Chronic obstructive pulmonary disease (COPD) is a complex condition associated with long-term exposure to environmental toxic gases and particles, most often cigarette smoke, on a susceptible genetic background and is a major cause of chronic morbidity and mortality globally [1-3]. In Korea, the prevalence of COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria is 17.2% among adults older than 45 years of age [4].

COPD represents a huge economic burden for the healthcare system [5-7], even though it is generally under-diagnosed and under-treated. This may be explained in part by the physician's insufficient knowledge of the patient's perception of COPD symptoms and poor adherence to COPD management guidelines [8,9]. There have been several studies [9-12] of patient perception of general symptoms, exacerbations, and treatments of COPD. In the PERCEIVE study [12], the most frequent complaint was that COPD limited daily activities. This is in part due to persistent and progressive breathlessness during daily activities or at rest, which eventually render the patient more physically passive [1].

Recent studies [13,14], based on the hypothesis that patients with COPD may have circadian variation in lung function [15-18], have shown that respiratory symptoms and the ability to perform physical activity in COPD patients were more problematic in the morning than at other times of the day. In addition, patients with severe COPD often perceive both daily and weekly variability of their symptoms in-between exacerbation periods [14]. Even though these were well-organized, multicenter, and international studies that recruited large patient populations, methodological limitations remain due to their cross-sectional design using an internet-based questionnaire survey [13] and phone interview [14], and the patient selection process.

The present study implemented a non-interventional and observational design aimed to assess patients' perception of COPD symptoms related to morning activities. Patients with severe airflow limitation were included together with a planned 2-month follow-up.

Our data demonstrate that 57% of COPD patients with severe airflow limitation have morning symptoms that limit their morning activities. Several previous studies [15-18] have reported that patients with COPD may experience diurnal variation in lung function. These studies determined that spirometry results over 24 hours, FEV₁, forced vital capacity, and inspiratory capacity exhibited circadian variation with maximum values at approximately noon and minimum values during the early morning [16,17]. This supports the observation that most COPD patients report more severe symptoms in the morning. In the internet-based questionnaire survey by Partridge et al. [13], 46% of patients with severe COPD reported that the morning was the worst time of day for COPD symptoms. However, this value may not represent the true prevalence of symptoms in severe COPD patients since spirometry data was not reported and severity was assessed according to regular use of COPD medication, dyspnea level, and exacerbation frequency. Therefore, our study provides valuable information on the prevalence of morning symptoms in COPD patients with severe airflow limitation, as defined by GOLD. The high frequency of awakenings in our patient population supports the perception that the morning is the most troublesome time of the day for experiencing COPD symptoms, as reported by Kessler et al. [14]. In general, co-morbid depressive symptoms and depressive disorders in COPD are associated with a negative course of disease, including increases in mortality and symptom burden, as well as decreases in functional status, quality of life and activities [22]. Disruptions to circadian rhythms, such as early morning waking, diurnal mood changes, and changes in sleep architecture have been found among patients with major depression [23]. For these reasons, we hypothesize that the high prevalence of depression in COPD may also be associated with the high prevalence of morning symptoms. However, this hypothesis in patients with COPD needs to be substantiated by further research.

Breathlessness, which was the most common COPD symptom in this study, is a hallmark symptom of COPD and is characteristically persistent and progressive [1,24]. According to a telephone survey of patients with COPD living in North America and in Europe [11], dyspnea was common and was more prevalent in older COPD subjects, over 65 years of age. This supports our results since all of the patients in our study were older and had severe or very severe end airflow limitations. In addition, respiratory conditions can limit many fundamental physical activities in COPD subjects of all ages [11,12]. For example, morning activities such as getting out of bed, using the toilet, washing, drying, dressing, and preparing or eating breakfast are essential to start the day. Limitations on these activities can greatly impact behavioral and psychosocial aspects of COPD patients. The present study showed that all COPD symptoms were more frequent and severe in patients with morning symptoms than in those without morning symptoms. Furthermore, getting out of bed, using the toilet, drying, and washing were the most frequent morning activities limited by morning symptoms. In an internet-based questionnaire survey by Partridge et al. [13], morning activities most affected by COPD were walking up and down stairs, putting on shoes and socks, making the bed, showering or bathing, drying their body with a towel and dressing. Even though some disparity in the frequency or severity of activities between the two studies is noted, likely resulting from differences in patient selection and life styles, it is clear that in patients with severe COPD, the disease has a considerable impact on morning activities.

There have been two interventional studies [25,26] using a MAQ as a clinical outcome assessment. That by Partridge et al. [25] showed that short-term budesonide/formoterol dry powder inhaler (DPI) or salmeterol/fluticasone DPI treatment was effective in improving lung function, symptoms, and morning activity in patients with severe COPD. Budesonide/formoterol, in particular, had a more rapid onset of effect compared with salmeterol/fluticasone and resulted in greater improvements in the ability to perform morning activities despite the lower inhaled corticosteroid dose. The CLIMB study [26] showed that budesonide/formoterol added to tiotropium versus tiotropium alone provides rapid and sustained improvements in lung function, health status, morning symptoms and activities, and reduces severe exacerbations. In this present study, long-acting muscarinic antagonists or inhaled corticosteroids combined with long-acting β2-agonists were used significantly less frequently in patients with morning symptoms than in patients without morning symptoms. Furthermore, treatment with a long-acting muscarinic antagonist was a preventive factor for the presence of morning symptoms. Collectively, these results suggest that morning symptoms in severe COPD patients can be improved by treatment based on the COPD guidelines and monitoring morning symptoms can provide useful clinical parameters for evaluating the effectiveness of COPD therapy. Although the present study was not of an interventional design, the severity of pulmonary function and morning activities were improved after a 2-month follow-up. This may be explained in part by physician adherence to COPD guidelines or increased patient self-awareness and compliance to COPD management following enrollment.

It is important to note that there was no significant correlation between the degree of improvement of FEV₁ and the changes of severity scores of all morning activities. The airflow limitation in COPD did not correlate well with patient-reported outcomes such as symptoms, exercise capacity, activities of daily living and health-related quality of life [27-31]. Moreover, as the disease severity increases, patients with COPD develop more co-morbid conditions compromising patient-reported outcomes [32,33]. Therefore, it seems likely that changes in these extrapulmonary conditions after treatment should influence improvement of morning activities in our COPD patients. Although spirometry is the most frequently recommended monitoring routine in clinical practice guidelines [34], useful information about lung function decline is unlikely to be provided from spirometry measurements performed more than once a year [1]; this is even more pronounced in severe COPD. Frequent check-ups of patient-reported outcomes is a more practical way to monitor disease progression and development of exacerbations and to evaluate the effectiveness of therapy [35,36]. Accordingly, our results provide additional valuable information for development of patient-reported outcomes related to morning activities [37].

This study has some limitations. Since we did not assess the health-related quality of life as an outcome measurement from the beginning of study, the relationship between quality of life and severity of morning activity remains to be determined. In addition, due to a lack of patient co-morbidity information, we could not evaluate the factors affecting morning symptoms in detail. Further research should be directed towards answering these questions.

In conclusion, 57% of COPD patients with severe airflow limitation have morning symptoms that limit their morning activities. These patients had more prevalent and severe COPD symptoms than those without morning symptoms. The results reported here provide additional valuable information necessary for development of patient-reported outcomes for evaluating the effectiveness of COPD therapy.