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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Although exacerbations of chronic obstructive pulmonary disease (COPD) are associated with symptomatic and physiological deterioration, little is known of the time course and duration of these changes. We have studied symptoms and lung function changes associated with COPD exacerbations to determine factors affecting recovery from exacerbation. A cohort of 101 patients with moderate to severe COPD (mean FEV1 41.9% predicted) were studied over a period of 2.5 yr and regularly followed when stable and during 504 exacerbations. Patients recorded daily morning peak expiratory flow rate (PEFR) and changes in respiratory symptoms on diary cards. A subgroup of 34 patients also recorded daily spirometry. Exacerbations were defined by major symptoms (increased dyspnea, increased sputum purulence, increased sputum volume) and minor symptoms. Before onset of exacerbation there was deterioration in the symptoms of dyspnea, sore throat, cough, and symptoms of a common cold (all p < 0.05), but not lung function. Larger falls in PEFR were associated with symptoms of increased dyspnea (p = 0.014), colds (p = 0.047), or increased wheeze (p = 0.009) at exacerbation. Median recovery times were 6 (interquartile range [IQR] 1 to 14) d for PEFR and 7 (IQR 4 to 14) d for daily total symptom score. Recovery of PEFR to baseline values was complete in only 75.2% of exacerbations at 35 d, whereas in 7.1% of exacerbations at 91 d PEFR recovery had not occurred. In the 404 exacerbations where recovery of PEFR to baseline values was complete at 91 d, increased dyspnea and colds at onset of exacerbation were associated with prolonged recovery times (p < 0.001 in both cases). Symptom changes during exacerbation do not closely reflect those of lung function, but their increase may predict exacerbation, with dyspnea or colds characterizing the more severe. Recovery is incomplete in a significant proportion of COPD exacerbations.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exacerbations of chronic obstructive pulmonary disease (COPD) are an important cause of the considerable morbidity and mortality found in COPD. Some patients with COPD are prone to frequent exacerbations, which are an important determinant of health status in this patient group (1). Exacerbations are associated with considerable symptomatic and physiological deterioration, though there is little information available on the time course of these changes, whether prior to onset or during recovery from exacerbation. Few studies of interventions in COPD have used exacerbation rate as a primary outcome measure. Information on the time course and recovery of exacerbations is important in standardizing and optimizing the length of treatment, and in planning appropriate follow-up and clinical studies involving COPD exacerbations. Improved knowledge of the particular symptoms preceding an exacerbation and their relationship to the length of the recovery period could indicate which symptoms require particular attention and early therapy.
Some exacerbations, especially in patients with moderate to severe COPD, may have prolonged symptomatic effects, though there are no data available on the duration of symptomatic recovery, or whether recovery is complete after an exacerbation. Indeed COPD exacerbation is a common cause of hospital admission, often after failed initial therapy in the community. It is also a frequent cause of readmission to hospital with persistent symptoms after an initial admission for treatment of an exacerbation (2).
In this study we have prospectively and continuously followed over a period of 2.5 yr, a cohort of 101 patients with moderate to severe COPD who recorded on daily diary cards, symptoms and lung function and were asked to report any deterioration in symptoms directly to the study team. The aim of this study was to evaluate the time course of these exacerbations with respect to symptoms and lung function. We also investigated the time to recovery of these parameters, together with factors affecting recovery of lung function and symptoms after an exacerbation, in order to describe the characteristics of a COPD exacerbation.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients
This study was conducted over 2.5 yr on 101 of 138 patients recruited between October 1995 and March 1998; 37 patients who did not complete at least 20% (184 d) of the study period owing to withdrawal, death, or inadequate completion of diary cards were excluded. Those 37 patients who were excluded did not differ from the remaining patients in the study in any of the characteristics shown in Table 1 except in that they had a slightly lower peak expiratory flow rate (PEFR) at 162 ± 102 L/min (mean ± SD), compared with the remaining 101 patients whose PEFR was 219 ± 87 L/min (mean difference 57 L/min; p < 0.05).
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The patients were all recruited from those attending the outpatient's clinics of the London Chest Hospital on the basis of their willingness to participate in a long-term study. All patients had a diagnosis of COPD and were stable at the time of recruitment with no
history of exacerbations requiring medical treatment for the previous
4 wk. Inclusion criteria were: FEV1 less than 70% predicted for age
and height, 
2-agonist reversibility of less than 15% and/or 200 ml,
and an absence of a history of asthma, bronchiectasis, carcinoma of
the bronchus, or other significant respiratory disease (5, 6). At recruitment, baseline measurements were made of height, weight, FEV1,
FVC, and PEFR by rolling seal spirometer (Sensor Medic Corp.,
Yorba Linda, CA), reversibility to 400 µg inhaled salbutamol, and
arterialized ear lobe blood gases (7). Smoking habits and details of
inhaled and oral steroid use were also noted. The majority of the patients were receiving inhaled steroids according to local clinical practice in this patient group.
All patients were asked to record on daily diary cards, morning postmedication PEFR (Mini-Wright peak flow meter; Clement Clarke International Ltd., Harlow, UK) and any increase in a predetermined list of symptoms over their chronic (stable) symptoms during the previous 24 h. Thirty-four randomly selected patients also measured FEV1 and FVC using a hand-held spirometer (Micro Medical Ltd., Rochester, Kent, UK). Peak flow meters and hand-held spirometers were provided specifically for the purposes of the study. All gas volumes were standardized at BTPS.
Patients were seen in clinic monthly during the winter months (October to March) and every 3 mo during the summer, and if necessary reeducated about how to complete their diary cards. Ethical permission for the study was obtained from the East London and City Health Authority Ethics Committee.
Exacerbations
Respiratory symptoms were classified as "major" symptoms (dyspnea, sputum purulence, sputum amount) or "minor" symptoms (wheeze, sore throat, cough, and symptoms of a common cold which were nasal congestion/discharge). Exacerbations were defined as the presence for at least two consecutive days of increase in any two "major" symptoms or increase in one "major" and one "minor" symptom according to criteria modified from Anthonisen and colleagues (8). The first of the two consecutive days was taken as the day of onset of exacerbation. Daily symptoms were binary coded and summed to give a daily symptom score.
Patients were asked to contact the clinical team by telephone to arrange a clinic visit if their symptoms deteriorated and were seen within 48 h. This visit was called a reported exacerbation and patients were either treated with a 10-d course of antibiotics and/or if the physician considered that the exacerbation was severe enough, a 2-wk course of oral steroids. If patients presented with exacerbations to their general practitioner instead, then the treatment was determined from the history when they were seen at clinic (unreported exacerbation). From November 1996 onward, records were available of the date of initiation and type of treatment prescribed to patients both at our clinic and also that prescribed by the general practitioner.
Recovery from Exacerbation and Time to the Next Exacerbation
The time course of an exacerbation was examined over a 106-d period comprising baseline, prodrome, onset, and recovery. The baseline value for comparison of lung function and symptom changes was taken as the mean value of that parameter over the interval 14 to 8 d preceding exacerbation onset, as no significant changes in lung function and symptoms were seen over this time period. The period 7 to 1 d before onset of exacerbation on Day 0 was termed the prodromal period. The change in any parameter at exacerbation was taken as the difference between values of the parameter at onset of exacerbation and baseline. The recovery time for any parameter was taken as the time for that parameter to return to baseline as measured from the day of onset of exacerbation. Ninety-one days was chosen as the maximum time we analyzed for recovery because it is the average follow-up time for most clinics. We also analyzed recovery from exacerbation at 35 d because in most clinical studies, a patient not having an exacerbation for 4 to 6 wk would be considered stable. The PEFR or symptom score recovery rate was taken as the ratio of the change in PEFR or symptom score at exacerbation to the PEFR or symptom score recovery time, respectively. The time to the onset of the next exacerbation was defined as the number of days from onset of one exacerbation to onset of the next exacerbation.
Statistical Analysis
Data are presented as mean ± SD or median (with interquartile range [IQR] shown in parentheses) and statistical analysis performed by parametric (Student t-test and analysis of variance [ANOVA]) or nonparametric (Wilcoxon matched-paired sign-rank, Mann-Whitney two sample, and Spearman's rank correlation) tests where appropriate. Logistic regression was used to test whether individual symptoms changed with time prior to exacerbation onset. Changes in PEFR, FEV1, FVC, and daily total symptom score were calculated as the difference between the day of onset and the baseline values. Recovery times were computed as the time by which a 3-d moving average was equal to or exceeded the baseline value. A moving average was used to avoid false early recoveries when lung function improved for just a single day, but then remained below baseline for a few more days. Generalized linear modeling for Poisson distribution was used to analyze the linear relationship of recovery times with symptoms where recovery was complete.
The proportion of exacerbations exhibiting a particular symptom was plotted for a 50-d peri-exacerbation period comprising 14 d before and 35 d after onset of exacerbation; where no data were recorded by the patient the percentage was of the smaller number of exacerbations. Over the same period, the time course of changes in PEFR during exacerbation was also constructed using the percentage change of each day's median values from baseline. Graphs using exacerbations for which no data were missing over the 50-d period showed similar patterns, as did graphs plotted using the last exacerbation for each patient.
PEFR and symptom score recovery times, PEFR and symptom score recovery rate, and the time to the next exacerbation were analyzed separately by Mann-Whitney U-test for the effects of treatment with oral prednisolone or antibiotics for the 154 exacerbations for which treatment was known and for the 132 of these exacerbations for which the time to the next exacerbation was known. All data were analyzed using the statistical package Stata 5.0.
As bias could be introduced by patients who experienced frequent exacerbations, we analyzed the time course of symptoms and lung function using the last exacerbation experienced by each patient and all exacerbations. Results were similar, and thus data involving all exacerbations are presented. Some data were missing because patients failed to record data; where appropriate the lesser number of observations used for analysis is indicated in brackets [ ]. There was no difference in falls or recovery times of lung function between exacerbations with one, two, or three major symptoms at exacerbation (p > 0.25 in all cases). Further, the only difference between reported and unreported exacerbations was in FVC recovery time. Thus, during analysis we did not distinguish between either reported or unreported exacerbations or between exacerbations with different numbers of major symptoms.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients
The 101 patients all had moderate to severe COPD and were mildly hypoxic (Table 1). Ninety-three patients used 1.22 ± 0.61 mg (mean ± SD) of inhaled steroids daily and 12 were on 6.6 ± 2.8 mg/d of prednisolone (10 patients used both oral and inhaled steroids and two were only on oral steroids). The patients were in the study for a median of 783 (IQR 457-881) d and had recorded diary card data for a median of 689 (IQR 383 to 851) d or 86% of the time in the study. The 34 patients (31 male, 3 female) in whom daily FEV1 and FVC were recorded, were on average 4.1 yr older (p = 0.02) and had a higher mean PEFR at 257 ± 90 L/min, compared with the remainder of the patients at 199 ± 79 L/min (mean difference 58 L/min; p = 0.002).
Exacerbations
Between October 1995 and March 1997, 91 of the 101 patients in the study had one or more exacerbations. Figure 1 shows that there were a total of 504 exacerbations of which 430 (85.3%) were identified from the symptom data recorded by the patients on their diary cards. A total of 250 (49.6%) exacerbations were reported directly to the clinical team and 254 were not reported. The median exacerbation rate was 2.4 (IQR 1.32 to 3.84) exacerbations per patient per year. There was no difference between reported and unreported exacerbations in the decrease in PEFR, FEV1, or FVC or increase in symptom score at onset of exacerbation or in recovery times for PEFR, FEV1, and symptom score at exacerbation (p > 0.11 in all cases). Reported exacerbations were associated with a longer recovery time for FVC (median recovery for unreported exacerbations at 3 [IQR 1 to 9] d, compared with 6 [1 to 15] d for reported ones [p = 0.019]). Data on treatment used at exacerbation were available for 154 exacerbations in all.
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Prodrome and Onset of Exacerbation
Figure 2 shows the time course of symptoms from 14 d before to 35 d after the onset of exacerbation. Over the prodromal period (the 7 d before onset of exacerbation), dyspnea, symptoms of a common cold, sore throat, and cough increased significantly (p < 0.05 in all cases). On the day of onset of exacerbation, reports of symptoms increased sharply with 64% of exacerbations associated with symptoms of dyspnea, 26% with increased sputum volume, 42% with sputum purulence, 35% with colds, 35% with wheeze, 12% with sore throat, and 20% with cough. Thirty-seven percent of exacerbations were associated with two major symptoms and 8% had three major symptoms on the day of onset of exacerbation. Symptom score increased from baseline by a median of 2 (IQR 2 to 3).
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Figure 3 illustrates the time course of daily median percentage change in PEFR from baseline values. Lung function did
not decrease significantly during the prodromal period, but by
Day 0, PEFR had fallen from baseline by a median 8.6 (IQR 0 to 22.9) L/min, FEV1 by 24.0 (IQR 
16.1 to 84.3) ml, and FVC
by 76.0 (IQR 40.4 to 216.4) ml. The declines in lung function, whether measured by PEFR, FEV1, or FVC, were all
highly significant (p < 0.001). Significantly greater decreases
in PEFR were seen when the exacerbation was associated with
symptoms of increased dyspnea (r = 0.12 [n = 449]; p = 0.014), colds (r = 0.09 [n = 449]; p = 0.047), or increased
wheeze (r = 0.12 [n = 449]; p = 0.009), but not with other
symptoms.
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Recovery from Exacerbation
Table 2 shows that a greater fall in PEFR, FEV1, FVC or rise in symptom score at exacerbation was significantly related to the length of the respective recovery time in these parameters. Table 3 shows that the median time to recovery of PEFR after exacerbation onset was similar at 6 (1 to 14) d, to that of symptoms at 7 (4 to 14) d. At 35 d, PEFR in 75.2% of exacerbations had returned to baseline levels, whereas 86.1% had attained symptomatic recovery. However, at 91 d, the PEFR in 7.1% of exacerbations had not returned to baseline lung function and in 3.4% of exacerbations a further exacerbation had occurred before recovery was complete. There was no significant difference in the recovery of symptoms or PEFR, FEV1, or FVC between smokers and nonsmokers. There was also no relationship between the exacerbation frequency and changes in lung function at exacerbation or recovery time.
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Table 4 shows the independent effects of individual symptoms at onset of exacerbation to recovery of PEFR for those exacerbations where recovery occurred at 91 d. Recovery was longer in the presence of dyspnea or symptoms of a common cold at exacerbation onset, though there was no effect of sputum purulence or increased sputum volume on recovery time. Exacerbations associated with wheeze and sore throat had shorter recovery times.
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During the study, 78 patients (86% of those who had exacerbations) had two or more exacerbations comprising a total of 491 exacerbations. From these data, 413 interexacerbation time intervals were calculated and of these treatment had been recorded at the start of the interval for 132. There was no significant difference between the 132 exacerbations for which treatment was known and those for which it was not, in lung function fall at exacerbation, recovery time, or symptoms and lung function at day of onset of exacerbation (p > 0.09 in all cases). The median duration of the 132 interexacerbation time intervals was 64 (33 to 144) d. For these exacerbations treatment was started a median of 3 (1 to 5) d after onset of exacerbation and prednisolone was given in 27.3% exacerbations, antibiotics in 85.6%, while 25% had been treated with both antibiotics and oral steroids and 12.1% exacerbations received no treatment.
Table 5 shows data on the effects of treatment with oral prednisolone at exacerbation on recovery and lung function. Exacerbations treated with steroids were more severe in that they were associated with larger falls in peak flow (p < 0.001), had a longer PEFR recovery time (p = 0.015), and a longer symptom score recovery time (p = 0.038). However, the rate of PEFR recovery was faster with prednisolone therapy (p = 0.003) though not the rate of symptom score recovery (p = 0.33). The median time to the next exacerbation was increased significantly with oral steroid therapy (p = 0.037). Antibiotic treatment had no effect on recovery time, rate of PEFR or symptom score recovery, or on time to the next exacerbation (p > 0.09 in all cases). In the subgroup of exacerbations associated with three major symptoms (n = 12) all patients received antibiotics so it was not possible to determine if antibiotics had an effect on time to the next exacerbation in this subgroup.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study is the first to our knowledge to follow prospectively the changes in lung function and symptoms immediately before as well as after COPD exacerbations. We found a number of important features of a COPD exacerbation in that symptoms and not lung function worsen significantly before an exacerbation. Although the lung function changes may be small, they can be persistent and in some cases lung function and symptoms did not recover to baseline values even at 3 mo. By requesting the patients to record increases in their symptoms on a daily basis, we were able to detect exacerbations that the patient for whatever reason did not report to the clinical team. Routine clinic visits ensured good compliance and accuracy, with missed data due mainly to holidays, hospitalization, and diary card loss. Our exacerbation rate was approximately double that reported in previous studies, owing to the inclusion of unreported exacerbations at approximately 50% of the total number (1, 8). We had previously shown that approximately 50% of exacerbations are unreported to clinicians and exacerbation symptoms are similar between reported and unreported exacerbations (1). The time course and recovery between exacerbations reported directly to us for treatment and those that were not reported to us were similar and thus we did not distinguish between reported and unreported exacerbations during analysis.
Patients recovered their lung function within a median time of 7 d, and the recovery of lung function was related to the magnitude of the decrease in lung function and the symptom score at the onset of exacerbation. However, there are no published data on prospective daily monitoring of symptoms and lung function before and after COPD exacerbation. In previous studies of COPD exacerbations where daily data were reported after exacerbation, monitoring was started only after the patients reported the exacerbation and thus there were no data available on baseline lung function before onset of exacerbation (8, 11, 12). These studies also showed small decreases in lung function at exacerbation as found in this study. The changes we observed in lung function at COPD exacerbation were smaller than those observed during asthmatic exacerbations, though the average duration of an asthmatic exacerbation with respect to lung function change from baseline was longer at 9.6 d, compared with 6 d in this study (13). In a recent descriptive study of asthma exacerbations, peak flow readings fell and symptom scores associated with exacerbation increased for approximately 7 d before exacerbation, in contrast to COPD exacerbations where there were no peak flow or FEV1 changes before onset of exacerbation, but symptoms increased before exacerbation (14). Thus, peak flow or FEV1 monitoring in patients with COPD to detect the early development of an exacerbation will not be useful in clinical practice.
Approximately only 75% of our exacerbations recovered to baseline lung function at 5 wk, by which time patients with COPD are usually assumed to be stable and 7% did not recover at 3 mo. These patients were more likely to have had large declines in lung function and thus more severe exacerbations. Another study of 71 COPD exacerbations with daily peak flow recordings reported a lower mean PEFR at Day 14 compared with baseline, though no further follow-up was available (12). The reasons for the incomplete recovery are not clear, but may involve inadequate treatment or persistence of the causative agent. The association of the symptoms of increased dyspnea and of the common cold at exacerbation with a prolonged recovery suggests that viral infections may lead to more prolonged exacerbations. Concentrations of the cytokine interleukin-6 in induced sputum were higher in the presence of a cold at exacerbation, suggesting that viral infections at exacerbations may increase airway inflammation (15). Patients should be routinely seen at a period of 4 to 6 wk after an exacerbation to ensure symptomatic and physiological recovery.
Though short-course oral steroids have little effect in stable COPD (16) they have been found to improve lung function acutely when used in patients, mainly hospitalized with exacerbation (11, 19). However, little data is available on the effect of steroid therapy in exacerbations treated in the community. Data analysis showed that short-course oral steroid treatment at exacerbation increased the PEFR recovery rate and increased the time to the next exacerbation. This finding should be investigated further as this study was not designed to evaluate oral steroid action. However, it is unlikely that the physician introduced further bias when treating the more severe exacerbations with a greater decrease in lung function with oral steroids, as no other differences were detected between the two treatment groups. Thus, oral steroids would be expected to decrease exacerbation frequency, which is an important determinant of quality of life in these patients (1). We found that dyspnea, symptoms of a common cold, sore throat, and cough increased significantly during the prodromal phase, and this suggests that respiratory viruses have early effects on individual respiratory symptoms at exacerbations. As colds are associated with longer exacerbations, patients with COPD who develop a cold may be prone to more severe exacerbations and should be considered for short-course oral steroid therapy at onset of symptoms. It is possible that early intervention could reduce the severity of a COPD exacerbation by reducing decreases in lung function and thus hastening recovery.
The mechanism for prolonging the time to the next exacerbation may include reduction of airway inflammation and perhaps reducing susceptibility to infective agents. Oral steroids have been shown to downregulate intercellular adhesion molecule-1 (ICAM-1) which is responsible for virus-epithelial cell interactions and thus could reduce the frequency of virus-associated COPD exacerbations (23). We found that antibiotic prescription had no effects on recovery from exacerbation or time to the next exacerbation, which is consistent with an earlier report (12). However, in our study only 45% of patients had major symptoms requiring antibiotic therapy (8), though antibiotics were used in a larger number, suggesting that antibiotics are overprescribed in clinical practice.
This study has several important implications for the management of patients with COPD. We recommend that patients with COPD should be made more aware of the symptoms of an exacerbation and encouraged to report these early to clinicians and therapy started. Closer monitoring of patients with COPD than currently performed in clinical practice, may be useful and all patients should be followed after an exacerbation until recovery has occurred. Thus, the high exacerbation frequency characteristic of patients with COPD and associated with poor health status may be decreased (1). This would have a considerable effect on reducing health burden in this disabling condition.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. J. A. Wedzicha, Academic Respiratory Medicine, Dominion House, St. Bartholomew's Hospital, London EC1A 7BE, UK. E-mail: J.A.Wedzicha{at}mds.qmw.ac.uk
(Received in original form August 6, 1999 and in revised form November 9, 1999).
Terence Seemungal was the recipient of a British Lung Foundation Fellowship.Acknowledgments: The authors are grateful for the assistance of Leonette John (Respiratory Function Unit, London Chest Hospital) and the staff of the Outpatients Department of the London Chest Hospital.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
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S Spencer and P W Jones Time course of recovery of health status following an infective exacerbation of chronic bronchitis Thorax, July 1, 2003; 58(7): 589 - 593. [Abstract] [Full Text] [PDF]
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S. D. Aaron, K. L. Vandemheen, P. Hebert, R. Dales, I. G. Stiell, J. Ahuja, G. Dickinson, R. Brison, B. H. Rowe, J. Dreyer, et al. Outpatient Oral Prednisone after Emergency Treatment of Chronic Obstructive Pulmonary Disease N. Engl. J. Med., June 26, 2003; 348(26): 2618 - 2625. [Abstract] [Full Text] [PDF]
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S. Burge and J.A. Wedzicha COPD exacerbations: definitions and classifications Eur. Respir. J., June 1, 2003; 21(41_suppl): 46S - 53s. [Abstract] [Full Text] [PDF]
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M R Partridge Patients with COPD: do we fail them from beginning to end? Thorax, May 1, 2003; 58(5): 373 - 375. [Full Text]
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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]
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J Garcia-Aymerich, E Farrero, M A Felez, J Izquierdo, R M Marrades, and J M Anto Risk factors of readmission to hospital for a COPD exacerbation: a prospective study Thorax, February 1, 2003; 58(2): 100 - 105. [Abstract] [Full Text] [PDF]
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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]
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N S Godtfredsen, J Vestbo, M Osler, and E Prescott Risk of hospital admission for COPD following smoking cessation and reduction: a Danish population study Thorax, November 1, 2002; 57(11): 967 - 972. [Abstract] [Full Text] [PDF]
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G C Donaldson, T A R Seemungal, A Bhowmik, and J A Wedzicha Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease Thorax, October 1, 2002; 57(10): 847 - 852. [Abstract] [Full Text] [PDF]
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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]
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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]
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N. R. Anthonisen Bacteria and Exacerbations of Chronic Obstructive Pulmonary Disease N. Engl. J. Med., August 15, 2002; 347(7): 526 - 527. [Full Text] [PDF]
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S.-s. Yeh, B. DeGuzman, and T. Kramer Reversal of COPD-Associated Weight Loss Using the Anabolic Agent Oxandrolone* Chest, August 1, 2002; 122(2): 421 - 428. [Abstract] [Full Text] [PDF]
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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]
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W. Willaert, M. Daenen, P. Bomans, G. Verleden, and M. Decramer What is the optimal treatment strategy for chronic obstructive pulmonary disease exacerbations? Eur. Respir. J., May 1, 2002; 19(5): 928 - 935. [Abstract] [Full Text] [PDF]
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J. K. Stoller Acute Exacerbations of Chronic Obstructive Pulmonary Disease N. Engl. J. Med., March 28, 2002; 346(13): 988 - 994. [Full Text] [PDF]
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