Am J Respir Crit Care Med Vol 157. pp 1418–1422, 1998

Effect of Exacerbation on Quality of Life in Patientswith Chronic Obstructive Pulmonary Disease

TERENCE A. R. SEEMUNGAL, GAVIN C. DONALDSON, ELIZABETH A. PAUL, JANINE C. BESTALL,DONALD J. JEFFRIES, and JADWIGA A. WEDZICHA

Academic Departments of Respiratory Medicine, Physiology, Environmental and Preventive Medicine, and Virology,St. Bartholomew’s and Royal London School of Medicine and Dentistry, London, United Kingdom

Exacerbations occur commonly in patients with moderate or severe chronic obstructive pulmonarydisease (COPD) but factors affecting their severity and frequency or effects on quality of life are un-known. We measured daily peak expiratory flow rate (PEFR) and daily respiratory symptoms for 1 yrin 70 COPD patients (52 male, 18 female, mean age [

6

SD] 67.5

6

8.3 yr, FEV

1

1.06

6

0.45 L, FVC2.48

6

0.82 L, FEV

1

/FVC 44

6

15%, FEV

1

reversibility 6.7

6

9.1%, Pa

O

2

8.8

6

1.1 kPa). Quality of lifewas measured by the St. George’s Respiratory Questionnaire (SGRQ). Exacerbations (E) were as-sessed at acute visit (reported exacerbation) or from diary card data each month (unreported exacer-bation). In 61 (87%) patients there were 190 exacerbations (median 3; range, 1 to 8) of which 93(51%) were reported. There were no differences in major symptoms (increase in dyspnea, sputumvolume, or purulence) or physiological parameters between reported and unreported exacerbations.At exacerbation, median peak flow fell by an average of 6.6 L/min (p

5

0.0003). Using the mediannumber of exacerbations as the cutoff point, patients were classified as infrequent exacerbators (E

5

0 to 2) or frequent exacerbators (E

5

3 to 8). The SGRQ Total and component scores were signifi-cantly worse in the group that had frequent exacerbations: SGRQ Total score (mean difference

5

14.8, p

,

0.001), Symptoms (23.1, p

,

0.001), Activities (12.2, p

5

0.003), Impacts (13.9, p

5

0.002).However there was no difference between frequent and infrequent exacerbators in the fall in peakflow at exacerbation. Factors predictive of frequent exacerbations were daily cough (p

5

0.018), dailywheeze (p

5

0.011), and daily cough and sputum (p

5

0.009) and frequent exacerbations in the pre-vious year (p

5

0.001). These findings suggest that patient quality of life is related to COPD exacer-bation frequency.

Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA.Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary dis-

ease.

AM J RESPIR CRIT CARE MED 1998;157:1418–1422.

Patients with moderate and severe chronic obstructive pulmo-nary disease (COPD) are prone to exacerbations; the frequencyof these exacerbations increases with the severity of COPD(1). However, there is little information on the effect of exac-erbation on quality of life. Some patients are prone to fre-quent exacerbations that may have considerable impact on ac-tivities of daily living and well-being, yet factors predictingdevelopment and severity of exacerbation have not been stud-ied. Impairment of quality of life can be quantified with dis-ease-specific quality-of-life measures, validated for use in chronicrespiratory disease (2, 3). Changes in lung function occur withexacerbation, but these are variable, because of the relativelyfixed airflow obstruction. However, quality-of-life scores showonly a moderate relationship with symptoms and physiological

parameters (4–7) and thus exacerbation may produce consid-erable distress to the patient, without change in lung function.

Previous studies of exacerbations have concentrated on pre-dictive factors for hospital admission in patients with COPD(8–11). Poor quality of life is related to likelihood of hospitaladmission and to increased use of resources. However, mostCOPD exacerbations are treated at home and are not associ-ated with hospital admission. There is no information as to theimpact of such exacerbations and their differing severity onthe daily life of COPD patients.

In this study, patients with moderate to severe COPD werefollowed prospectively over 12 mo. Patients recorded dailysymptoms and daily peak flow on diary cards and reported ex-acerbations to the clinical team. We have investigated the ef-fect of exacerbation frequency and severity on health-relatedquality of life and evaluated factors that predispose to exacer-bation.

METHODS

Patients

Eighty-four (57 male, 27 female) of 125 (81 male, 44 female) patientswith COPD who attended the outpatient clinics were recruited in Oc-

(

Received in original form September 9, 1997 and in revised form December 11,1997)

Supported by the British Lung Foundation and the Hedley Foundation.

Correspondence and requests for reprints should be addressed to Dr. J. A. Wed-zicha, Academic Department of Respiratory Medicine, The London Chest Hospi-tal, Bonner Road, London E2 9JX, UK.

Seemungal, Donaldson, Paul,

et al.

: Effect of Exacerbation on QOL in COPD 1419

tober 1995. Inclusion criteria were: FEV

1

,

70% predicted for ageand height,

b

2

-agonist reversibility

,

15% or 200 ml (12, 13), and noexacerbations for the previous 4 wk. Exclusion criteria were asthma,bronchiectasis, carcinoma of the bronchus, or inability to complete di-ary cards. During the study period there were three deaths, one fromallergic bronchopulmonary aspergillosis and two from acute exacerba-tions of COPD. Eleven patients withdrew, 10 because of poor compli-ance and one because of reactivation of tuberculosis. Thus, the num-ber of patients who remained in the study was 73 (54 male, 19 female)with 70 patients (52 male, 18 female) completing the study.

At recruitment, measurements were made of FEV

1

and FVC (roll-ing seal spirometer; Sensor Medic Corp., Yorba Linda, CA), revers-ibility to salbutamol (400

m

g by metered-dose inhaler) after withdraw-ing bronchodilators for 4 h, arterialized ear lobe blood gases (model278 Blood Gas Analyzer; Ciba-Corning, Medfield, MA) (14), the num-ber of exacerbations during the previous year (past exacerbations), andthe cardiovascular history. Steroid use, vaccine history, and daily symp-toms (dyspnea, cough, wheeze, sputum production) were recorded.

Patients completed daily diary cards after morning medication torecord peak expiratory flow rate (PEFR) using a Mini-Wright peakflow meter (Clement Clarke International Ltd, Harlow, UK), increasein upper respiratory tract symptoms (nasal discharge, sore throat), andincrease in lower respiratory tract symptoms (dyspnea, sputum, cough,wheezing) and fever. Patients were reviewed monthly until April 1996and every three months during the summer months for a total follow-up of 12 mo. Approval for this study was obtained from the ethicscommittee of the East London and City Health Authority.

Exacerbations

An exacerbation was diagnosed (15) if the following symptom pat-terns were experienced for at least two consecutive days: either two ormore of three major symptoms (increase in dyspnea, sputum puru-lence, and increased sputum volume); or any one major symptom to-gether with any one of the following minor symptoms—increase in na-sal discharge, wheeze, sore throat, cough, or fever. When patientsnoticed deterioration in symptoms, they telephoned a member of theclinical team and were seen within 48 h. If their symptoms were com-patible with a reported exacerbation, spirometry was measured andtreatment prescribed of antibiotics and/or oral steroids and/or in-creased inhaled steroids. Exacerbations identified from the diarycards at clinic visits when patients were not reviewed acutely weretermed “unreported exacerbations.”

Health-related Quality Of Life (HRQOL)

Indices of health-related quality of life (HRQOL) were obtained us-ing the St. George’s Respiratory Questionnaire (SGRQ) (2, 16).Three component indices were calculated using empirically derivedweightings: Symptom, Activity, and Impact scores from which a Totalscore was computed. Scores vary from 0 (no disability) to 100 (maxi-mum disability). Patients were also asked to complete the MedicalResearch Council (MRC) dyspnea scale questionnaire (17) whichconsists of five grades: 1—shortness of breath with strenuous exercise;2—shortness of breath when hurrying; 3—walking slower than peopleof same age; 4—needing to stop after walking 100 yards on level; 5—too breathless to leave the house. The questionnaires were completedby the patients at the last clinic visit without directions from the re-searchers.

Statistical Analysis

Reported and unreported exacerbations were compared by acutesymptoms (chi-square test) and changes in PEFR at the time of exac-erbation (Mann-Whitney U test). The Wilcoxon signed rank test wasused to test significance of PEFR change over the 2 d prior to exacer-bation from zero. Baseline PEFR was taken as the mean of Days 14 to7 prior to onset of exacerbation. Recovery of PEFR was defined asthe time at which the 3-d moving average of PEFR exceeded or wasnearest baseline.

The 14 patients who could not complete the study were comparedwith the 70 patients who completed the study on the baseline physio-logical measures, history of symptoms, and past exacerbations. Con-tinuous variables were compared using

t

tests and discrete variablesusing the chi-squared test. FEV

1

and Pa

CO

2

were not normally distrib-

uted and log transformation of these variables was used in all analy-ses. For each patient the mean fall in PEFR over all exacerbations wascalculated. MRC grade was divided into two groups, grades 2 and 3,and grades 4 and 5. The median number of exacerbations was 3 perpatient and this was taken as a cutoff point to divide the patients intotwo groups: those who had 0, 1, or 2 exacerbations during the year andthose with 3 or more. The relationship between exacerbation groupand individual variables was described using univariate logistic regres-sion. The effect of all variables together on exacerbation group wasthen explored using backward logistic regression. The SGRQ was nor-mally distributed and

t

tests were used to compare group means for di-chotomous variables which included exacerbation group, MRC grade,past exacerbations, sex, and symptoms. Physiological variables wereentered into individual regression equations with SGRQ as the out-come variable and then combined in a backward multiple regression.

RESULTS

Description of the Cohort

Table 1 shows the baseline data on the 73 patients who re-mained in the study, though all further analysis was carriedout only on the 70 who completed the study. Twenty-seven ofthe 70 patients had cardiac failure, 14 had ischemic heart dis-ease, 38 had three or more past exacerbations, and nine wereon long-term oxygen therapy. The median MRC dyspneascore was 4 (range, 2 to 5). Twenty-two were current smokers,with a mean of 46

6

35 pack-years for the cohort. Sixty-six pa-tients were receiving inhaled steroids (beclomethasone, budes-onide, or fluticasone) using a mean dose of 1.11

6

0.66 mg dailyfor 4.78

6

3.75 yr. Ten patients were on regular prednisolone(range, 2 to 10 mg/d) and 11 on daily theophylline, 400 mg. The14 patients who did not complete the study were not signifi-cantly different from the 70 who did, in any baseline parame-ters shown in Table 1. Diary card PEFR data were recorded fora mean of 307

6

49 or for 84

6

13% of the year study period.

Exacerbations

There were 190 exacerbations (mean 2.7; median 3; range, 1 to8) in the 70 patients over the year of follow-up. Six unreportedexacerbations were treated at other centers with no recordingon their diary cards; these were therefore excluded from fur-ther analyses. Of the 184 exacerbations, 93 were reported,providing a reporting rate of 1.5 per patient per year. Therewere no differences between reported and unreported exacer-

TABLE 1

CLINICAL AND PHYSIOLOGICAL DATA ATSTART OF STUDY (n

5

73)

Mean SD

Age, yr 67.8 8.3FEV

1

, L 1.05 0.45FEV

1

, % 40 19FEV

1

reversibility, % 6.7 9.1FVC, L 2.48 0.82FEV

1

/FVC, % 44 15PEFR, L/min 235 89Pa

O2

, mm Hg 66 8.3Pa

CO2

, mm Hg 45.6 7.2Daily inhaled steroids, mg 1.11 0.66Past exacerbations* 3.0 2.6

Daily symptoms % n

Cough 58 42Sputum 62 45Cough and sputum 45 33Wheeze 34 25Dyspnea 49 36

* Exacerbations in year prior to recruitment.

1420

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 157 1998

bations for the major symptoms (p

.

0.15). For the minorsymptoms, reported exacerbations were associated with ahigher incidence of increased cough (p

5

0.02), but a lower in-cidence of increased wheeze (p

5

0.03). There were no differ-ences in PEFR fall over the 2 d prior to exacerbation (p

5

0.77) nor duration of PEFR change at exacerbation (p

5

0.41).There was no difference in reporting rate between the firstand second 6 mo of the study (p

5

0.85).At exacerbation the PEFR fell by a median [interquartile

range (IQR)] of 6.6 (

2

16.6, 0) L/min (p

5

0.0003). Recoveryof PEFR to baseline occurred after 11.1

6

6.1 d. Seventeenpatients were admitted to the hospital for a total of 23 exacer-bations. There was no difference in PEFR change at exacerba-tion between those who were admitted for exacerbation andthose who were not (p

5

0.95).

Quality-of-life Scores

The mean (

6

SD) SGRQ Total score for the cohort was56.7

6

16.7 (component scores: Impacts, 43.5

6

19.1, Symp-toms 66.4

6

19.8, and Activities 74.5

6

17.8). The mean timebetween completion of the SGRQ and the preceding exacer-bation was 101

6

74 d. The Total quality-of-life score wasworse in MRC grades 4 and 5 patients (p

5

0.002), amongyounger patients (p

5

0.0029), and those with frequent pastexacerbations (p

5

0.0014). Wheeze was the only daily symp-tom associated with a reduced quality of life. Blood gases andlung function showed no association with the SGRQ Totalscore. The Symptom score was worse for patients with fre-quent past exacerbations (r

5

0.45, p

5

0.0005), daily wheeze(r

5

0.39, p

5

0.001), daily sputum (r

5

0.30, p

5

0.011), bron-chitic symptoms (r

5

0.26, p

5

0.03), and daily dyspnea (r

5

0.27, p

5

0.023). The Activities score was higher with frequentpast exacerbations (r

5

0.24, p

5

0.047) and with MRC Groups4 and 5 (r

5

0.37, p

5

0.002) and was related to FEV

1

(r

52

0.26, p

5

0.03). The Impact score was worse in younger pa-tients (r

5

2

0.39, p

5

0.001) frequent past exacerbations (r

5

0.26, p

5

0.033), MRC Groups 4 and 5 (r

5

0.35, p

5

0.003),and in patients with wheeze (r

5

0.39, p

5

0.001). Table 2shows that SGRQ Total and component scores were all signif-icantly higher in patients who had frequent exacerbations (p

,

0.005). There was a 15-point mean difference in SGRQ Totalscore between the frequent and infrequent exacerbators.

Factors Predisposing to Frequent Exacerbations

Exacerbations were more frequent in patients with frequentpast exacerbations (odds ratio [OR]

5

5.5, p

5

0.001), thosewith daily cough (OR

5

3.3, p

5

0.019), or daily wheeze(OR

5

4.2, p

5

0.011). Exacerbation frequency was also re-lated to bronchitic symptoms (OR

5

3.8, p

5

0.009), but notto daily sputum production alone nor dyspnea. No other base-line factors or PEFR change at exacerbation were related to

exacerbation frequency. When all factors were taken together,three factors that showed a univariate association with exacer-bation frequency contributed independently to exacerbationfrequency: frequent past exacerbations (OR

5

1.43, p

5

0.013), daily wheeze (OR

5

1.34, p

5

0.042), and bronchiticsymptoms (OR

5

1.56, p

5

0.009).

SGRQ Scores and Predisposing Factors

Table 3 shows the multiple regression analyses between theSGRQ scores and the factors predictive of either a high exac-erbation frequency or showing a univariate association withSGRQ. The exacerbation frequency was strongly correlatedto the SGRQ Total and each of the component scores. Inclu-sion of time to preceding exacerbation did not affect the re-gression. Past exacerbations were only related to the SGRQSymptoms score (p

5

0.0428). MRC grade was significantly re-lated to the SGRQ Total, Impacts, and Activities scores. SGRQscore was not related to PEFR changes at exacerbation nor tofrequency of hospital admissions (p

.

0.59 in all cases). Thismodel accounted for 46% of the variance in SGRQ Total scoreand 40% of that in the Symptoms component.

DISCUSSION

This study was designed to evaluate the effect of exacerba-tions on health status in COPD patients, and to determine thepredisposing factors to exacerbations. Patients were moni-tored daily at home and asked to report exacerbations as soonas possible after onset. Health status, measured with the SGRQ,

TABLE 2

RELATIONSHIP BETWEEN SGRQ SCORES AND EXACERBATION FREQUENCY

ExacerbationFrequency n Total Symptoms Activities Impacts

0–2 32 48.9

6

15.6 53.2

6

17.2 67.7

6

17.2 36.3

6

18.23–8 38 64.1

6

14.6 77.0 6 15.8 80.9 6 16.0 50.4 6 17.6Mean difference 215.1 221.9 212.2 214.1CI 222.3 to 27.8 229.7 to 214.0 221.2 to 25.3 222.9 to 25.6p Value , 0.0005 , 0.0005 0.001 0.002

Definition of abbreviation: CI 5 95% confidence interval.* Mean 6 SD.

TABLE 3

MULTIPLE REGRESSION ANALYSIS WITH THE SGRQ SCORESAS OUTCOME VARIABLES (n 5 70)

R2 b* SE b* p Value

SGRQ Total score 0.46Exacerbation frequency 11.54 3.26 0.0008MRC grades 4 and 5 12.68 3.04 0.0001Daily wheeze 7.83 3.48 0.0280Age 20.46 0.19 0.0207

SGRQ Symptoms 0.40Exacerbation frequency 16.1 4.18 0.0003Past exacerbations 8.69 4.21 0.0428

SGRQ Activities 0.29Exacerbation frequency 13.44 3.71 0.0006MRC grades 4 and 5 13.28 3.72 0.0007

SGRQ Impacts 0.41Exacerbation frequency 9.18 3.84 0.0200Daily wheeze 10.23 4.10 0.0152MRC grades 4 and 5 13.84 3.63 0.0003Age 20.66 0.23 0.0056

* b 5 regression coefficient.

Seemungal, Donaldson, Paul, et al.: Effect of Exacerbation on QOL in COPD 1421

was strongly related to the number of exacerbations over theyear study period and to the number of past exacerbations.

Patients with COPD develop significant disability with pro-gressive disease, and measures of lung function such as FEV1may not accurately predict disability (18, 19). Respiratory dis-ease–specific questionnaires, such as the SGRQ, provide sen-sitive measurements of disturbance to daily life and well-being.The SGRQ has been evaluated in patients with all grades ofseverity of COPD, including chronic respiratory failure (2, 7,20) and correlates quite well with exercise capacity (3, 6, 21).Although the level of the FEV1 was not predictive of exacer-bation in this study, the SGRQ Total and three componentscores all related strongly to exacerbation frequency. Thus ahigh SGRQ score may be used to predict patients at risk fromfrequent exacerbations. As the SGRQ was administered at thelast clinic visit we cannot be certain that reduced health statusis a consequence of high exacerbation frequency. Because themean time between administering the SGRQ and the preced-ing exacerbation was 101 d, it is unlikely that a current exacer-bation affected the response. In bronchiectatic patients, SGRQscores were also found to be related to the exacerbation fre-quency (22). In our study the MRC dyspnea score was stronglyrelated to SGRQ scores, but not to exacerbation frequency;thus indicating that while dyspnea is a weak discriminating fac-tor for frequent exacerbations, it is associated with reducedquality of life. PEFR changes at exacerbation, though signifi-cant, were not related to SGRQ scores.

Patients were asked to report exacerbations according toworsening of symptoms. However, despite considerable in-struction and clinic visits, only 50% of the exacerbations werereported. The reporting rate in this study is comparable to astudy in children with asthma, where 33% of exacerbationswere reported (23). Patients with COPD are accustomed tofrequent symptom changes and thus may tend to underreportexacerbations to physicians. These patients have high levels ofanxiety and depression and may accept their situation (7),though there is no evidence that unreported exacerbations ledto increased morbidity. There were no differences in any ofthe major symptoms, exacerbation frequency, duration, or peakflow changes between reported or unreported exacerbations,though reported exacerbations were associated with changesin the minor symptoms; a greater incidence of cough and lesswheeze. We found no differences in PEFR changes in thosepresenting with cough and/or wheeze, and thus for analysis,combined reported and unreported exacerbations. The tendencyof patients to underreport exacerbations may explain the highertotal rate of exacerbation of 2.7 per patient per year detectedin this study as compared with that reported by Anthonisenand coworkers (15) where the exacerbation rate was 1.1 perpatient per year and unreported exacerbations were diagnosedfrom patients’ recall of symptoms.

A previous study of acute infective exacerbations ofchronic bronchitis found that one of the factors predicting ex-acerbation was the number in the previous year (24). How-ever, this study was limited to exacerbations presenting withpurulent sputum only, without bacteriological evidence of in-fection and no baseline or exacerbation-related physiologicaldata was available. We also found that patients with frequentpast exacerbations were more likely to have an exacerbationduring the study year. Patients who had chronic cough orwheeze also tended to have a higher exacerbation frequency,though frequency was not related to chronic sputum produc-tion. Patients with chronic productive cough may be more sus-ceptible to infection, or to environmental factors such as airpollution, temperature changes, or humidity.

Coexisting cardiac and pulmonary disease has been previ-

ously identified as the only other risk factor for exacerbations(24). We found no relationship between congestive cardiacfailure, ischemic heart disease, and exacerbation frequency,but this may be due to the relatively small number of patientswith cardiac disease in this study. However our study revealeda strong relationship between bronchitic symptoms and exac-erbation frequency. Jousilahti and colleagues (25) found thatthe presence of bronchitic symptoms predicted the risk of cor-onary artery disease independently of other known risk fac-tors. Thus there may be an association between exacerbationfrequency and coronary artery events in COPD patients.

In our study, only 16% of the exacerbations required hos-pital admission; this is representative of community-acquiredCOPD exacerbations. There was no relation between hospitaladmission and exacerbation frequency. One recent retrospec-tive study found a relationship between poor quality-of-lifemeasures and hospital readmission (8). However, reasons forhospital admission are complex, with patients with COPD ex-acerbations often admitted to the hospital late in the evolutionof the disease, when usual therapy has failed. The purpose ofthis study was to consider COPD exacerbations at onset in thecommunity as commonly found in clinical practice before sec-ondary complications have occurred.

This study shows that COPD exacerbation may have im-portant effects on health status and is a useful outcome mea-sure in clinical studies of the disease. Reduction of exacerba-tion frequency would be expected to improve well-being, thoughthis has not been formally tested in an interventional study.Health status measures show a strong relationship with exac-erbation frequency and thus may be useful in determining whichpatients are at risk of exacerbation and associated disability.Earlier identification of patients at particular risk may consid-erably reduce the morbidity and mortality from complicationsassociated with COPD exacerbations.

Acknowledgment : The writers thank Claire Evans for help in data collec-tion, and the staff of the Respiratory Function unit of the London ChestHospital for assistance with physiological measurements.

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