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Influence of Season on Exacerbation Characteristics in Patients With COPD
CHEST
Original Research COPD
Influence of Season on Exacerbation Characteristics in Patients With COPD Gavin C. Donaldson, PhD; James J. Goldring, MBBS; and Jadwiga A. Wedzicha, MD
Background: Patients with COPD experience more frequent exacerbations in the winter. However, little is known about the impact of the seasons on exacerbation characteristics. Methods: Between November 1, 1995, and November 1, 2009, 307 patients in the London COPD cohort (196 men; age, mean, 68.1 years [SD, 8.4]; FEV1, mean, 1.12 L [SD, 0.46]; FEV1, mean, % predicted, 44.4% [SD, 16.1]) recorded their increase in daily symptoms and time outdoors for a median of 1,021 days (interquartile range [IQR], 631-1,576). Exacerbation was identified as ⱖ 2 consecutive days with an increase in two different symptoms. Results: There were 1,052 exacerbations in the cold seasons (November to February), of which 42.5% and 50.6% were patients who had coryzal and cough symptoms, respectively, compared with 676 exacerbations in the warm seasons (May to August), of which 31.4% and 45.4% were in patients who had coryzal and cough symptoms, respectively (P , .05). The exacerbation recovery period was longer in the cold seasons (10 days; IQR, 6-19) compared with the warm seasons (9 days; IQR, 5-16; P , .005). The decrease in outdoor activity during exacerbation, relative to a pre-exacerbation period (214 to 28 days), was greater in the cold seasons (20.50 h/d; IQR, 21.1 to 0) than in the warm seasons (20.26 h/d; IQR, 20.88 to 0.18; P 5 .048). In the cold seasons, 8.4% of exacerbations resulted in patients who were hospitalized, compared with 4.6% of exacerbations in the warm seasons (P 5 .005). Conclusions: Exacerbations are more severe between November and February. This contributes to the increased morbidity during the winter seasons. CHEST 2012; 141(1):94–100 Abbreviations: IQR 5 interquartile range
is a major cause of morbidity and mortality COPD and is predicted to become the third-leading
cause of death worldwide by 2020.1 Most contacts with health-care professionals for COPD are for acute episodes of worsening symptoms that may warrant treatment and are termed exacerbations. Frequent exacerbations result in poorer quality of life,2
Manuscript received February 22, 2011; revision accepted June 2, 2011. Affiliations: From the Academic Unit of Respiratory Medicine, UCL Medical School, Royal Free Campus, London, England. Funding/Support: The London COPD cohort is funded by the Medical Research Council, United Kingdom [Grant MRC G0800570]. Correspondence to: Gavin C. Donaldson, PhD, Academic Unit of Respiratory Medicine, UCL Medical School, Royal Free Campus, Rowland Hill St, Hampstead, London, NW3 2PF, England; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.11-0281
faster decline in lung function,3 and increased mortality.4 The trigger for a large proportion of exacerbations is infection with a respiratory virus, particularly with human rhinovirus, the cause of the common cold.5 Respiratory viruses are more prevalent in the winter of temperate countries.6-8 There are also many more deaths, hospital admissions, and general practitioner consultations for COPD in winter,9,10 along with poorer health-related quality of life11 and worse anxiety and depression scores.12 This increase in mortality and morbidity places a heavy burden on health and care services in winter. Exacerbations are more frequent in the winter, but it is not known whether their severity is worse. In this study, we examine whether symptom composition, symptom duration (recovery), hospitalization rates, and impact on outdoor activity vary between warm and cold seasons. A greater understanding of the nature of winter exacerbations could help reduce
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hospital admissions and inform preventative strategies. The information could be also important for the design, analysis, and interpretation of data from interventional clinical trials, and relevant to the evaluation of COPD admission health forecasting and alert services.13 Some of the results of these studies have been previously reported in the form of an abstract at the 2009 European Respiratory Society meeting in Vienna, Austria.14 Materials and Methods Patients This study involved 307 patients with COPD enrolled in the London COPD cohort and included their contributing data from at least 1 year between November 1, 1995, and November 1, 2009. The patients and exacerbations have been the subject of previous publications, but the current analysis and its interpretation are, to our knowledge, completely novel. COPD was defined as an FEV1 , 80%, predicted from age, height, and sex, and FEV1/FVC , 70%. Patients with significant respiratory disease other than COPD, such as bronchiectasis, were excluded. The study had ethics approval from the Royal Free Hospital National Health Service Trust (09/H0720/8), and patients provided written informed consent. Recruitment At recruitment, a history was taken of smoking habits (pack years of smoking and current smoking status), and patients were asked if they produced sputum for . 3 months per year. Measurements were made of FEV1 and FVC using a routinely calibrated rolling seal spirometer (Sensor Medics Corp) or volumetric storage spirometer (Vitalograph 2160; Maids Moreton). Monitoring and Diagnosis of Exacerbation Patients were instructed to record each morning on daily diary cards any increase over normal levels in their respiratory symptoms. Major symptoms were dyspnea, sputum purulence, or sputum volume, and minor symptoms were coryza (nasal discharge/congestion), wheeze, sore throat, and cough. From March 1996, the patients also recorded hours spent outside the home. Onset of exacerbation was identified as the first of ⱖ 2 consecutive days with an increase in either two major symptoms or one major and one minor symptom.2,15 Exacerbations were treated according to the prevailing guidelines and clinical judgment, and records were kept of whether the exacerbation involved admission to the hospital. Treatment delay was defined as the time between exacerbation onset and physician consultation,16 and hospital delay as the time between onset and admission. Exacerbation Recovery, Frequency, and Symptoms Exacerbation recovery was defined as the number of days after onset that symptoms persisted. If no symptoms were recorded on a single day but the day with no symptoms was bracketed by days when symptoms were present, the exacerbation was considered to be continuing throughout.17 Thus, 2 symptom-free days defined the end of the exacerbation. To examine whether prolonged exacerbation recovery was due only to prolonged minor symptoms, recovery was additionally defined as the duration for which major symptoms were present. The maximum duration of an exacerbation was capped at 100 days. www.chestpubs.org
The annual exacerbation frequency was calculated by dividing the number of exacerbations by the years of diary card data available. Exacerbation symptoms were defined as being recorded on at least 1 day during exacerbation recovery, and stable symptoms were defined as occurring outside of these intervals. To examine whether patients experienced a greater burden from exacerbations in winter, we also calculated the number of exacerbation days as the product of the number of exacerbations and the average length of exacerbation. Temperature Data Hourly readings were averaged to provide daily mean temperatures at Heathrow Airport, London, England. These readings were provided by the Meteorological Office and supplied through the British Atmospheric Data Centre. Statistical Analysis Data were analyzed using STATA 8.2 software (StataCorp). Normally distributed data were expressed as mean and SD, and skewed data as median and interquartile range (IQR). Random effects cross-sectional regression models for Poisson or binomial distributed dependent variables were used to assess their relationship to temperature on the day of exacerbation onset. These models allowed for repeated measures on the same patient. Illustrative plots were drawn by averaging in 1°C temperature intervals. Differences between a 4-month cold season (NovemberFebruary) and a 4-month warm season (May-August) were examined using a x2 test, and differences in exacerbation recovery were examined using a Wilcoxon sign-ranked test. Seasonal changes in symptoms were calculated using the following formula: (cold season prevalence 2 warm season prevalence)/warm season prevalence 3 100. A 4-month period was chosen to ensure capture in the variable British climate of the coldest and warmest periods of each year. Change in outdoor activity at exacerbation was calculated as the average time spent outdoors during recovery minus the average time spent outdoors on days 14 to 8 before each exacerbation started. The average for the exacerbations taking place in the cold and warm seasons was then calculated for each patient and compared using a paired t test.
Results Table 1 shows the patient characteristics of the 307 patients with COPD. There were 100 (32.9%) active smokers at recruitment; 303 had a history of smoking, with a mean consumption of 50.5 pack years (SD, 35.9). Also, 262 patients (86.5%) were taking a median dose of 1,000 mg of beclomethasone equivalents (IQR, 500-1,000) of inhaled steroids; 41 patients (13.3%) were not taking inhaled steroids, and the dosage was unknown for four patients. The patients recorded diary card data for 1,037 patient years and experienced 2,606 exacerbations, a median of 2.13 per patient per year (IQR, 0.94-3.32). Of these, 676 exacerbations were experienced by 212 patients in the warm seasons, and 1,052 exacerbations by 251 patients in the cold seasons: 197 patients experienced exacerbations in both seasons, and outside of the two seasons, 878 exacerbations were experienced. CHEST / 141 / 1 / JANUARY, 2012
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Table 1—Characteristics of the 307 Patients Characteristic
Value
Age, y FEV1, L FEV1, % predicted FVC, L FEV1/FVC Smoking, pack y Time in study, median, (IQR), d Exacerbations, median, (IQR), No. Exacerbations per year Male, No. (%) Chronic sputum, No. (%) Current smoking, No. (%)
68.1 (8.4) 1.12 (0.46) 44.4 (16.1) 2.51 (0.83) 0.45 (0.12) 50.5 (35.9) 1,021 (631-1,576) 6 (2-12) 2.13 (0.94-3.32) 196 (63.8) 158 (51.6) 100 (32.9)
Data are given as mean (SD) unless otherwise indicated. Smoking history missing for four patients at recruitment. IQR 5 interquartile range.
There was no difference in the proportion of exacerbations treated at our clinic or by the patient’s primary care practitioner to untreated exacerbations in the cold seasons (661 of 966 [68.4%]; P 5 .318) compared with the warm seasons (416 of 630 [66.0%]). There was also no difference in antibiotic use, with 607 of 966 exacerbations (62.8%) treated in the cold seasons vs 370 of 630 exacerbations (58.7%; P 5 .100) in the warm seasons, or in oral steroids use, with 414 of 966 exacerbations (42.9%) treated in the cold seasons compared with 268 of 630 exacerbations (42.5%; P 5 .900) in the warm seasons. There were fewer exacerbations involved in this analysis of therapy because treatment was not recorded during the first year of the study. Symptoms
Patients were under observation in summer for a median 352 days (IQR, 224-523) and in winter for a median 338 days (IQR, 222-525). There were 55.6% more exacerbations in the cold seasons compared with the warm seasons. The average temperature in the warm seasons was 16.7°C (range, 6.4 to 28.2), and in the cold seasons, 6.6°C (range, 23.5 to 15.6). Exacerbation Recovery and Temperature The median recovery time from all symptoms in the warm seasons was shorter at 9 days (IQR, 5-16; n 5 595) compared with 10 days in the cold seasons (IQR, 6-19; n 5 892; P 5 .005). Similarly, with the alternative definition of recovery in terms of just major symptoms, recovery was shorter at 7 days (IQR, 4-13) in the warm seasons compared with 9 days (IQR, 5-16; P 5 .0005) in the cold seasons. Recovery times were undeterminable for 81 exacerbations (12.0%) in the warm seasons and 160 exacerbations (15.2%) in the cold seasons (P 5 .06). The number of exacerbation days was significantly higher in the winter at 26 days (IQR, 2-70) compared with 11 days (IQR, 0-42) in the summer (P , .001). Cross-sectional Poisson regression models, which allowed for repeated measures on the same patient, showed that exacerbation recovery for all seven symptoms took longer as temperatures on the day of exacerbation onset fell. The exponentiated coefficient was 0.996 (95% CI, 0.994-0.998; P , .001) (Fig 1). The treatment delay between onset and physician consultation averaged 3 days (IQR, 2-5). There was no difference in treatment delay between the cold seasons at 3 days (IQR, 2-5) and the warm seasons at 3 days (IQR, 2-5; P 5 .667). There was also no relationship over the whole year between delay in treatment and temperature on the day of exacerbation onset (P 5 .723).
Table 2 gives the percentages for exacerbations with specific symptoms in the cold and warm seasons. It also shows the percentages for days in the cold and warm seasons in which specific symptoms were recorded when the patient was stable. During periods of exacerbation, coryzal and cough symptoms were significantly more likely in the cold seasons (P , .001), with a seasonal change of 35.3% and 11.5%, respectively. To illustrate these differences in symptom composition, Figure 2 shows the timecourse in the prevalence of dyspnea, coryzal, and cough symptoms for exacerbations in the cold and warm seasons. All stable-state respiratory symptoms, apart from dyspnea, were significantly higher in relative terms (P , .05) in the cold seasons compared with the warm seasons. However, the differences are small and unlikely to explain the longer recoveries in the cold seasons.
Figure 1. Average exacerbation recovery time, in days, from all symptoms at 1°C intervals of the average daily mean outdoor temperature. The line joins together the predicted values from the random effects Poisson regression model.
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Table 2—Exacerbation and Stable Symptoms in Cold and Warm Seasons Respiratory Symptom Exacerbations, d Dyspnea Sputum purulence, Sputum volume Coryza Wheeze Sore throat Cough Stable (outside exacerbation), d Dyspnea Sputum purulence Sputum volume Coryza Wheeze Sore throat Cough
Cold Season Warm Season P value 1,052 71.2 36.8 54.1 42.5 46.0 20.2 50.6 110,144 9.5 1.0 2.7 3.4 4.8 1.1 3.5
676 74.9 39.1 54.4 31.4 46.5 17.9 45.4 118,959 9.6 0.8 2.4 1.9 3.4 0.6 2.5
.096 .343 .887 , .001 .857 .247 .036 .403 , .001 , .001 , .001 , .001 , .001 , .001
P 5 .697) and 8 days (IQR, 5-16), respectively, or in the delay between exacerbation onset and hospitalization, 5 days (IQR, 3-9.5; P 5 .762) and 6 days (IQR, 2.5-17), respectively.
Discussion This study has shown that COPD exacerbations in colder periods of the year take longer to recover from and are more likely to involve cough or coryzal symptoms. We have also shown that exacerbations in the cold seasons have a greater impact on daily activity, with patients spending more time indoors and being more likely to be hospitalized. A possible explanation for our findings could be that a greater proportion of
Data are given as % of d unless otherwise indicated.
Outdoor Activity Throughout the year, patients changed their outdoor activities nonlinearly with temperature (Fig 3). Excluding periods of heat stress, when the average daytime and nighttime temperature was . 20.5°C, fewer patients go out as temperatures get colder; the OR was 1.028 per 1°C rise (95% CI, 1.024-1.032). At , 2.5°C, there was a significantly faster reduction in the likelihood of patients going outdoors with temperature (P , .001), with the OR at 1.13 per 1°C rise (95% CI, 1.09-1.18; P , .001). During heat stress, as temperatures exceeded 20.5°C, patients also reduced outdoor activity, with an OR at 0.96 per °C (95% CI, 0.93-0.999; P 5 .044). Because outdoor activity varied markedly with temperature, calculations of the effects of exacerbations on outdoor activity were made relative to a baseline (14-8 days) prior to exacerbation onset. Patients in the warm seasons were more active during exacerbation recovery and had a smaller reduction in the time spent outside, 20.26 h/d (IQR, 20.88 to 0.18), compared with 20.50 h/d (IQR, 21.1 to 0.0) in the cold seasons (Wilcoxon signed rank test; P 5 .048). Hospitalization In the cold seasons, there was a significant increase in the proportion of exacerbations requiring hospitalization; 88 of 1,052 exacerbations (8.4%) resulted in patients being hospitalized in the cold seasons compared with 31 of 676 exacerbations (4.6%) exacerbations in the warm seasons (P 5 .002). There was no difference between the cold and warm seasons in the length of the hospital stay, 11 days (IQR, 5-15.5; www.chestpubs.org
Figure 2. Time course of dyspnea, coryzal, and cough symptoms in the cold seasons (䊊) and warm seasons (䊉). CHEST / 141 / 1 / JANUARY, 2012
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Figure 3. Percentage of patients going outside the home against the daily mean temperature throughout the year. Points are at the center of each 1°C interval; vertical lines are at 2.5°C and 20.5°C.
exacerbations that require treatment in cold conditions are associated with respiratory viral infection. We have previously reported on the prevalence of symptomatic colds and higher exhaled nitric oxide levels in winter, which we attributed to a greater prevalence of respiratory viruses.18,19 Patients with COPD who are hospitalized are likely to have a respiratory virus,20 and we found that 8.4% of cold-period exacerbations required hospitalization, compared with 4.4% in the warm period. The proportion of untreated exacerbations was not affected by season, indicating that the increase in the proportion of exacerbations that resulted in patient hospitalization in the winter was due to a decrease in the proportion of exacerbations that received only drug treatment. There is also evidence that patients with COPD stay longer in the hospital in winter21; the patients spent 11 days in the hospital in the cold seasons, compared with 8 days in the warm seasons, but this did not achieve statistical significance. There was no seasonal difference in the time patients took to receive treatment, discounting the possibility that the longer exacerbation recoveries were due to a reluctance of patients to leave home on cold days, thereby delaying treatment, which can prolong exacerbation recovery.16 We found that the reductions in outdoor activity associated with exacerbation22 were greater in the cold seasons. This suggests that viral-associated exacerbations may have a greater impact on activity than exacerbations triggered by other causes. The clinical implications of these findings are that patients who suffer frequent respiratory virus infections may need to focus on maintaining activity, particularly in the winter, and may need to be enrolled as a priority into pulmonary rehabilitation programs targeted at patients with exacerbations.23 We also found that patients spend less time outdoors during very hot
weather, an adaptation to climate change that has been predicted24 but, to our knowledge, not previously substantiated. Outside of exacerbations when the patients were stable, daily respiratory symptoms were more common during the cold seasons than the warm seasons. These seasonal differences were small in absolute terms but large in relative terms and highly significant. Patients with chronic respiratory disease may report more symptoms during cold weather,25 but it is possible that there are more “subclinical” viral infections in cold seasons, a possibility consistent with the finding of airway viruses in patients who are stable.5,26 The strengths of this study are that we have examined data from a large group of patients with moderate to severe COPD who were observed over many winters. The symptomatic definition of exacerbation has been used by our group consistently for 15 years and validated against important outcome measures, including airway inflammation,27 lung function decline,3 and health status.2 The definition identifies mild (untreated) exacerbations because they are a clinically important feature of the disease28 and patients with a greater proportion of untreated exacerbations experience a poorer health-related quality of life.16,29 Exacerbation recovery was measured using prospectively collected daily data. Our simple comparison between two seasons was confirmed by a more sophisticated examination of the relationship with outdoor temperatures that allowed for repeated measures and more complex distributions in the data. The seasonal comparison did, however, include the effects of temperature and other seasonal influences such as hours of sunshine and relative humidity. There are also a number of limitations to this study. It was not feasible to sample and test the patients during each exacerbation for the presence of a respiratory virus. Temperature data from Heathrow Airport (London, England) will not match local temperatures where the patients live, but differences are likely to be small compared with the uncertainties of individual heat and cold exposures. We did not make any comparisons with the general population, but we have previously commented that the incidence of upper respiratory tract viral infections in the elderly community is similar to that experienced by the patients.30 In conclusion, in winter, patients with COPD have exacerbations that take longer to recover, they remain housebound for longer, and they are more likely to be admitted to the hospital. These findings may be explained by the greater prevalence of respiratory viral infections in winter. This has implications for winter health-care planning in hospitals, health economics, and the evaluation of healthforecasting services, such as those provided by the
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meteorologic office. It emphasizes the need for clinical trials to take place during both summer and winter so as to not overrepresent or underrepresent particular types of exacerbations. A more comprehensive understanding of exacerbations, particularly in winter, may lead to strategies to reduce their prevalence and burden.
9. 10.
11.
Acknowledgments Author contributions: Dr Donaldson: had the original idea for the study, did the statistical analysis, was involved in drafting and editing the manuscript prior to submission, and has seen and approved the final version of the manuscript. Dr Goldring: had the original idea for the study, was involved in drafting and editing the manuscript prior to submission, and has seen and approved the final version of the manuscript. Dr Wedzicha: had the original idea for the study, was involved in drafting and editing the manuscript prior to submission, and has seen and approved the final version of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript. Other contributions: We would like to thank all the patients with COPD in the London COPD cohort, who have contributed to collecting the data described in this study. We would also like to thank all the clinical fellows and nurses who have treated the patients in the cohort.
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Original Research COPD
Influence of Season on Exacerbation Characteristics in Patients With COPD Gavin C. Donaldson, PhD; James J. Goldring, MBBS; and Jadwiga A. Wedzicha, MD
Background: Patients with COPD experience more frequent exacerbations in the winter. However, little is known about the impact of the seasons on exacerbation characteristics. Methods: Between November 1, 1995, and November 1, 2009, 307 patients in the London COPD cohort (196 men; age, mean, 68.1 years [SD, 8.4]; FEV1, mean, 1.12 L [SD, 0.46]; FEV1, mean, % predicted, 44.4% [SD, 16.1]) recorded their increase in daily symptoms and time outdoors for a median of 1,021 days (interquartile range [IQR], 631-1,576). Exacerbation was identified as ⱖ 2 consecutive days with an increase in two different symptoms. Results: There were 1,052 exacerbations in the cold seasons (November to February), of which 42.5% and 50.6% were patients who had coryzal and cough symptoms, respectively, compared with 676 exacerbations in the warm seasons (May to August), of which 31.4% and 45.4% were in patients who had coryzal and cough symptoms, respectively (P , .05). The exacerbation recovery period was longer in the cold seasons (10 days; IQR, 6-19) compared with the warm seasons (9 days; IQR, 5-16; P , .005). The decrease in outdoor activity during exacerbation, relative to a pre-exacerbation period (214 to 28 days), was greater in the cold seasons (20.50 h/d; IQR, 21.1 to 0) than in the warm seasons (20.26 h/d; IQR, 20.88 to 0.18; P 5 .048). In the cold seasons, 8.4% of exacerbations resulted in patients who were hospitalized, compared with 4.6% of exacerbations in the warm seasons (P 5 .005). Conclusions: Exacerbations are more severe between November and February. This contributes to the increased morbidity during the winter seasons. CHEST 2012; 141(1):94–100 Abbreviations: IQR 5 interquartile range
is a major cause of morbidity and mortality COPD and is predicted to become the third-leading
cause of death worldwide by 2020.1 Most contacts with health-care professionals for COPD are for acute episodes of worsening symptoms that may warrant treatment and are termed exacerbations. Frequent exacerbations result in poorer quality of life,2
Manuscript received February 22, 2011; revision accepted June 2, 2011. Affiliations: From the Academic Unit of Respiratory Medicine, UCL Medical School, Royal Free Campus, London, England. Funding/Support: The London COPD cohort is funded by the Medical Research Council, United Kingdom [Grant MRC G0800570]. Correspondence to: Gavin C. Donaldson, PhD, Academic Unit of Respiratory Medicine, UCL Medical School, Royal Free Campus, Rowland Hill St, Hampstead, London, NW3 2PF, England; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.11-0281
faster decline in lung function,3 and increased mortality.4 The trigger for a large proportion of exacerbations is infection with a respiratory virus, particularly with human rhinovirus, the cause of the common cold.5 Respiratory viruses are more prevalent in the winter of temperate countries.6-8 There are also many more deaths, hospital admissions, and general practitioner consultations for COPD in winter,9,10 along with poorer health-related quality of life11 and worse anxiety and depression scores.12 This increase in mortality and morbidity places a heavy burden on health and care services in winter. Exacerbations are more frequent in the winter, but it is not known whether their severity is worse. In this study, we examine whether symptom composition, symptom duration (recovery), hospitalization rates, and impact on outdoor activity vary between warm and cold seasons. A greater understanding of the nature of winter exacerbations could help reduce
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hospital admissions and inform preventative strategies. The information could be also important for the design, analysis, and interpretation of data from interventional clinical trials, and relevant to the evaluation of COPD admission health forecasting and alert services.13 Some of the results of these studies have been previously reported in the form of an abstract at the 2009 European Respiratory Society meeting in Vienna, Austria.14 Materials and Methods Patients This study involved 307 patients with COPD enrolled in the London COPD cohort and included their contributing data from at least 1 year between November 1, 1995, and November 1, 2009. The patients and exacerbations have been the subject of previous publications, but the current analysis and its interpretation are, to our knowledge, completely novel. COPD was defined as an FEV1 , 80%, predicted from age, height, and sex, and FEV1/FVC , 70%. Patients with significant respiratory disease other than COPD, such as bronchiectasis, were excluded. The study had ethics approval from the Royal Free Hospital National Health Service Trust (09/H0720/8), and patients provided written informed consent. Recruitment At recruitment, a history was taken of smoking habits (pack years of smoking and current smoking status), and patients were asked if they produced sputum for . 3 months per year. Measurements were made of FEV1 and FVC using a routinely calibrated rolling seal spirometer (Sensor Medics Corp) or volumetric storage spirometer (Vitalograph 2160; Maids Moreton). Monitoring and Diagnosis of Exacerbation Patients were instructed to record each morning on daily diary cards any increase over normal levels in their respiratory symptoms. Major symptoms were dyspnea, sputum purulence, or sputum volume, and minor symptoms were coryza (nasal discharge/congestion), wheeze, sore throat, and cough. From March 1996, the patients also recorded hours spent outside the home. Onset of exacerbation was identified as the first of ⱖ 2 consecutive days with an increase in either two major symptoms or one major and one minor symptom.2,15 Exacerbations were treated according to the prevailing guidelines and clinical judgment, and records were kept of whether the exacerbation involved admission to the hospital. Treatment delay was defined as the time between exacerbation onset and physician consultation,16 and hospital delay as the time between onset and admission. Exacerbation Recovery, Frequency, and Symptoms Exacerbation recovery was defined as the number of days after onset that symptoms persisted. If no symptoms were recorded on a single day but the day with no symptoms was bracketed by days when symptoms were present, the exacerbation was considered to be continuing throughout.17 Thus, 2 symptom-free days defined the end of the exacerbation. To examine whether prolonged exacerbation recovery was due only to prolonged minor symptoms, recovery was additionally defined as the duration for which major symptoms were present. The maximum duration of an exacerbation was capped at 100 days. www.chestpubs.org
The annual exacerbation frequency was calculated by dividing the number of exacerbations by the years of diary card data available. Exacerbation symptoms were defined as being recorded on at least 1 day during exacerbation recovery, and stable symptoms were defined as occurring outside of these intervals. To examine whether patients experienced a greater burden from exacerbations in winter, we also calculated the number of exacerbation days as the product of the number of exacerbations and the average length of exacerbation. Temperature Data Hourly readings were averaged to provide daily mean temperatures at Heathrow Airport, London, England. These readings were provided by the Meteorological Office and supplied through the British Atmospheric Data Centre. Statistical Analysis Data were analyzed using STATA 8.2 software (StataCorp). Normally distributed data were expressed as mean and SD, and skewed data as median and interquartile range (IQR). Random effects cross-sectional regression models for Poisson or binomial distributed dependent variables were used to assess their relationship to temperature on the day of exacerbation onset. These models allowed for repeated measures on the same patient. Illustrative plots were drawn by averaging in 1°C temperature intervals. Differences between a 4-month cold season (NovemberFebruary) and a 4-month warm season (May-August) were examined using a x2 test, and differences in exacerbation recovery were examined using a Wilcoxon sign-ranked test. Seasonal changes in symptoms were calculated using the following formula: (cold season prevalence 2 warm season prevalence)/warm season prevalence 3 100. A 4-month period was chosen to ensure capture in the variable British climate of the coldest and warmest periods of each year. Change in outdoor activity at exacerbation was calculated as the average time spent outdoors during recovery minus the average time spent outdoors on days 14 to 8 before each exacerbation started. The average for the exacerbations taking place in the cold and warm seasons was then calculated for each patient and compared using a paired t test.
Results Table 1 shows the patient characteristics of the 307 patients with COPD. There were 100 (32.9%) active smokers at recruitment; 303 had a history of smoking, with a mean consumption of 50.5 pack years (SD, 35.9). Also, 262 patients (86.5%) were taking a median dose of 1,000 mg of beclomethasone equivalents (IQR, 500-1,000) of inhaled steroids; 41 patients (13.3%) were not taking inhaled steroids, and the dosage was unknown for four patients. The patients recorded diary card data for 1,037 patient years and experienced 2,606 exacerbations, a median of 2.13 per patient per year (IQR, 0.94-3.32). Of these, 676 exacerbations were experienced by 212 patients in the warm seasons, and 1,052 exacerbations by 251 patients in the cold seasons: 197 patients experienced exacerbations in both seasons, and outside of the two seasons, 878 exacerbations were experienced. CHEST / 141 / 1 / JANUARY, 2012
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Table 1—Characteristics of the 307 Patients Characteristic
Value
Age, y FEV1, L FEV1, % predicted FVC, L FEV1/FVC Smoking, pack y Time in study, median, (IQR), d Exacerbations, median, (IQR), No. Exacerbations per year Male, No. (%) Chronic sputum, No. (%) Current smoking, No. (%)
68.1 (8.4) 1.12 (0.46) 44.4 (16.1) 2.51 (0.83) 0.45 (0.12) 50.5 (35.9) 1,021 (631-1,576) 6 (2-12) 2.13 (0.94-3.32) 196 (63.8) 158 (51.6) 100 (32.9)
Data are given as mean (SD) unless otherwise indicated. Smoking history missing for four patients at recruitment. IQR 5 interquartile range.
There was no difference in the proportion of exacerbations treated at our clinic or by the patient’s primary care practitioner to untreated exacerbations in the cold seasons (661 of 966 [68.4%]; P 5 .318) compared with the warm seasons (416 of 630 [66.0%]). There was also no difference in antibiotic use, with 607 of 966 exacerbations (62.8%) treated in the cold seasons vs 370 of 630 exacerbations (58.7%; P 5 .100) in the warm seasons, or in oral steroids use, with 414 of 966 exacerbations (42.9%) treated in the cold seasons compared with 268 of 630 exacerbations (42.5%; P 5 .900) in the warm seasons. There were fewer exacerbations involved in this analysis of therapy because treatment was not recorded during the first year of the study. Symptoms
Patients were under observation in summer for a median 352 days (IQR, 224-523) and in winter for a median 338 days (IQR, 222-525). There were 55.6% more exacerbations in the cold seasons compared with the warm seasons. The average temperature in the warm seasons was 16.7°C (range, 6.4 to 28.2), and in the cold seasons, 6.6°C (range, 23.5 to 15.6). Exacerbation Recovery and Temperature The median recovery time from all symptoms in the warm seasons was shorter at 9 days (IQR, 5-16; n 5 595) compared with 10 days in the cold seasons (IQR, 6-19; n 5 892; P 5 .005). Similarly, with the alternative definition of recovery in terms of just major symptoms, recovery was shorter at 7 days (IQR, 4-13) in the warm seasons compared with 9 days (IQR, 5-16; P 5 .0005) in the cold seasons. Recovery times were undeterminable for 81 exacerbations (12.0%) in the warm seasons and 160 exacerbations (15.2%) in the cold seasons (P 5 .06). The number of exacerbation days was significantly higher in the winter at 26 days (IQR, 2-70) compared with 11 days (IQR, 0-42) in the summer (P , .001). Cross-sectional Poisson regression models, which allowed for repeated measures on the same patient, showed that exacerbation recovery for all seven symptoms took longer as temperatures on the day of exacerbation onset fell. The exponentiated coefficient was 0.996 (95% CI, 0.994-0.998; P , .001) (Fig 1). The treatment delay between onset and physician consultation averaged 3 days (IQR, 2-5). There was no difference in treatment delay between the cold seasons at 3 days (IQR, 2-5) and the warm seasons at 3 days (IQR, 2-5; P 5 .667). There was also no relationship over the whole year between delay in treatment and temperature on the day of exacerbation onset (P 5 .723).
Table 2 gives the percentages for exacerbations with specific symptoms in the cold and warm seasons. It also shows the percentages for days in the cold and warm seasons in which specific symptoms were recorded when the patient was stable. During periods of exacerbation, coryzal and cough symptoms were significantly more likely in the cold seasons (P , .001), with a seasonal change of 35.3% and 11.5%, respectively. To illustrate these differences in symptom composition, Figure 2 shows the timecourse in the prevalence of dyspnea, coryzal, and cough symptoms for exacerbations in the cold and warm seasons. All stable-state respiratory symptoms, apart from dyspnea, were significantly higher in relative terms (P , .05) in the cold seasons compared with the warm seasons. However, the differences are small and unlikely to explain the longer recoveries in the cold seasons.
Figure 1. Average exacerbation recovery time, in days, from all symptoms at 1°C intervals of the average daily mean outdoor temperature. The line joins together the predicted values from the random effects Poisson regression model.
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Table 2—Exacerbation and Stable Symptoms in Cold and Warm Seasons Respiratory Symptom Exacerbations, d Dyspnea Sputum purulence, Sputum volume Coryza Wheeze Sore throat Cough Stable (outside exacerbation), d Dyspnea Sputum purulence Sputum volume Coryza Wheeze Sore throat Cough
Cold Season Warm Season P value 1,052 71.2 36.8 54.1 42.5 46.0 20.2 50.6 110,144 9.5 1.0 2.7 3.4 4.8 1.1 3.5
676 74.9 39.1 54.4 31.4 46.5 17.9 45.4 118,959 9.6 0.8 2.4 1.9 3.4 0.6 2.5
.096 .343 .887 , .001 .857 .247 .036 .403 , .001 , .001 , .001 , .001 , .001 , .001
P 5 .697) and 8 days (IQR, 5-16), respectively, or in the delay between exacerbation onset and hospitalization, 5 days (IQR, 3-9.5; P 5 .762) and 6 days (IQR, 2.5-17), respectively.
Discussion This study has shown that COPD exacerbations in colder periods of the year take longer to recover from and are more likely to involve cough or coryzal symptoms. We have also shown that exacerbations in the cold seasons have a greater impact on daily activity, with patients spending more time indoors and being more likely to be hospitalized. A possible explanation for our findings could be that a greater proportion of
Data are given as % of d unless otherwise indicated.
Outdoor Activity Throughout the year, patients changed their outdoor activities nonlinearly with temperature (Fig 3). Excluding periods of heat stress, when the average daytime and nighttime temperature was . 20.5°C, fewer patients go out as temperatures get colder; the OR was 1.028 per 1°C rise (95% CI, 1.024-1.032). At , 2.5°C, there was a significantly faster reduction in the likelihood of patients going outdoors with temperature (P , .001), with the OR at 1.13 per 1°C rise (95% CI, 1.09-1.18; P , .001). During heat stress, as temperatures exceeded 20.5°C, patients also reduced outdoor activity, with an OR at 0.96 per °C (95% CI, 0.93-0.999; P 5 .044). Because outdoor activity varied markedly with temperature, calculations of the effects of exacerbations on outdoor activity were made relative to a baseline (14-8 days) prior to exacerbation onset. Patients in the warm seasons were more active during exacerbation recovery and had a smaller reduction in the time spent outside, 20.26 h/d (IQR, 20.88 to 0.18), compared with 20.50 h/d (IQR, 21.1 to 0.0) in the cold seasons (Wilcoxon signed rank test; P 5 .048). Hospitalization In the cold seasons, there was a significant increase in the proportion of exacerbations requiring hospitalization; 88 of 1,052 exacerbations (8.4%) resulted in patients being hospitalized in the cold seasons compared with 31 of 676 exacerbations (4.6%) exacerbations in the warm seasons (P 5 .002). There was no difference between the cold and warm seasons in the length of the hospital stay, 11 days (IQR, 5-15.5; www.chestpubs.org
Figure 2. Time course of dyspnea, coryzal, and cough symptoms in the cold seasons (䊊) and warm seasons (䊉). CHEST / 141 / 1 / JANUARY, 2012
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Figure 3. Percentage of patients going outside the home against the daily mean temperature throughout the year. Points are at the center of each 1°C interval; vertical lines are at 2.5°C and 20.5°C.
exacerbations that require treatment in cold conditions are associated with respiratory viral infection. We have previously reported on the prevalence of symptomatic colds and higher exhaled nitric oxide levels in winter, which we attributed to a greater prevalence of respiratory viruses.18,19 Patients with COPD who are hospitalized are likely to have a respiratory virus,20 and we found that 8.4% of cold-period exacerbations required hospitalization, compared with 4.4% in the warm period. The proportion of untreated exacerbations was not affected by season, indicating that the increase in the proportion of exacerbations that resulted in patient hospitalization in the winter was due to a decrease in the proportion of exacerbations that received only drug treatment. There is also evidence that patients with COPD stay longer in the hospital in winter21; the patients spent 11 days in the hospital in the cold seasons, compared with 8 days in the warm seasons, but this did not achieve statistical significance. There was no seasonal difference in the time patients took to receive treatment, discounting the possibility that the longer exacerbation recoveries were due to a reluctance of patients to leave home on cold days, thereby delaying treatment, which can prolong exacerbation recovery.16 We found that the reductions in outdoor activity associated with exacerbation22 were greater in the cold seasons. This suggests that viral-associated exacerbations may have a greater impact on activity than exacerbations triggered by other causes. The clinical implications of these findings are that patients who suffer frequent respiratory virus infections may need to focus on maintaining activity, particularly in the winter, and may need to be enrolled as a priority into pulmonary rehabilitation programs targeted at patients with exacerbations.23 We also found that patients spend less time outdoors during very hot
weather, an adaptation to climate change that has been predicted24 but, to our knowledge, not previously substantiated. Outside of exacerbations when the patients were stable, daily respiratory symptoms were more common during the cold seasons than the warm seasons. These seasonal differences were small in absolute terms but large in relative terms and highly significant. Patients with chronic respiratory disease may report more symptoms during cold weather,25 but it is possible that there are more “subclinical” viral infections in cold seasons, a possibility consistent with the finding of airway viruses in patients who are stable.5,26 The strengths of this study are that we have examined data from a large group of patients with moderate to severe COPD who were observed over many winters. The symptomatic definition of exacerbation has been used by our group consistently for 15 years and validated against important outcome measures, including airway inflammation,27 lung function decline,3 and health status.2 The definition identifies mild (untreated) exacerbations because they are a clinically important feature of the disease28 and patients with a greater proportion of untreated exacerbations experience a poorer health-related quality of life.16,29 Exacerbation recovery was measured using prospectively collected daily data. Our simple comparison between two seasons was confirmed by a more sophisticated examination of the relationship with outdoor temperatures that allowed for repeated measures and more complex distributions in the data. The seasonal comparison did, however, include the effects of temperature and other seasonal influences such as hours of sunshine and relative humidity. There are also a number of limitations to this study. It was not feasible to sample and test the patients during each exacerbation for the presence of a respiratory virus. Temperature data from Heathrow Airport (London, England) will not match local temperatures where the patients live, but differences are likely to be small compared with the uncertainties of individual heat and cold exposures. We did not make any comparisons with the general population, but we have previously commented that the incidence of upper respiratory tract viral infections in the elderly community is similar to that experienced by the patients.30 In conclusion, in winter, patients with COPD have exacerbations that take longer to recover, they remain housebound for longer, and they are more likely to be admitted to the hospital. These findings may be explained by the greater prevalence of respiratory viral infections in winter. This has implications for winter health-care planning in hospitals, health economics, and the evaluation of healthforecasting services, such as those provided by the
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meteorologic office. It emphasizes the need for clinical trials to take place during both summer and winter so as to not overrepresent or underrepresent particular types of exacerbations. A more comprehensive understanding of exacerbations, particularly in winter, may lead to strategies to reduce their prevalence and burden.
9. 10.
11.
Acknowledgments Author contributions: Dr Donaldson: had the original idea for the study, did the statistical analysis, was involved in drafting and editing the manuscript prior to submission, and has seen and approved the final version of the manuscript. Dr Goldring: had the original idea for the study, was involved in drafting and editing the manuscript prior to submission, and has seen and approved the final version of the manuscript. Dr Wedzicha: had the original idea for the study, was involved in drafting and editing the manuscript prior to submission, and has seen and approved the final version of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript. Other contributions: We would like to thank all the patients with COPD in the London COPD cohort, who have contributed to collecting the data described in this study. We would also like to thank all the clinical fellows and nurses who have treated the patients in the cohort.
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16.
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