Abstract
Treatment of chronic obstructive pulmonary disease (COPD) exacerbations improves outcomes; however, responses to treatment are variable, and patients with COPD often delay presentation or fail to seek therapy. The impact on exacerbation outcomes, hospitalization, and health status of delaying or failing to seek treatment is poorly understood. We studied between 1996 and 2002 a cohort of 128 patients with COPD, mean (SD) FEV1 of 1.07 (0.43) L. Patients recorded respiratory symptoms daily and reported exacerbations to the outpatient-based study team or to their primary care physician; 1,099 exacerbations were recorded by the patients, of which 658 were reported to a physician. The time between exacerbation onset and treatment was a median (interquartile range) of 3.69 (2.0–5.57) days, and the exacerbation recovery time was 10.7 (7.0–14.0) days. Earlier treatment was associated with a faster recovery (regression coefficient 0.42 days/day delay) (confidence interval, 0.19–0.65; p < 0.001). Patients who reported a higher proportion of exacerbations for treatment had better health-related quality of life than those patients with more untreated exacerbations (rho = −0.22, p = 0.018). Failure to report exacerbations was associated with an increased risk of emergency hospitalization (rho = 0.21, p = 0.04). Patient recognition of exacerbation symptoms and prompt treatment improves exacerbation recovery, reduces risks of hospitalization, and is associated with a better health-related quality of life.
Chronic obstructive pulmonary disease (COPD) is characterized by acceleration in the normal decline in lung function with age and by exacerbations. These exacerbations are associated with both worsening symptoms and lung function (1). The frequency of exacerbations has been shown to be an important determinant of the impaired health-related quality of life seen in COPD (2) and to affect decline in lung function (3, 4). Exacerbations are a frequent cause of physician consultation in primary and secondary care and a major cause of hospital admission (5–7). Consequently, the management of exacerbations places a considerable burden on the health services both in terms of physician consultation time and healthcare costs (8–10). A reduction in exacerbation frequency would have a number of benefits for patients and health services alike; however, currently available preventative therapies have been found to have only a relatively small effect (11–13).
Current therapies for exacerbations include antibiotics, oral corticosteroids, and increased bronchodilator medications. Although there is evidence that antibiotics (14) and corticosteroids (15–18) hasten the rate of recovery of certain exacerbations, there are few data in the literature on the effects or importance of the timing of initiation of exacerbation treatment on outcome measures such as recovery time, which relates to exacerbation severity (1, 19). We hypothesize that early presentation of the patient to the physician with an exacerbation would allow early intervention and a reduction of exacerbation severity and would potentially reduce disease progression; however, patients with COPD often have poor understanding of their disease and symptoms, with the result that exacerbations are often not reported to healthcare professionals for treatment (2). Thus, if delay in presentation can be shown to affect exacerbation recovery, this provides a potentially important issue that can be addressed in the management of patients with COPD.
In this study, we have followed prospectively 128 well-characterized patients with moderate to severe COPD over 6 years from November 1996 and collected daily symptoms and exacerbation treatment data on 1,099 exacerbations. This daily monitoring enabled us to investigate how exacerbation outcomes and markers of severity such as recovery time were affected by the timing of presentation to the physician for treatment. We also studied how patient and exacerbation characteristics influenced the patterns of healthcare use and outcomes of therapy. Some of the results of these studies have been previously reported in the form of abstracts (20, 21).
This study was conducted between November 1996 and October 2002. One hundred twenty-eight patients with COPD recruited during this period, who had recorded daily data for 1 year or more, were included in the analysis. Ethics approval was obtained from the East London and City Health Authority Research Ethics committee, and all patients provided written informed consent before recruitment. The inclusion criteria for this study have previously been published (1–3, 22–24) and include FEV1 of less than 70% predicted for age and height, β2 agonist reversibility of less than 15% of baseline and/or less than 200 ml, and an FEV1/FVC of less than 70%. This patient cohort has been the subject of previous articles on various aspects of COPD exacerbations (1–3, 22–24).
At recruitment, measurements were made of FEV1, FVC, and PEF by rolling seal spirometer (Sensor Medic Corp., Yorba Linda, CA), reversibility to 400 μg of inhaled salbutamol, and arterialized ear lobe blood gases (model 278 Blood Gas Analyzer; Ciba-Corning, Medfield, MA). A history was taken of smoking habits (years of smoking, cigarettes smoked per day, current smoking status). Patients gave a history of smoking (mean [SD] duration of 46.6 [31.4] pack-years, with 42 active smokers). Patients were asked about their stable respiratory symptoms and also about their long-term inhaled and oral corticosteroid use.
At recruitment, patients were taught how to record on diary cards each morning, postbronchodilator PEF (Mini-Wright Clement Clark International Ltd., Harlow, UK). Patients recorded a change in their symptoms using a letter-annotated system. When well or stable, the patients were instructed not to record any of the symptom letters on the diary. When they perceived an increase over their normal, stable condition in symptoms dyspnea, sputum purulence or sputum volume (major symptoms), and colds (nasal discharge/congestion), wheeze, sore throat, cough (minor symptoms), they noted the corresponding symptom letter on the diary. Therefore, patients record symptom letters if a symptom was perceived as worse, for example, dyspnea or of new onset (e.g., a sore throat) (as the latter is not usually present).
The validated diagnostic criteria of the presence of at least two major or one major and one minor symptom for at least 2 days were then used in the analysis of diary card records. This method is explained more fully in the Methods section of the online supplement.
Patients were reviewed every 3 months in the study clinic when stable to monitor compliance with data collection, record changes in medication, and baseline lung function.
Indices of Health-Related Quality of Life were obtained using the St. George's Respiratory Questionnaire (SGRQ) at the beginning of the study either at recruitment or during the first annual review (25).
The diagnosis of an exacerbation was based on symptomatic criteria previously validated by our group (1, 2). An exacerbation was defined as the presence for at least 2 consecutive days of increase in any two “major” symptoms (dyspnea, sputum purulence, sputum amount) or increase in one “major” and one “minor” symptom (wheeze, sore throat, cough, symptoms of a common cold). Exacerbation onset was taken as the first day on which these symptom criteria were met (1). Figure 1
From the diary card data and treatment records, the time between exacerbation onset and physician consultation at which treatment was initiated was calculated and called the treatment delay.
A total daily count of individual symptoms recorded on diary cards was calculated as the sum of the seven symptoms with the presence of a symptom scored 1 and its absence 0.
To determine recovery to baseline levels and therefore exacerbation recovery time, a diary card symptom baseline was determined from the diary card for each exacerbation. The baseline symptom count was taken as the mean total daily symptom count over days 14 to 8 preceding exacerbation onset. Exacerbation total recovery time was calculated as the time from exacerbation onset for a 3-day moving average of the total daily symptom count to return to this baseline. The use of a 3-day moving average minimized the effect of day-to-day symptom variation without biasing the results. Treated recovery time was taken as the time between consultation and recovery.
Symptom severity at exacerbation was calculated as the difference between the average daily symptom count at baseline (Days 14 to 8 preceding the exacerbation onset) and the number of symptoms at exacerbation onset. Individual symptoms themselves were recorded as increased (1) or not (0) (see the online supplement for further explanation).
Patients were encouraged to report symptom changes to the study team. They were assessed within 24 hours in the study clinic by a respiratory physician before initiation of therapy for the exacerbation. Patients did not report all symptom changes to the study team but also reported a number of these episodes to their primary care physician for assessment and treatment. The prescription of treatment for all exacerbations was at the discretion of the attending physician and included prednisolone and/or antibiotic therapy. Exacerbation treatment in the study therefore represented the usual practice of the primary care or study physician attending the patient. Records were kept of the date of initiation and type of treatment prescribed to patients for each exacerbation, both at our clinic and also for therapy prescribed by the patient's primary care physician.
The exacerbations seen by the study clinical team or the patient's general practitioner were classified as “physician reported exacerbations” with those unseen by either but recorded on diary cards termed “unreported exacerbations.” Records of hospitalization were kept throughout the study. Additional detail on the diagnosis of exacerbations is available in the online supplement.
Normally distributed data are presented as mean (SD) and skewed data as median (interquartile range) values and associations tested by Spearman's correlation or chi-squared test. A p value of less than 0.05 was considered statistically significant.
Exacerbation total recovery time was calculated as the time from exacerbation onset for a 3-day moving average of the total daily symptom count to return to baseline (1). Treated recovery time was taken as the time between consultation and recovery. Symptom severity at exacerbation was calculated as the difference in total daily symptom count at baseline and at exacerbation onset. Figure 1 illustrates a diagrammatic timeline of an exacerbation with a definition of terms used.
Assessment of the effect of delay and treatment on recovery with or without allowance for severity, type of treatment, or nonrecovery was made with a generalized linear model with adjustments for Poisson distribution in the dependent variable. Additional detail on the method for making these measurements is provided in the online supplement.
The physiologic characteristics of the 128 (88 male) patients at recruitment for the study are summarized in Table 1
Age, yr | 67.3 (7.6) |
|---|---|
| FEV1, L | 1.07 (0.43) |
| FEV1% predicted | 40.8 (15.6) |
| FVC, L | 2.51 (0.81) |
| FEV1/FVC % | 43.50 (0.13) |
| PEF, L/min | 191 (88) |
| PaO2, kPa | 8.93 (1.00) |
| PaCO2, kPa | 5.89 (0.89) |
| Number of active smokers | 42 |
| Pack years of smoking | 46.6 (31.4) |
| Inhaled steroid dosage, mg/day | 1.21 (0.68) |
During the study, the patients experienced a total of 1,099 exacerbations. Of this total, 658 (59.9%) were reported to a physician, either a primary care physician or the study team. The median (interquartile range) number of exacerbations per patient per year was 2.51 (1.41 to 3.75) for all 128 patients. Eight patients had no exacerbations. Of the 1,099 exacerbations, 441 (40.1%) were diagnosed solely from review of diary card symptoms and were not seen by a physician. These unreported exacerbations were only considered in the analysis of hospitalization and Indices of Health-Related Quality of Life with respect to reporting. The 658 remaining exacerbations were all seen by physicians; however, of these, 17 (2.6%) exacerbations received no additional treatment, and 16 (2.4%) involved physician consultation in the prodromal period before formal exacerbation onset, as defined by the diagnostic criteria. These 33 exacerbations were excluded, leaving 625 that were analyzed for the effects of physician reporting and treatment on recovery. A summary of reporting and treatment measures is illustrated in Figure 2
Figure 2. Reporting and treatment characteristics of 1,099 exacerbations recorded in this study.
[More] [Minimize]Increased dyspnea was present in 63.7% of the 1,099 exacerbations, increased sputum purulence in 26.6%, increased sputum volume in 41.3%, cold symptoms in 29.1%, increased wheeze in 31.7%, sore throat in 13.0%, and increased cough in 30.7%.
Figure 2 shows the reporting and treatment characteristics of the exacerbations recorded in the study. Of the 625 exacerbations that were treated with prescribed oral therapy, a total of 266 exacerbations were treated with oral corticosteroids. Six hundred of the exacerbations were treated with antibiotics, and of these, 241 were treated with both oral corticosteroids and antibiotics. As 93.6% of exacerbations were treated with antibiotics, this precludes a meaningful statistical analysis of the effect of antibiotic therapy on exacerbation outcomes, as the nontreated group is too small. Oral prednisolone therapy hastened treated recovery by 2.63 days (p = 0.001) compared with exacerbations not treated with prednisolone.
The median (interquartile range) treatment delay (time from the onset of exacerbation to the initiation of treatment) was 3.69 (2.00 to 5.57) days. The median exacerbation total recovery time was 10.7 (7.0 to 14.0) days. The median treated recovery time (time between the start of treatment to symptom recovery) was 6.9 (3.0 to 10.5) days. Figure 3
Figure 3. Effect of early treatment on recovery of exacerbation symptoms. Patient mean total recovery time (days) plotted against the patient mean treatment delay (i.e., time from onset of exacerbation symptoms to initiation of therapy) (days) in 108 patients (regression coefficient 0.42 day/day delay; confidence interval, 0.19 to 0.65; p < 0.001).
[More] [Minimize]The benefits of early physician consultation and treatment on exacerbation recovery time were potentially confounded by the fact that patients with more severe symptoms had longer exacerbations (2.68 days per symptom, 2.06 to 3.31, p < 0.001) and also tended to report earlier (−0.28 days per symptom, −0.66 to 0.10, p = 0.15). After an adjustment for symptom severity by its inclusion in the regression model, the relationship between early treatment and faster recovery became more pronounced (0.52 days/day delay, 0.31 to 0.74, p < 0.001). Treatment with oral corticosteroids could also confound the relationship if exacerbations reported earlier were preferentially treated with oral corticosteroids; however, the relationship between recovery time and treatment delay remained significant if allowance was made for both symptom severity and the treatment with oral corticosteroids (0.57 days/day delay, 0.34 to 0.79, p < 0.001).
An analysis of patient characteristics with respect to mean treatment delay for each patient revealed that older patients received treatment earlier (rho = −0.19, p = 0.04); however, there were no observed significant relationships between treatment delay and baseline FEV1 (rho = 0.19, p = 0.11), percentage predicted FEV1 (rho = 0.11, p = 0.25), SGRQ total score (rho = −0.12, p = 0.21), active smoking status (rho = 0.03, p = 0.72), or baseline symptoms such as daily sputum production (rho = −0.16, p = 0.08) or dyspnea (rho = 0.11, p = 0.24).
Symptom | Regression Coefficient (days) (95% CI) | p Value |
|---|---|---|
| Dyspnea | −0.42 (−0.76 to −0.08) | 0.016 |
| Sputum purulence | −1.26 (−1.60 to −0.92) | 0.001 |
| Wheeze | −0.59 (−0.93 to −0.25) | 0.001 |
| Sore throat | −0.78 (−1.23 to −0.33) | 0.001 |
| Cold | 0.31 (−0.05 to 0.67) | 0.093 |
| Sputum volume | 0.02 (−0.31 to 0.34) | 0.924 |
| Cough | 0.01 (−0.34 to 0.37) | 0.945 |
Patients in the study could consult either the study team or their own primary care physician at exacerbation; 37.6% of the physician-treated exacerbations were seen by a general practitioner, and 62.4% were seen by a member of the study team. Prescribing practices at exacerbation were very similar irrespective of where the consultation took place, with the primary care physician prescribing oral corticosteroids in 43.8% and antibiotics in 96.2% of treated exacerbations and the study team in 41.8% (chi-squared, p = 0.618) and 95.9% (p = 0.868), respectively.
The time to physician consultation was earlier in the primary care physician-treated group by 0.36 days (−0.69 to −0.04, p = 0.030); however, when an adjustment for symptom severity was made, no significant differences in timing of consultation were found. Despite similar prescribing practices, patients reviewed by a respiratory specialist in the study team had a shorter recovery time than those seen in general practice (0.82 days, p = 0.047).
Not all of the exacerbations experienced by a patient were reported to a physician for treatment. The median (interquartile range) percentage of physician-reported exacerbations for the 120 patients with an exacerbation was 66.7% (50 to 83.3%). Stable SGRQ scores were recorded on 118 of these 120 patients. Figure 4
Figure 4. Relationship between total and component St. George's Respiratory Questionnaire (SGRQ) scores (higher scores represent poorer health-related quality of life) and percentage of recorded exacerbations (in quartile groups) that were reported to and treated by a physician. The rho and p values from Spearman's Rank correlations of total and component SGRQ scores with proportion of exacerbations treated on a per patient basis are (a) total SGRQ score, rho = −0.22, p = 0.018; (b) impact score, rho = −0.19, p = 0.04; (c) activity score, rho = −0.21, p = 0.02; (d) symptoms score, rho = −0.13, p = 0.16. The bars represent SEs.
[More] [Minimize]During the study, 6.4% of the 1,099 exacerbations required hospitalization. The median annual unreported exacerbation rate was 0.77 per year (0.33 to 1.60) for the 120 patients who had at least one. The annual rate for physician-reported but not hospitalized exacerbations was 1.53 per year (0.86 to 2.37), and for hospitalized exacerbations the median rate was 0 per year (0 to 0.40).
Of the 120 patients, those who tended not to seek treatment from their general practitioner or the study clinicians at exacerbation (as measured by high annual rates of unreported exacerbations) were more likely to be admitted to the hospital for treatment of an exacerbation than those who routinely reported their exacerbations for treatment (rho = 0.21, p = 0.04).
This is the first prospective study to demonstrate the important effects of early treatment on COPD exacerbation outcomes. The findings show that patients who receive prompt therapy after the onset of their exacerbation are likely to recover more rapidly than those who delay reporting and thus initiation of treatment. Furthermore, patients who habitually fail to seek therapy for their exacerbations have poorer health-related quality of life and are more likely to be hospitalized for the management of an exacerbation.
This study has been performed using well characterized patients collecting daily data over a number of years and has used a symptom-based definition of exacerbations that is well validated (1–3, 22–24). The collection of such prospective data allowed us to establish precisely the start of the exacerbation from the diary card entries and then the point at which therapy is commenced, in addition to in-depth analysis of the time course and recovery time of the exacerbations. Our group and others have previously demonstrated that the recovery time of an exacerbation is an important measure of its severity and can be affected by various etiologic factors such as respiratory viruses (22, 26, 27) and therapies (14–18). The delay between symptom onset and therapy and its effect on exacerbation outcomes has not been studied previously, as most studies evaluating exacerbations have focused on healthcare use and therefore have missed the period between symptom onset and the initiation of therapy. The finding that earlier treatment improves exacerbation recovery has confirmed for the first time the clinical suspicion that treating these episodes promptly offers additional benefit to the patient. It is also the first to establish the size of this effect and the role that improving exacerbation reporting behavior may play in reducing morbidity.
A possible alternative interpretation of this finding would be that patients with milder exacerbations seek treatment earlier and thus recover more quickly; however, the data on the nature of symptoms at presentation demonstrate that this was not the case. Patients with more symptoms at exacerbation onset tended to present earlier for treatment, and those exacerbations with more symptoms were indeed more severe, as they took longer to recover. Therefore, the milder and less symptomatic exacerbations were in fact presenting slightly later, and when this effect is taken into account, the benefit of early treatment became more pronounced.
In this study, we have studied exacerbations across a spectrum of exacerbation severities and not only those more severe exacerbations requiring hospitalization. The patients in this study were treated either by the dedicated study team or by their primary care physician, and the exacerbation treatment reflected prescribing practices of both physician groups, which were very similar, as reflected by similar exacerbation recovery times for both treatment groups. In the linear regression model of the effects of treatment delay on recovery time, allowance was made for the exacerbation treatment prescribed. A potential bias of variation in oral antibiotic therapy was not apparent, as over 93% of treated exacerbations received this form of therapy. The effect of oral prednisolone prescription was to shorten exacerbations; if the prescription of this treatment was included in the regression model, the key finding that early treatment hastens recovery time became more pronounced.
These reported exacerbations that received treatment are in keeping with another definition of exacerbations recently suggested (28). Therefore, the findings of this study may be generalized to the COPD population treated both in primary and secondary care, and the validated methods used are suitable for future investigation into the relationships between reporting behavior and exacerbation outcomes.
Exacerbations are heterogeneous in etiology and in the nature of presenting symptoms (22, 29). The symptom characteristics of an exacerbation affected presentation of the exacerbation to the physician. Symptoms of increased dyspnea, sputum purulence, wheeze, and sore throat were associated with earlier presentation, whereas the presence of a common cold at exacerbations was associated with a trend toward later presentation. The factors affecting how patients with COPD interpret changes in their symptoms are likely to be complex, including their understanding of COPD, which is often poor (30), the relationship with disease severity, and psychologic overlay in a group of patients with high levels of anxiety and depression (31). Further studies into the mechanisms of symptom recognition are required to determine how to improve the reporting behavior of patients with COPD and therefore exacerbation outcomes. These may include investigation of the role of patient education, self-management plans, and methods of assessing and improving compliance.
An additional advantage of collecting daily prospective data on symptom changes is that episodes when patients experience an exacerbation and record their symptoms but do not consult their general practitioner or a study physician can be analyzed. In this study of 1,099 exacerbations recorded on diary cards, only 658 were reported to a physician for treatment, and these rates are in keeping with published clinical trials (13). The finding that on an annual basis patients who are less likely to report their exacerbations are more likely to undergo emergency hospital admission for treatment is an important one. These patients may be less aware of the importance of the changes in their symptoms at exacerbation, or indeed, they may subjectively experience less severe symptoms for a given severity of exacerbation. Thus, they are less likely to seek treatment from a physician in the early stages of their exacerbation, which may prevent the need for hospitalization. Furthermore, we found that patients who had a lower proportion of their exacerbations treated had worse health-related quality of life, as measured by the SGRQ total score, impact score, and activity score, than those patients who sought treatment for a higher proportion of exacerbations. We can postulate that failure to report and therefore receive treatment for exacerbations contributes to additional morbidity from these events and thus adversely affects health-related quality of life. However, it may also be the case that patients with poor health-related quality of life are less likely to seek physician intervention for their exacerbation, and thus, a cycle of decline in quality of life and appropriate healthcare use may become established. Identification and education of the patient group who delay or fail to seek treatment for exacerbations in particular may increase and improve the rate and timing of physician consultation reduce patient morbidity and the considerable burden of inpatient treatment of exacerbations on healthcare services.
Analysis of factors that affected time to presentation of an exacerbation showed that older patients were likely to receive therapy earlier, but there was no relationship between disease severity, baseline symptoms, or the patient's health status. Adequate access to healthcare is important, and the affect of age on presentation in our study suggests that the older patients are receiving medical attention for exacerbations earlier than the younger patients in the group. This finding may be related to the higher degree of disability and comorbidity in the older population (32), causing them to recognize and report symptoms at an earlier stage.
This study has been performed in a population of patients with COPD who were encouraged to report exacerbations, who were likely to have heightened awareness of changes in their symptoms because of the use of daily diary cards, and who had improved access to healthcare. Therefore, the findings of this study that early treatment of COPD exacerbations hasten recovery time and that patients who do not report to a physician are more likely to be hospitalized may be an underestimation of the scale of these effects in the general population of patients with COPD. Indeed, patients with COPD often have a poor understanding of their disease (30) and often delay or fail to report symptom changes to their physician. To date, there have been no significant initiatives to encourage reporting and early presentation of exacerbations in this patient group.
This study has demonstrated the important finding that the early recognition of exacerbation symptoms and prompt treatment by a physician is beneficial to the recovery of the exacerbation. This result suggests that improving patient and physician understanding of the nature of exacerbations and the benefits of early treatment will improve the outcomes of therapy of exacerbations of this extremely prevalent disease. There is a vital role for new, more efficacious treatments for COPD exacerbations. However, by optimizing the use of existing exacerbation therapies and by improving patients' awareness of exacerbations and access to healthcare, we can improve the current excessive burden of exacerbation-related morbidity and mortality.
The authors thank Dr. Simon Lloyd-Owen, Dr. Irem Patel, Dr. Angshu Bhowmik, Dr. Simon Leedham, and Dr. Mark Rowland for their help in data collection.
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