Skip Navigation

Clinical Predictors of Bacterial Involvement in Exacerbations of Chronic Obstructive Pulmonary Disease

  1. Paul van der Valk1,
  2. Evelyn Monninkhof1,
  3. Job van der Palen1,
  4. Gerhard Zielhuis3,
  5. Cees van Herwaarden4, and
  6. Ron Hendrix2
  1. 1Department of Pulmonary Medicine, Medisch Spectrum Twente, Nijmegen, The Netherlands
  2. 2Regional Laboratory of Public Health, Enschede, and Departments of Epidemiology and Biostatistics, Nijmegen, The Netherlands
  3. 3Departments of Epidemiology and Biostatistics, University Medical Centre, Nijmegen, The Netherlands
  4. 4Department of Pulmonary Medicine, University Medical Centre, Nijmegen, The Netherlands
  1. Reprints or correspondence: Dr. Paul van der Valk, Dept. of Pulmonary Medicine, Medisch Spectrum Twente, PO Box 50000, 7500 KA Enschede, The Netherlands (valkpapa@knmg.nl).
 
Next Section

Abstract

Background. The wide use of antibiotics for treatment of exacerbations of chronic obstructive pulmonary disease (COPD) lacks evidence. The efficacy is debatable, and bacterial involvement in exacerbation is difficult to verify. The aim of this prospective study was to identify factors that can help to estimate the probability that a microorganism is involved in exacerbation of COPD and, therefore, predict the success of antibiotic treatment.

Methods. Clinical data and sputum samples were obtained from 116 patients during exacerbation of COPD. Bacterial infection was defined by the abundant presence of ⩾1 potential pathological microorganism in relation to the normal flora in sputum.

Results. Of 116 exacerbations, 22 (19%) had bacterial involvement. The combination of a negative result of a sputum Gram stain, a relevant nonclinical decrease in lung function (compared with baseline measurements), and occurrence of <2 exacerbations in the previous year were 100% predictive of a nonbacterial origin of the exacerbation. The presence of all 3 of these clinical characteristics yielded a positive predictive value of 67% for a bacterial exacerbation.

Conclusions. Patients presenting with an exacerbation who have a negative result of a sputum Gram stain, do not have a clinically relevant decrease in lung function, and who have not experienced <2 exacerbations of COPD in the previous year do not require antibiotic treatment. A treatment protocol taking into account these variables might lead to a 5%–24% reduction in unnecessary treatment with antibiotics, depending on actual prescription rates.

The clinical course of chronic obstructive pulmonary disease (COPD) is, despite optimal pharmacological treatment, one of gradual progressive impairment, which may lead to substantial functional limitations and, eventually, to respiratory failure [1, 2]. Morbidity and mortality among patients with COPD are, for the most part, related to acute exacerbations of COPD [3], which occur an average of 1–3 times per year [4]. The definition of an acute exacerbation of COPD is a major point of criticism in many of the studies dealing with that issue [5, 6]. Recently, an acute exacerbation of COPD was redefined as a sustained worsening of a patient's condition from a stable state (beyond normal day-to-day variations) that is acute in onset and that may warrant additional treatment in a patient with underlying COPD [6, 7].

The etiology of exacerbations is heterogeneous and still under discussion. Recent studies have stated that at least one-third of COPD exacerbations may be triggered by viral infections [8, 9]. Undoubtedly, bacteria also play a role in exacerbations of COPD [10]. It is estimated that up to 50% of sputum samples obtained during exacerbation of COPD yield relevant bacteria [11–14].

The management of exacerbations is usually empirical and includes therapy with corticosteroids and often antibiotics. Recent studies have shown that a course of oral corticosteroids is superior to placebo for the treatment of exacerbations in hospitalized patients and outpatients [15, 16]. However, there is a lack of evidence favoring the wide use of antibiotics for treatment of COPD exacerbations, and the efficacy of this treatment is debatable. It is difficult to predict a bacterial cause of an exacerbation of COPD [17, 18].

For a physician, it is hard to decide, on clinical grounds, whether to prescribe antibiotics to a patient with an exacerbation of COPD at the time of presentation. Recently Ewig et al. [18] proposed that antibiotic treatment of acute exacerbations of COPD should only regularly be administered to patients who meet ⩾2 of the Winnipeg criteria for increased dyspnea, sputum volume, and purulence [19, 20], patients with ⩾4 exacerbations during the past year and/or significant cardiopulmonary comorbidity [21], and patients presenting with severe airway obstruction or severe respiratory failure requiring ventilatory support [18]. Evidence for these criteria and the diagnostic value of many diagnostic tools (e.g., sputum purulence, Gram stain, radiography, determination of C-reactive protein levels, and determination of lung function parameters) for predicting a bacteriological origin of exacerbations are still under debate [13, 17, 20, 22–27]. Furthermore, microbiological analyses of sputum samples are often not performed, and microbiological criteria for the interpretation of the results are often poorly defined and are reported to have had little impact on treatment, because the test results are not available at presentation of the exacerbation [28].

The aim of this prospective study was to identify predictive factors for exacerbations of COPD caused by bacteria for which treatment with antibiotics is indicated by correlating clinical signs, symptoms, and rapidly available laboratory data on presentation of an acute exacerbation of COPD and by using clear-cut definitions for interpretation of bacterial culture results.

Previous SectionNext Section

Patients and Methods

Patients. From May 1999 through March 2000, patients were recruited from the outpatient pulmonary clinic of the Medisch Spectrum Twente, a 1150-bed teaching hospital in Enschede, The Netherlands. To be eligible for the study, the patients had to have met the following criteria: (1) a clinical diagnosis of stable COPD, as defined by American Thoracic Society criteria [29]; (2) no history of asthma; (3) no exacerbation or antecedent use of an antibiotic in the month prior to enrollment; (4) status as a current or former smoker; (5) age of 40–75 years; (6) baseline prebronchodilator forced expiratory volume in 1 s (FEV1) of 25%–80% of predicted value; (7) prebronchodilator ratio of FEV1 to inspiratory vital capacity (IVC) of ⩽60%; (8) reversibility of FEV1 after inhalation of 80 µg of ipratropium bromide (via a metered-dose inhalator), with an aerochamber of ⩽12% of the predicted value [30]; (9) total lung capacity (TLC) greater than the predicted TLC - (1.64 × SD); (10) no maintenance treatment with oral steroids or antibiotics; (11) no medical condition associated with a low survival rate or serious psychiatric morbidities (e.g., cardiac insufficiency and alcoholism); (12) and absence of any other active lung disease (e.g., sarcoidosis). Use of such medications as nasal corticosteroids and theophyllines, chronic use of acetylcysteine, and all other use of bronchodilators was allowed.

The hospital's medical ethics committee approved this study. All patients provided written informed consent.

Study design. This study was part of a randomized, double-blind, single center study that investigated the role of inhaled corticosteroids in COPD [31]. From this study, patients were recruited at presentation of the first exacerbation of COPD. Any time that patients experienced worsening of their respiratory symptoms, they were instructed to contact the study personnel by telephone. They were subsequently invited to visit the outpatient department within 12 h for spirometry measurements, sputum sample collection, and consultation with one of the study physicians. Lung function data and sputum samples were collected. On a standardized exacerbation report, staff doctors registered the presence of “major” symptoms (i.e., increase in dyspnea, cough, increase in sputum volume, and sputum purulence) and “minor” symptoms (i.e., nasal discharge/congestion, wheeze, sore throat, cough, fever, and need of extra bronchodilator) [19] and the treatment prescribed. Furthermore, the study physician reported his/her clinical judgment about the severity of the exacerbation (judged as no exacerbation or mild, moderate, or severe exacerbation) before being informed of the results of the lung function tests and Gram stains.

Clinically, an exacerbation was defined as a worsening of respiratory symptoms that led the patient to contact the study office. Classification of the type of an exacerbation was expressed using the Anthonisen score [19]. Lung function was measured by spirometry. Well-trained lung function technicians performed spirometry on water-sealed spirometers, in accordance with standardized guidelines. FEV1 and IVC were measured until 3 reproducible recordings (<5% difference) were obtained. The highest values were used for analyses. A clinically relevant decrease in FEV1 was defined as a decrease of >12% and 200 mL from the baseline level [32]. The most recent result of the lung function test in stable state was used as a baseline value to calculate the decrease in FEV1 at exacerbation. Body mass index (BMI) was computed as kg/m2. In patients with COPD, a poor nutritional status is indicated by a BMI of <22 kg/m2.

Sputum samples. The laboratory technicians processing the sputum samples were unaware of the clinical condition of the patients. Spontaneously expectorated sputum was collected in sterile vials and processed in the laboratory within 4 h after collection. Total sputum samples were homogenized by incubation at 37°C for 15 min with an equal volume of 0.1% dithiothreitol. Gram-stained sputum samples were examined microscopically and had to contain <105 epithelial cells per mL-1 (i.e., <1 epithelial cell per high-power field) to be considered representative bronchial samples. Polymorphonuclear cell count was not one of the criteria. A positive Gram stain result suggested the presence of a single pathogenic organism or demonstrated the abundant presence of a potentially pathogenic microorganism (PPM), compared with the background flora (i.e., >1-log difference). Appropriate dilutions of homogenized sputum samples were placed on blood, chocolate, cysteine lactose electrolyte deficient medium, and Sabouraud agar plates. Bacterial and mycological isolation and identification were performed with the use of standard techniques of the American Society for Microbiology [33]. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, and Staphylococcus aureus were considered to be PPM. Other bacterial species were classified as normal flora (non-PPM).

A bacterial exacerbation was defined in 2 ways. First, it was defined in accordance with the primary criteria used for pneumonia [33]: by the abundance of ⩾1 PPM (i.e., >107 colony-forming units [cfu]/mL) in excess (⩾1 log) of the normal microbiological flora in sputum. Second, because these criteria have been under debate with regard to exacerbations of COPD, a secondary analysis was performed using the following secondary criteria for bacterial exacerbation of COPD: PPMs were regarded as significant if they reached a level of absolute growth of >106 cfu/mL, except for S. pneumoniae, for which a level of growth of >105 cfu/mL was deemed sufficient, irrespective of the presence of non-PPMs [13].

Statistical analyses. Baseline characteristics are reported as means ± SD for continuous variables or as percentages for categorical or dichotomous variables stratified by presence or absence of bacterial exacerbation. To avoid dependency between exacerbations, we included only the first exacerbation during which a sputum sample was obtained.

First, univariate logistic regression analyses were performed to identify the subset of independent variables that were associated with a bacterial exacerbation. The a priori list of potential predicting variables included Gram stain (positive vs. negative), relevant decrease of FEV1, clinical judgment (moderate or severe exacerbation vs. mild or no exacerbation), BMI (⩽22 vs. >22), number of exacerbations in the year preceding the study (0–1 vs. ⩾2), sex, smoking status, fever, sore throat, nasal discharge, increase in sputum volume, sputum color, dyspnea, and Anthonisen score (type 1 vs. other) [19]. Only those variables with a significance level of P ⩽ .15 were considered to be candidate variables for the multivariate logistic regression analysis. For the development of the predictive model, we started with all candidate variables (full model). Subsequently, we eliminated the variables step by step, starting with the highest P value, until the model fit decreased significantly (based on likelihood-ratio test results).

Finally, we calculated positive and negative predictive values for the variables in the final multivariate regression model (separately and combined). We plotted receiver operating characteristic (ROC) curves and estimated the area under the curve (AUC) and 95% CIs. The AUC was used to provide an overall estimate of the diagnostic performance of the prediction rule to differentiate bacterial exacerbations from nonbacterial exacerbations.

For the secondary analysis, the same statistical procedure was applied. In this analysis, only the microbiological criterion for a bacterial exacerbation was changed, as described above.

Previous SectionNext Section

Results

In total, 123 sputum samples were obtained at the time of presentation with the first acute exacerbation of COPD. For 116 of these 123 exacerbations, the presence of a bacterial infection could be analyzed. According to the primary criteria used for pneumonia [33], 22 patients (19%) had a bacterial exacerbation, and 94 patients (81%) did not. Table 1 shows the baseline characteristics of the patients stratified by presence or absence of bacterial exacerbation.

Figure 1
View larger version:
Figure 1

Receiver operating characteristic curves for the model with all 3 predictors (Gram stain result, decrease in the forced expiratory volume in 1 s, and number of exacerbations in preceding year; solid line) and for the model with Gram stain result and number of exacerbations in the preceding year (dotted line).

Figure 2
View larger version:
Figure 2

Potential savings in the rate of antibiotic treatment for different prescribing prevalences

Table 1
View larger version:
Table 1

Baseline characteristics of patients, stratified by bacterial exacerbation status, according to the primary criteria for bacterial origin of an exacerbation of chronic obstructive pulmonary disease (COPD).

The following variables were associated with a bacterial exacerbation according to the primary criteria in univariate analysis: Gram stain result, relevant decrease in the FEV1, clinical judgment, BMI, and number of exacerbations in preceding year. These were included in a multivariate logistic regression model (table 2). This analysis revealed that Gram stain result, decrease in the FEV1, and number of exacerbations in preceding year together best predict the existence of a bacterial exacerbation (final model). Table 3 shows the positive and negative predictive values of all combinations of these variables, together and separately. The positive predictive value for these variables together is 67% (95% CI, 36%–97%), and the negative predictive value if all 3 are absent is 100%. The second best combination (Gram stain result and number of exacerbations in the year preceding the study) reduced the positive predictive value to 63% and the negative predictive value to 97%. The ROC curves for all 3 variables and the second best combination (Gram stain and number of exacerbations in the year preceding the study) yielded AUCs of 0.78 (95% CI, 0.68–0.88) and 0.76 (95% CI, 0.64–0.87), respectively (figure 1).

Table 2
View larger version:
Table 2

Clinical characteristics of patients, stratified by bacterial exacerbation status, according to the primary criteria for bacterial origin of an exacerbation of chronic obstructive pulmonary disease (COPD).

Table 3
View larger version:
Table 3

Positive and negative predictive values for the 3 variables (and combinations of the 3 variables), according to the primary criteria for bacterial origin of an exacerbation of chronic obstructive pulmonary disease, in the final multivariate logistic regression model.

Analysis of the prescription of antibiotics by chest physicians showed that antibiotic therapy was appropriate for only 14 (28%) of 50 recipients with exacerbations, as determined on the basis of our microbiological criteria for a bacterial exacerbation. Moreover, 8 (36%) of 22 bacterial exacerbations were not treated with antibiotics (table 4).

Table 4
View larger version:
Table 4

Prescription of antibiotics, in relation to a bacterial exacerbation of chronic obstructive pulmonary disease (COPD), according to primary criteria.

If the variables of negative Gram stain result, no reduction in FEV1, and 0–1 exacerbations in the preceding year were taken into account, 11 (40%) of 28 exacerbations were found to have been unnecessarily treated with antibiotics. Table 5 shows the implications for the combinations of all 3 of these predictors for antibiotic therapy.

Table 5
View larger version:
Table 5

Implications of the combination of all 3 predictors for antibiotic use.

Only 35% of those with positive results of Gram stains of sputum samples obtained at presentation for the exacerbation had a positive culture result. Furthermore, for 59% of those with positive sputum culture results, the results of Gram stains were also positive.

The prevalence of bacterial exacerbation increased from 19% using the primary criteria to 46% (56 of 123 cases) using the secondary criteria. Forty percent of these so-classified bacterial infections occurred in individuals who also had a positive Gram stain result. The variables significantly associated with a bacterial exacerbation in univariate analysis were Gram stain result, clinical judgment, BMI, number of exacerbations in preceding year, sputum color, and increase in sputum volume. These were included in a multivariate logistic regression model. This analysis revealed that Gram stain result and number of exacerbations in preceding year together best predicted the existence of bacterial exacerbation according to the less-strict criteria. The positive predictive value of these variables together is 75% (95% CI, 54%–96%), and the negative predictive value is 62% (95% CI, 55%–69%).

Previous SectionNext Section

Discussion

The most common decision a doctor has to make when treating a patient with an acute exacerbation in COPD is whether to prescribe antibiotic therapy. We are not aware of a study combining the aforementioned clinical signs, symptoms, and rapidly available laboratory data at first presentation as predictors of an acute bacterial exacerbation of COPD. This study, which investigated the clinical predictors of bacterial involvement in exacerbations of moderate-to-severe COPD, revealed 4 important new findings. First, we found a 100% negative predictive value for nonbacterial involvement with a combination of a negative result of a sputum Gram stain, a clinically nonrelevant decrease in lung function (compared with baseline measurements), and <2 exacerbations in the previous year. Second, the best positive predictive value for a bacterial exacerbation of COPD was a combination of a positive result of a sputum Gram stain, a clinically relevant decrease in lung function, and ⩾2 exacerbations of COPD in the previous year. Third, the classic Anthonisen type I criteria (dyspnea, sputum volume, and sputum purulence) were not predictors of bacterial origin of an exacerbation. Finally, using the clear-cut definition of bacterial infection from the American Society for Microbiology criteria for pneumonia in defining bacterial origin of COPD exacerbations [33], this study found that only 19% of the primary exacerbations originated with a bacterial infection.

It takes ∼45 min to obtain the results of a Gram stain and basic spirometry. The 100% negative predictive value for a nonbacterial origin of an exacerbation, which occurred in 25% of all exacerbations in this study, might help physicians decide whether to forego what may be unnecessary treatment. Also the combination of the variables negative results of a sputum Gram stain and <2 exacerbations in the previous year results in a high negative predictive value and a comparable diagnostic performance, as estimated by the AUC. This study demonstrated once again that more-objective criteria for use of antibiotic therapy in exacerbations of COPD are needed to prevent overuse of antibiotics [25, 34].

In our population, ∼40% of the exacerbations of moderate-to-severe COPD were treated with antibiotics, a figure that represents the Dutch practice fairly well. Use of our prediction rule would reduce this percentage to 35%, an absolute reduction of 5%. Because regular prescription rates for these patients in other countries are much higher, the potential savings made by applying this prediction rule might increase to 24% in situations in which every exacerbation of COPD is treated with antibiotics (figure 2).

The positive predictive value for a bacterial exacerbation of these variables (positive result of a sputum Gram stain, a relevant decrease in lung function, and ⩾2 exacerbations in the previous year) was 67%, raising the likelihood of a bacterial exacerbation (19%) by 48%. Unfortunately, this only pertains to 8% of the exacerbations.

The yield of Gram stains has proven to be highly dependent on whether a skilled investigator applies strict criteria [35]. In a study of nosocomial pneumonia, the negative predictive value for Gram stains of endotracheal aspirate specimens was reported to be as high as 94%, which is comparable to the results we obtained using the primary exacerbation criteria [36]. Similar to other studies [23], in our study, the presence of a positive sputum Gram stain result at presentation does not predict a positive culture result very well; on the other hand, a positive culture result was not a strong predictor of a positive sputum Gram stain result. Prior measurements of lung function are reported to be useful for comparison with measurements made during an acute exacerbation [1], but the importance of change from baseline spirometry findings as a tool for predicting a bacterial cause of an exacerbation has not yet been demonstrated.

Historically, on the basis of the results of the Anthonisen study, patients presenting with type I criteria (dyspnea and change in sputum characteristics [increased volume or purulence]) are almost always treated with antibiotics [19]. Although these criteria define a type of exacerbation, they do not define its (bacterial) etiology. We found no association between bacterial exacerbations and Anthonisen type 1 exacerbations.

Because we included patients with less severe COPD, compared with the Anthonisen study, the prevalence of PPMs during the exacerbation is expected to be lower [13] and might explain the lack of the aforementioned association in our study between bacterial exacerbations and Anthonisen type 1 exacerbations [5, 13, 37, 38].

In contrast to the study of Stockley et al. [17], sputum purulence was not a predictor of bacterial exacerbation. This not only means that patients with mucoid sputum production during the exacerbation are known to improve without antibiotic therapy [17], but also that patients with purulent sputum during the exacerbation might not be candidates for antibiotic treatment.

In conclusion, we believe that patients who present with an exacerbation of COPD and who have a negative sputum Gram stain result, no clinically relevant decrease in lung function (compared with baseline measurements), and a history of <2 exacerbations of COPD in the previous year do not need additional antibiotic treatment for an exacerbation. However, before it is implemented in clinical practice, this prediction rule should be validated in an external population. Furthermore, future studies are needed to determine whether other subgroups of patients with COPD exist in whom bacteria are likely to play an important role and for whom antibiotic treatment is thus indicated.

Previous SectionNext Section

Acknowledgments

We gratefully acknowledge the members of the Department of Pulmonary Medicine at the Medisch Spectrum Twente hospital (Enschede, The Netherlands), especially the technicians of the lung function department and the data managers Betty Rinsma and Petra Meerlo; and the technicians of the Regional Laboratory of Public Health, Enschede.

Financial support. The Netherlands Asthma Foundation, Amicon Health Care Insurance Company, Boehringer Ingelheim, and GlaxoSmithKline BV.

Conflict of interest. All authors: No conflict.

  • Received October 16, 2003.
  • Accepted May 17, 2004.
Previous Section
 

References

  1. ↵
    1. Pauwels RA,
    2. Buist AS,
    3. Calverley PM,
    4. Jenkins CR,
    5. Hurd SS
    . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256-76.
    FREE Full Text
  2. ↵
    1. Wouters EFM
    . Pulmonary rehabilitation in chronic obstructive pulmonary disease. Eur Respir Rev 1999;9:189-92.
  3. ↵
    1. Seneff MG,
    2. Wagner DP,
    3. Wagner RP,
    4. Zimmerman JE,
    5. Knaus WA
    . Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA 1995;274:1852-7.
    Abstract/FREE Full Text
  4. ↵
    1. Seemungal TA,
    2. Donaldson GC,
    3. Bhowmik A,
    4. Jeffries DJ,
    5. Wedzicha JA
    . Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608-13.
    Abstract/FREE Full Text
  5. ↵
    1. Eller J,
    2. Ede A,
    3. Schaberg T,
    4. Niederman MS,
    5. Mauch H,
    6. Lode H
    . Infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function. Chest 1998;113:1542-8.
    Abstract/FREE Full Text
  6. ↵
    1. Burge S,
    2. Wedzicha JA
    . COPD exacerbations: definitions and classifications. Eur Respir J Suppl 2003;41:46-53.
  7. ↵
    1. Rodriguez-Roisin R
    . Toward a consensus definition for COPD exacerbations. Chest 2000;117(Suppl 5):398-401.
    Abstract/FREE Full Text
  8. ↵
    1. Greenberg SB
    . Viral respiratory infections in elderly patients and patients with chronic obstructive pulmonary disease. Am J Med 2002;112(Suppl 6A):28-32.
    CrossRefWeb of Science
  9. ↵
    1. Seemungal TA,
    2. Donaldson GC,
    3. Paul EA,
    4. Bestall JC,
    5. Jeffries DJ,
    6. Wedzicha JA
    . Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418-22.
    MedlineWeb of Science
  10. ↵
    1. Saint S,
    2. Bent S,
    3. Vittinghoff E,
    4. Grady D
    . Antibiotics in chronic obstructive pulmonary disease exacerbations: a meta-analysis. JAMA 1995;273:957-60.
    Abstract/FREE Full Text
  11. ↵
    1. Fagon JY,
    2. Chastre J,
    3. Trouillet JL,
    4. et al
    . Characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis: use of the protected specimen brush technique in 54 mechanically ventilated patients. Am Rev Respir Dis 1990;142:1004-8.
    MedlineWeb of Science
    1. Monso E,
    2. Ruiz J,
    3. Rosell A,
    4. et al
    . Bacterial infection in chronic obstructive pulmonary disease: a study of stable and exacerbated outpatients using the protected specimen brush. Am J Respir Crit Care Med 1995;152:1316-20.
    Abstract/FREE Full Text
  13. ↵
    1. Miravitlles M,
    2. Espinosa C,
    3. Fernandez LE,
    4. et al
    . Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest 1999;116:40-6.
    Abstract/FREE Full Text
  14. ↵
    1. Murphy TF,
    2. Sethi S,
    3. Niederman MS
    . The role of bacteria in exacerbations of COPD: a constructive view. Chest 2000;118:204-9.
    Abstract/FREE Full Text
  15. ↵
    1. Niewoehner DE,
    2. Erbland ML,
    3. Deupree RH,
    4. et al
    . Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group [see comments]. N Engl J Med 1999;340:1941-7.
    CrossRefMedlineWeb of Science
  16. ↵
    1. Aaron SD,
    2. Vandemheen KL,
    3. Hebert P,
    4. et al
    . Outpatient oral prednisolone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003;348:2618-25.
    CrossRefMedlineWeb of Science
  17. ↵
    1. Stockley RA,
    2. O'Brien C,
    3. Pye A,
    4. Hill SL
    . Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000;117:1638-45.
    Abstract/FREE Full Text
  18. ↵
    1. Similowski T,
    2. Whitelaw W,
    3. Derenne J
    1. Ewig S,
    2. Rodriguez-Roisin R,
    3. Torres A
    . Indications for and choice of antibiotics in COPD. In: Similowski T, Whitelaw W, Derenne J, editors. Clinical management of chronic obstructive pulmonary disease. New York: Marcel Dekker; 2002. p. 201-20.
  19. ↵
    1. Anthonisen NR,
    2. Manfreda J,
    3. Warren CP,
    4. Hershfield ES,
    5. Harding GK,
    6. Nelson NA
    . Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196-204.
    Abstract/FREE Full Text
  20. ↵
    1. Sethi S
    . Acute exacerbations of COPD. J Respir Dis 2002;23:217-25.
  21. ↵
    1. Ball P
    . Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995;108(Suppl 2):43-52.
    CrossRef
  22. ↵
    1. Woolhouse IS,
    2. Hill SL,
    3. Stockley RA
    . Symptom resolution assessed using a patient directed diary card during treatment of acute exacerbations of chronic bronchitis. Thorax 2001;56:947-53.
    Abstract/FREE Full Text
  23. ↵
    1. Huchon GJ
    . Management of adult community-acquired lower respiratory tract infections. Eur Respir Rev 1998;8:391-426.
    Medline
    1. McCrory DC,
    2. Brown C,
    3. Gelfand SE,
    4. Bach PB
    . Management of acute exacerbations of COPD: a summary and appraisal of published evidence. Chest 2001;119:1190-209.
    Abstract/FREE Full Text
  25. ↵
    1. Smith RP,
    2. Lipworth BJ,
    3. Cree IA,
    4. Spiers EM,
    5. Winter JH
    . C-reactive protein: a clinical marker in community-acquired pneumonia. Chest 1995;108:1288-91.
    Abstract/FREE Full Text
    1. Emerman CL,
    2. Connors AF,
    3. Lukens TW,
    4. May ME,
    5. Effron D
    . A randomized controlled trial of methylprednisolone in the emergency treatment of acute exacerbations of COPD. Chest 1989;95:563-7.
    Abstract/FREE Full Text
  27. ↵
    1. Melbye H,
    2. Kongerud J,
    3. Vorland L
    . Reversible airflow limitation in adults with respiratory infection. Eur Respir J 1994;7:1239-45.
    Abstract/FREE Full Text
  28. ↵
    1. Woodhead M,
    2. Gialdroni GG,
    3. Huchon GJ,
    4. Leophonte P,
    5. Manresa F,
    6. Schaberg T
    . Use of investigations in lower respiratory tract infection in the community: a European survey. Eur Respir J 1996;9:1596-600.
    Abstract/FREE Full Text
  29. ↵
    1. American Thoracic Society
    . Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:s77-s120.
  30. ↵
    1. Brand PL,
    2. Quanjer PH,
    3. Postma DS,
    4. et al
    . Interpretation of bronchodilator response in patients with obstructive airways disease. The Dutch Chronic Non-Specific Lung Disease (CNSLD) Study Group. Thorax 1992;47:429-36.
    Abstract/FREE Full Text
  31. ↵
    1. van der Valk P,
    2. Monninkhof E,
    3. van der Palen J,
    4. Zielhuis G,
    5. van Herwaarden C
    . Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE Study. Am J Respir Crit Care Med 2002;166:1358-63.
    Abstract/FREE Full Text
  32. ↵
    1. American Thoracic Society
    . Medical Section of the American Lung Association. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144:1202-18.
    MedlineWeb of Science
  33. ↵
    1. Isenberg HD
    . Clinical microbiology procedures handbook. Washington, DC: American Society for Microbiology Press; 1992.
  34. ↵
    1. Jacobsen SK
    . Use of antibiotics in patients admitted to the hospital due to acute exacerbation of COPD. Eur J Intern Med 2002;13:514-7.
    CrossRefMedline
  35. ↵
    1. Ewig S,
    2. Schlochtermeier M,
    3. Goke N,
    4. Niederman MS
    . Applying sputum as a diagnostic tool in pneumonia: limited yield, minimal impact on treatment decisions. Chest 2002;121:1486-92.
    Abstract/FREE Full Text
  36. ↵
    1. Blot F,
    2. Raynard B,
    3. Chachaty E,
    4. Tancrede C,
    5. Antoun S,
    6. Nitenberg G
    . Value of Gram stain examination of lower respiratory tract secretions for early diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 2000;162:1731-7.
    Abstract/FREE Full Text
  37. ↵
    1. Martinez JA,
    2. Rodriguez E,
    3. Bastida T,
    4. Buges J,
    5. Torres M
    . Quantitative study of the bronchial bacterial flora in acute exacerbations of chronic bronchitis. Chest 1994;105:976.
    MedlineWeb of Science
  38. ↵
    1. Soler N,
    2. Torres A,
    3. Ewig S,
    4. et al
    . Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. Am J Respir Crit Care Med 1998;157:1498-505.
    MedlineWeb of Science
| Table of Contents

This Article

  1. Clin Infect Dis. (2004) 39 (7): 980-986. doi: 10.1086/423959
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free
  4. A correction has been published

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most