Background
Despite being preventable and treatable, chronic obstructive pulmonary disease (COPD) is associated with considerable morbidity and mortality [
1],[
2] and its prevalence is expected to increase in the coming decades [
3]. The characteristic symptoms of COPD include breathlessness, cough and increased sputum production and, based on cohort studies, there is now extensive evidence that COPD symptoms have a considerable impact on patients’ daily activities, health status and quality of life [
4]-[
8]. Furthermore, while COPD is diagnosed clinically based on persistent airflow limitation, it is the impact of symptoms on patients’ daily lives that generally drives them to seek a diagnosis. The importance of considering COPD symptoms in the overall assessment of COPD, and in determining appropriate treatment approaches, is now recognised [
9]. Reducing symptoms, improving health status and increasing physical activity are major goals in the management of stable COPD [
9].
COPD symptoms have been reported to vary throughout the day [
10]-[
12]. In cohort studies, patients with COPD who were receiving ongoing treatment with their normal COPD medication reported that their symptoms were worst in the morning [
10],[
12]. Morning symptoms impact on patients’ normal activities [
8],[
10],[
12],[
13] and have been demonstrated to be associated with worse health status and a higher risk of COPD exacerbations [
8],[
13]. In the working population, morning symptoms were also significantly associated with increased annual absenteeism [
13]. With regard to night-time symptoms, a recent real-world study also demonstrated that patients with night-time symptoms had significantly worse health status, more sleep disturbances and higher healthcare resource utilisation than patients without night-time symptoms [
7].
In a pan-European, observational study, patients’ perception of the variability of their breathlessness was associated with both the severity of breathlessness and frequent exacerbations [
10], while the pattern of COPD symptom variability has been shown to be influenced by disease severity [
12]. Previous studies have also shown an association between morning or night-time symptoms and reduced lung function [
7],[
13],[
14]. However, the association between symptoms in each part of the 24-hour day and the severity of airflow obstruction and the inter-relationship between 24-hour COPD symptoms has not previously been investigated in a single patient cohort.
In this observational study, we investigated the prevalence and severity of night-time, early morning and daytime symptoms in patients with stable COPD being treated in clinical practice and explored the relationship between symptoms in each part of the 24-hour day. Additionally, to better understand the relationship between 24-hour symptoms and other aspects of a patient’s overall well-being, we assessed their association with the severity of airflow obstruction and other patient-reported outcomes, including self-perceived dyspnoea, health status, anxiety and depression levels, sleep quality and physical activity level.
Discussion
In this observational study, more than half of patients reported experiencing COPD symptoms throughout the whole 24-hour day, despite receiving ongoing treatment for their COPD and almost 80% of patients had symptoms during at least two parts of the 24-hour day. While early morning and daytime symptoms were most frequent, night-time symptoms were also very common and almost two-thirds of patients experienced at least one night-time symptom during the week before baseline. Importantly, any symptoms in the early morning, daytime or night-time were associated with worse outcomes across a range of patient-reported measures including more severe dyspnoea, higher anxiety and depression levels and worse health status and sleep quality.
The observation that a large majority of patients experienced symptoms during at least two parts of the 24-hour day is consistent with results from a recent real-world study in almost 1500 patients. The study by Roche et al. showed that most patients had symptoms during the daytime and night-time and only 34% of patients experienced COPD symptoms in isolation during one part of the 24-hour day [
13]. However, in contrast to the results reported here, in the previous study daytime symptoms were by far the most prevalent (97% of patients) with just over one-third of patients reporting symptoms when getting up in the morning. This discrepancy may relate to the different definitions of morning symptoms used; the Roche et al. study defined morning symptoms as those present on waking and did not include those symptoms that persisted later in the morning [
13].
There is no objective definition of `night-time symptoms’ in patients with COPD, and it has been suggested that night-time symptoms may be under-reported by physicians or may not be reported by patients [
26]. The results of our study are consistent with a previous study in 2807 patients, which demonstrated that approximately 70% of patients reported experiencing night-time symptoms [
7]. Together these data suggest a high prevalence of night-time symptoms in patients with COPD. Lung function exhibits circadian variation with reduced airflow during the night-time period [
27]. The amplitude of this circadian variation has been shown to be increased in patients with COPD [
28],[
29] and it may contribute to night-time symptoms [
26],[
28]. In a previous study, wheezing was the most troublesome symptom at night, followed by cough [
10]. In the present study cough and bringing up phlegm were the most prevalent night-time symptoms suggesting that, in addition to reduced airflow, other mechanisms may be involved in mediating night-time symptoms including mucus hypersecretion, reduced ciliary activity or increased cough sensitivity. Further investigation of these processes is required to better understand the pathophysiology underlying night-time COPD symptoms.
Early morning symptoms have been reported to be most problematic for patients with COPD and can significantly impact on daily activities [
10]-[
12] and working life [
13]. Furthermore, in a previous study, a quarter of patients with COPD reported that night-time symptoms were most troublesome and night-time was the second most problematic time for patients with severe COPD [
12]. However, despite patients frequently reporting night-time symptoms, the impact that symptoms at night has on daily activities, such as getting up for work, is often under-estimated by physicians [
7]. Previous studies have shown a significant association between night-time symptoms and the severity of airflow obstruction in patients with COPD [
7],[
14]. Interestingly, our results show that whilst there was a significant relationship between early morning and daytime symptoms and the severity of airflow limitation, this association was not significant for night-time symptoms and the prevalence of night-time symptoms was comparable across all severities of airflow limitation. Furthermore, symptoms in each part of the 24-hour day were inter-related, an observation that was consistent irrespective of COPD severity. These data suggest that the presence of night-time symptoms is not merely a consequence of more severe airflow limitation. Other mechanisms, such as decreased mucociliary clearance, could be involved. However, this study did not differentiate between different phenotypes of patients with COPD and further studies are required to determine if night-time symptoms are associated with a specific phenotype.
In each part of the 24-hour day, symptoms were associated with worse dyspnoea, health status, higher anxiety and depression levels, and greater sleep impairment. These are all outcomes that can impact on patients’ daily living and overall well-being. The difference in CAT scores between patients with and without symptoms in each period exceeded the estimated minimal clinically important difference (2 points) recently proposed [
30], suggesting that symptoms in any part of the 24-hour day may be associated with a clinically meaningful worsening of health status. Moreover, anxiety and depression levels were also significantly higher in patients with symptoms compared with patients without symptoms. In general, anxiety levels tended to be highest in patients who had any combination of night-time symptoms and depression levels were highest in patients with any combination of night-time/early morning symptoms. Depression is a common comorbidity in patients with COPD [
2] and patients with severe COPD have a 2.5-fold higher risk of depression compared with matched controls [
31]. Comorbid depression is associated with an increased risk of exacerbation and mortality in patients with COPD [
32]. Since symptoms of depression tend to be worse in the morning we cannot rule out that higher levels of depression contribute to night-time and morning COPD symptoms. Of note, examining questions on COPD symptoms and the HADS questionnaire does not reveal common items, making confounding by wording unlikely. Finally, a similar pattern in the magnitude of HADS scores and symptom combinations was observed in patients with no medical history of anxiety or depression. Sleep was also significantly impaired in patients with symptoms in any part of the 24-hour day compared with patients without symptoms. As expected, the greatest impairment was observed in patients with night-time symptoms. Poor sleep quality or sleep disturbance in patients with COPD has been shown to be associated with worse health status, more exacerbations, increased healthcare resource utilisation and increased mortality [
7],[
33]. In this study, we also observed a significant relationship between symptoms in any part of the 24-hour day and physical activity levels: patients who were sedentary had more symptoms in each period than patients who were even moderately active. This may be important as low physical activity levels are significantly associated with poor quality of life and increased incidence of depression in patients with COPD [
34] and have been shown to be a strong predictor of mortality in patients with COPD [
35],[
36], and improving physical activity is an important goal in the treatment of COPD [
9].
Overall, our results support previous studies showing that symptoms during the morning and the night-time are independently associated with worse outcomes in patients with COPD [
7],[
13]. COPD symptoms when getting up in the morning have been shown to be independently associated with worse health status and more exacerbations, and have a negative impact on daily activities [
13]. Similarly, patients with night-time symptoms had significantly worse breathlessness and health status and were more likely to have morning symptoms than patients without night-time symptoms, even when these analyses were controlled for confounding factors such as disease severity [
7]. Our results extend these studies by demonstrating that there is an inter-relationship between symptoms in each part of the 24-hour day and that symptoms in any part of the day are associated with worse patient-reported outcomes.
While these results demonstrate significant relationships between symptoms in each part of the 24-hour day and various aspects of patients’ well-being, the analyses do not take into account confounding factors such as disease severity or comorbid conditions, which may also impact on patient-reported outcomes. Furthermore, no causal relationship can be inferred from the analyses as this was an observational study. Further investigation of the specific relationship between symptoms in each part of the 24-hour day and each outcome is required to establish whether symptoms are independently associated with the outcome, irrespective of underlying disease. While this study enrolled patients with mild to very severe COPD, only patients being treated in clinical practice (both primary care and specialist centres) were assessed. As such, the relevance of these observations for the wider population of patients with COPD, including those with undiagnosed COPD, requires further consideration.
Competing interests
Marc Miravitlles has received speaker fees from Almirall, Boehringer Ingelheim, Pfizer, AstraZeneca, Chiesi, Esteve, GlaxoSmithKline, Menarini, Talecris-Grifols, Takeda-Nycomed, and Novartis, and consulting fees from Almirall, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Gebro Pharma, MedImmune, Novartis, Talecris-Grifols and Takeda-Nycomed.
Heinrich Worth has received speaker fees from Almirall, Bayer, Boehringer Ingelheim, AstraZeneca, Bionorica, Chiesi, GlaxoSmithKline, Klosterfrau, Berlin Chemie, Novartis, Takeda and consulting fees from Almirall, Berlin Chemie, Mundipharma, Bionorica, Intermune, Novartis and Takeda.
Juan José Soler Cataluña has received speaker fees from Almirall, AstraZeneca, Bayer Schering, Boehringer Ingelheim, Esteve, Ferrer, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Takeda and Pfizer, and consulting fees from Almirall, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, AstraZeneca, Bayer Schering, Ferrer, Novartis, Merck Sharp & Dohme, Uriach and Takeda.
David Price has served on advisory boards for Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva. He has consultant arrangements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, and Teva. He or his research team has received grants (or grants pending) and support for research in respiratory disease from the following organizations in the last 5 years: UK National Health Service, British Lung Foundation, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva and Zentiva. He has received unrestricted funding for investigator-initiated studies from Aerocrine, AKL Ltd, Almirall, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, Zentiva. He has received funding for patient enrollment or completion of research from Almirall, Chiesi, Teva and Zentiva. He has received payments for lectures/speaking from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, Skyepharma, Takeda and Teva; travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis and Teva; manuscript preparation from Mundipharma and Teva; development of educational materials from GlaxoSmithKline and Novartis. He has patents and shares with AKL Ltd and owns 80% of Research in Real Life Ltd and its subsidiary social enterprise Optimum Patient Care.
Fernando De Benedetto has received over the past 5 years fees for speaking, participation in advisory boards or consulting from Almirall, Biofutura, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Nycomed-Takeda.
Nicolas Roche has received over the past 5 years (i) fees for speaking, organising education, participation in advisory boards or consulting from Almirall, Altana Pharma-Nycomed-Takeda, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MEDA, MSD-Chibret, Mundipharma, Novartis, Pfizer, Teva; (ii) research grants from Novartis, Nycomed, Boehringer Ingelheim and Pfizer.
Nina Skavlan Godtfredsen has received honoraria from Almirall for participating in Danish and Nordic advisory boards.
Thys van der Molen has no competing interests to declare.
Claes-Göran Löfdahl has received some reimbursement for lectures and ad-hoc advisory boards from Almirall, AstraZeneca, Boehringer Ingelheim, Novartis and Takeda.
Laura Padullés and Anna Ribera are employees of Almirall, Barcelona, Spain.