for these positive
samples was 7.5 x 106 cfu/mL (interquartile
range [IQR], 6x105 to
7.5 x 106), but only four samples cultured
> 107 cfu/mL (Fig 1)
.
|
|
|
The numbers of each bacterial species cultured from the positive samples was similar to the results obtained for the mucoid exacerbations in the clinically stable state (median, 6.2 x 107; IQR, 7.6 x 106 to 8.6 x 108 cfu/mL). The range of bacterial species identified was similar to that at presentation: 69.6% H influenzae, 8.7% H parainfluenzae, 13.0% M catarrhalis, and 8.7% either Pseudomonas aeruginosa or S aureus.
Relationship of Sputum Number to Bacterial Culture
At the start of the study when patients presented with an acute
exacerbation, the presence of purulent sputum ( grade 3) was
associated with 73 of 86 samples having a positive bacterial culture
and 67 of 71 samples in which the bacterial growth was
> 107 cfu/mL. These results gave an overall
sensitivity of 84.9% and 94.4%, respectively (Table 2
). However, some of the purulent samples had cultures that were negative
for bacteria or had lower numbers of organisms, giving a specificity of
83.9% and 77.0% for positive bacterial culture and
> 107cfu/mL bacterial load, respectively. The
comparable figures for sputum neutrophilia and organism seen on Gram’s
stain are indicated in Table 2
.
|
Lung Function
Spirometry was measured (when possible) after bronchodilator
administration in 92 of the patients on entry to the study. The
FEV1 predicted for the patient’s age and sex
showed a wide range of abnormality, with 33% having moderate to severe
impairment (< 50% predicted). The average results for both groups
are summarized in Table 1 . However, in view of the unstable nature of
lung function during an exacerbation, the patients were retested in the
stable clinical state (when possible). The results for 104 patients
were stratified into mild (FEV1 > 50%
predicted), moderate (35 to 49% predicted), and severe (< 35%
predicted) groups. These stratifications are compared with the initial
microbiology and proportion of samples that were purulent at
presentation (Table 3 ).
|
|
Discussion |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
|---|
Previous authors have suggested that the presence of > 25 neutrophils/low-power field20 or a positive Gram’s stain21 indicates a bacterial cause. However, neutrophils are usually present in the secretions of patients with COPD when clinically stable.22 Indeed, in the current study, > 25 neutrophils/low-power field were seen in the sputum from 68 of the 89 samples collected in the stable state. Thus, although sputum neutrophilia was a highly sensitive and specific test to identify samples with a positive or high bacterial culture (Table 1) , it was present in 93% of the samples at presentation. Similarly, Gram’s stain usually predicted the positive cultures and large bacterial load, although it has been shown to be less reliable at detecting the presence of bacteria than sputum culture itself.21 Nevertheless, both methods require laboratory assessment, and this limits their practical use.
Sputum purulence, on the other hand, is clinically detectable and would be consistent with increased neutrophil recruitment, indicative of a new or significant bacterial stimulus. In the presence of increased breathlessness and sputum volume, this would fit the clinical syndrome shown by Anthonisen et al14 to benefit from antibiotics. However, purulence is a subjective term and not further defined; hence, treatment on the basis of this observation may also be partly empirical.
In the current study, the nature of the sputum was compared with a standard color chart of increasing intensity. In most samples (117 of 121), this resulted in a clear separation of mucoid samples from purulent ones. In the remaining four samples, the sputum was not homogenous in color, and three were labeled as purulent (sputum grade 3) because more than half the sample was colored. With this separation, the purulent nature of the sputum remained highly sensitive and specific for a positive bacterial culture and high bacterial load (Table 1) .
The improvement of the sputum characteristics when the patients were clinically stable, with a reduction in color and culture positivity, would suggest that bacteria played an important role in the increased symptoms of many of these patients. The higher C-reactive protein concentration and its fall confirm that the patients were systemically unwell, consistent with the study reported by Dev and colleagues23 in 50 patients who presented with purulent sputum but in whom only 29 patients (58%) had a positive bacterial culture. The authors noted that a positive bacterial culture is not the most dependable factor of an acute exacerbation and proposed that a positive C-reactive protein may help. However, the C-reactive protein measurement is not readily available, particularly in primary care, and our study would suggest that careful assessment of sputum color is more effective in identifying samples that are likely to have a positive bacterial culture (84% of the samples).
The increased color observed in sputum samples represents the presence of myeloperoxidase (the green-colored enzyme from the neutrophil azurophil granules), and our original hypothesis was based on the presumption that bacteria in the bronchial tree would not be the cause of acute symptoms unless there was activation of secondary host defenses leading to significant neutrophil recruitment. This concept is consistent with the study described by Monso and colleagues,10 who obtained protected brush specimens of the lower respiratory tract during exacerbations of COPD. These authors confirmed in their invasive study that a positive bacterial culture was more likely during an acute exacerbation (associated with purulent sputum) but was still present in some 25% of stable patients. In addition, their study indicated that the bacterial load was increased during the exacerbation (as seen in our results). These observations were endorsed in the review by Chodosh20 and supported by Medici and Chodosh,17 who also noted the increase in neutrophils seen microscopically during a bacterial exacerbation, although such episodes were not defined clinically.
Our second group of patients, those with mucoid exacerbations, did not have purulent sputum as assessed by the color chart. Thirty-two patients (86.5%) had at least two symptoms consistent with the criteria of Anthonisen et al14 for an acute exacerbation and would thus require antibiotic according to the British Thoracic Society guidelines.5 However, despite a positive bacterial culture in 38% of the samples, the viable bacterial numbers were low, and only two patients deteriorated, requiring antibiotics (both associated with the subsequent development of purulent sputum, grades 4 and 5). These mucoid exacerbations were different from those classified as purulent from the sputum characteristics (Gram’s stain, positive culture, and high microbial load). In addition, these patients demonstrated little evidence of a systemic effect of the illness (the C-reactive protein concentrations were low), and the sputum characteristics were unchanged when the patients were restudied in the stable clinical state.
The nature of these mucoid exacerbations remains to be determined. It is possible that these represent nonbacterial inflammation or increased airflow obstruction. Certainly, steroids can influence the outcome in acute exacerbations,24 although, again, the episodes are also poorly defined. It is possible that the major benefit of steroids is in the mucoid exacerbations described here. However, further studies will need to be performed to determine this possibility.
We considered that our initial classification could have identified two different subsets of COPD patients. For this reason, we have analyzed and reported the sputum data when the patients were reviewed in the stable clinical state. The results emphasize the similarity between both groups when clinically stable as well as the clear difference in the purulent exacerbations at presentation and the lack of change in the group with mucoid exacerbations. In addition, the C-reactive protein concentrations were higher and clearly fell in the purulent group to the point at which they were no longer different from those of the mucoid group, providing further support for the similarity of both groups in the stable clinical state. Indeed, the only difference we have noted between the groups was that more of those presenting with purulent sputum were ex-smokers (p < 0.008).
The organisms isolated from these outpatients at presentation and when clinically stable are similar to those described by others,25 26 but dissimilar to those isolated from patients requiring admission.27 This may partly reflect our exclusion of patients who had recently had antibiotics or required steroid therapy, thus reflecting the milder nature of the episode. Nevertheless, the patients did have a wide spectrum of airflow obstruction, suggesting that FEV1 is not the determinant of the bacterial cause of exacerbations in nonhospitalized patients. It is of interest to note, however, that a greater proportion of the patients with moderate and severe airflow obstruction presented with purulent sputum (Table 3) .
|
Conclusions |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
|---|
Classification of exacerbations by sputum color may enable antibiotic therapy to be withheld at present in some patients. In addition, the current study provides data to enable the design of future antibiotic studies in COPD to determine their role and comparative efficacy more clearly.
|
Footnotes |
|---|
Supported by an educational grant provided by Glaxo Wellcome plc.
Received for publication May 18, 1999. Accepted for publication February 10, 2000.
|
References |
|---|
|
TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
|---|
in induced sputum for patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153,530-534[Abstract]
This article has been cited by other articles:
|
|
 |
|
  B. R. Celli Update on the Management of COPD Chest, June 1, 2008; 133(6): 1451 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Vijayasaratha and R. A. Stockley Reported and Unreported Exacerbations of COPD: Analysis by Diary Cards Chest, January 1, 2008; 133(1): 34 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Jones and A. G. N. Agusti Outcomes and markers in the assessment of chronic obstructive pulmonary disease. Eur. Respir. J., April 1, 2006; 27(4): 822 - 832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Sapey and R A Stockley COPD exacerbations {middle dot} 2: Aetiology. Thorax, March 1, 2006; 61(3): 250 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G C Donaldson and J A Wedzicha COPD exacerbations {middle dot} 1: Epidemiology Thorax, February 1, 2006; 61(2): 164 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Woodhead, F. Blasi, S. Ewig, G. Huchon, M. Leven, A. Ortqvist, T. Schaberg, A. Torres, G. van der Heijden, and T. J. M. Verheij Guidelines for the management of adult lower respiratory tract infections Eur. Respir. J., December 1, 2005; 26(6): 1138 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barnes and R. A. Stockley COPD: current therapeutic interventions and future approaches Eur. Respir. J., June 1, 2005; 25(6): 1084 - 1106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lode, J. Eller, A. Linnhoff, M. Ioanas, and the Evaluation of Therapy-Free Interval in COPD Pa Levofloxacin versus clarithromycin in COPD exacerbation: focus on exacerbation-free interval Eur. Respir. J., December 1, 2004; 24(6): 947 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J R Hurst and J A Wedzicha Chronic obstructive pulmonary disease: the clinical management of an acute exacerbation Postgrad. Med. J., September 1, 2004; 80(947): 497 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Pauwels Similarities and Differences in Asthma and Chronic Obstructive Pulmonary Disease Exacerbations Proceedings of the ATS, April 1, 2004; 1(2): 73 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Miravitlles and A. Torres No More Equivalence Trials for Antibiotics in Exacerbations of COPD, Please Chest, March 1, 2004; 125(3): 811 - 813. [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]
|
|
|
|
|
|
G.C. Donaldson, T.A.R. Seemungal, I.S. Patel, S.J. Lloyd-Owen, T.M.A. Wilkinson, and J.A. Wedzicha Longitudinal changes in the nature, severity and frequency of COPD exacerbations Eur. Respir. J., December 1, 2003; 22(6): 931 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. A. Wilkinson, I. S. Patel, M. Wilks, G. C. Donaldson, and J. A. Wedzicha Airway Bacterial Load and FEV1 Decline in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., April 15, 2003; 167(8): 1090 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W A Biernacki, S A Kharitonov, and P J Barnes Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD Thorax, April 1, 2003; 58(4): 294 - 298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Walter, A. Beiser, R. J. Givelber, G. T. O'Connor, and D. J. Gottlieb Association between Glycemic State and Lung Function: The Framingham Heart Study Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 911 - 916. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. A. Wedzicha Exacerbations* : Etiology and Pathophysiologic Mechanisms Chest, May 1, 2002; 121(5_suppl): 136S - 141S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Stockley Neutrophils and the Pathogenesis of COPD* Chest, May 1, 2002; 121(5_suppl): 151S - 155S. [Full Text] [PDF]
|
|
|
|
|
|
T. F. Murphy, S. Sethi, S. L. Hill, and R. A. Stockley INFLAMMATORY MARKERS IN BACTERIAL EXACERBATIONS OF COPD Am. J. Respir. Crit. Care Med., January 1, 2002; 165(1): 132 - 132. [Full Text] [PDF]
|
|
|
|
|
