What have we learned from observational studies and clinical trials of mild to moderate COPD?

Chronic obstructive pulmonary disease (COPD) is characterised by chronic airflow limitation, which is usually progressive. This disease is a major cause of morbidity and is currently the fourth leading cause of death worldwide [1, 2]. Although it is mostly related to exposure to tobacco smoking, patients exposed to biomass and pollution are also at risk of developing COPD.

The impact of COPD on each patient depends on the degree of airflow limitation, the severity of symptoms and comorbidities. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging system categorises COPD into 4 severity stages (based on post-bronchodilator FEV1): stage I or mild, FEV1 ≥ 80% predicted; stage II or moderate, FEV1 ≥ 50% and < 80% predicted; stage III or severe, FEV1 ≥ 30% and < 50% predicted; and stage IV or very severe, FEV1 < 30% predicted [3]. As the disease progresses, there is greater restriction in daily activity with impaired quality of life and an increase of symptoms and exacerbations.

Nonetheless, the reduction in daily activity is already present in mild disease [4]. Since COPD is progressive, it is important to identify and treat patients at early stages in order to prevent further deterioration. Patients with mild (stage I) COPD already have measurable physiological impairment with increased morbidity and a higher risk of mortality compared with healthy non-smoking controls [5]. It is well established that patients with mild to moderate disease represent the majority of patients with COPD [6]. However, this subpopulation is both underdiagnosed and undertreated [7]. In addition, most clinical trials include cohorts of patients with worse lung function and worse quality of life, which are very different from those usually seen in primary care (PC) [8].

Encouragement of smoking cessation, in conjunction with management of symptoms and treating activity limitations and exacerbations by appropriate pharmacologic and non-pharmacologic management at the earliest possible stage can positively affect the impact and progression of the disease [9]. In recent years, newer strategies and a growing number of new pharmacologic agents to treat COPD have also been introduced and show promise in improving the management of COPD [10]. New disease lung models to predict patient-specific drug deposition are also being developed in order to individualise therapy [11].

The aim of this article is to review the current evidence on the epidemiology, natural history and management of mild to moderate COPD (defined as an FEV1 > 50% predicted), highlighting the importance of treatment in earlier stages of the disease to try to prevent progression.

The World Health Organization estimates that up to 328 million people around the world have COPD with a global prevalence of 1% [12]. This prevalence increases to 8–10% for individuals above 40 years old [13]. A recent systematic review aimed at estimating the prevalence of COPD across world regions among people aged 30 years or more found an overall prevalence of 10.7% in 1990, which increased to 11.7% in 2010 (14.3% in men and 7.6% in women) [14]. However, the prevalence of COPD varied widely among world regions, being the highest in the American region (14.1%), and the lowest in South East Asia (7.8%) [14]. This variability might be explained by differences in exposures and environmental and genetic factors. Indeed, according to the BOLD study, conducted at 12 sites around the world (n = 8775), the overall prevalence of COPD ranged from 11.4 to 26.1%; the prevalence of GOLD I being between 1.4–15.5% and the prevalence of GOLD II between 5.1 and 12.4% [6]. The Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) examined the prevalence of COPD in adults > 40 years of age and reported crude rates of GOLD stage I between 5.2 and 12.5% and GOLD II between 1.9 and 6.4% in five Latin American countries [15]. Another systematic review estimated a pooled prevalence for GOLD I of 9.8% (95% confidence interval (CI) 5.9–15.8) and of 5.5% for GOLD II (95%CI 3.3–9.0) [13].

In Europe, a systematic review by Atsou et al. [16] found a prevalence of COPD from 2.1 to 26.1% depending on the country, the age group and the methods used, the majority being GOLD I and II.

In Spain, the IBERPOC study conducted in 1997 showed a mean prevalence of COPD of 9.1% in subjects between 40 and 69 years of age [17]. Ten years later, the EPI-SCAN trial estimated a prevalence of 10.2% in subjects between 40 and 80 years of age [18]. A sub-analysis of these studies reported an increase of patients in milder stages over time, ranging from 38.3% for mild and 39.7% for moderate in the 1997 study to 85.6% for mild and 13.0% for moderate in the 2007 study [19]. Despite the wide variability of the results found in these population-based studies, the majority of the patients diagnosed had mild or moderate COPD, independently of the classification criteria used (Table 1).

One of the main concerns in COPD is underdiagnosis, which is more marked in early stages of the disease. It has been estimated that 73–78% of patients with GOLD stages I-II COPD remain undiagnosed [18]. Llordés et al. carried out a study to quantify the rate of underdiagnosis and the accuracy of COPD diagnosis in PC [20]. The study included 1738 subjects over the age of 45 with a history of smoking and found a rate of underdiagnosis of 73%. Recently, the same group performed a case-finding study in smokers or former smokers older than 40 years and found a prevalence of COPD of 26.7%, with the majority of patients being in GOLD stages I and II (42.1 and 49.1%, respectively) [21]. Up to 29% of patients with underdiagnosed COPD are asymptomatic [22], which contributes to late detection. In addition, patients often under-recognize the significance of respiratory symptoms, or they may accept that their symptoms are caused by smoking and ignore them rather than consult. Another cause for underdiagnosis might also be a deficient active search for COPD by health care professionals [21]. Some of the diagnostic initiatives that have been tested to improve COPD diagnosis are early detection programs [23] and other tools such as the use of peak-flow meters or mini spirometers [24], and screening questionnaires [21, 25].

In contrast to underdiagnosis, the definition of COPD based on FEV1/FVC instead of lower limit of normality (LLN) might lead to the overdiagnosis of mild COPD in individuals older than 65 years old [26].

The natural history of COPD is usually described by the rate of decline in lung function. The rate of decline in FEV1 in GOLD stages I-II is faster than in patients with stages III-IV [27‐29]. Recently, in a cohort of smokers and ex-smokers, the COPD Gene group showed that functional alteration of the small airways measured by computerized tomography was significantly associated with a decline of FEV1, particularly in mild to moderate stages of the disease, and this association was also evident even before the detection of obstruction in the spirometry [30].

Exacerbations have a negative impact on the natural history of COPD, and their presence has been associated with a faster decline of FEV1, in particular in GOLD stagesI and II [31], in which the effect of each exacerbation on rate of FEV1 decline has been estimated to be − 23 ml/year in GOLD 1 and − 10 ml/year in GOLD 2 for any exacerbation, increasing up to -87 ml/year and -20 ml/year for GOLD 1 and 2 respectively for each severe exacerbation. Frequent exacerbators also have a worse quality of life and an increased risk of death [32‐34]. Thus, the prevention of exacerbations should be a target for every COPD patient, irrespective of the severity of the disease.

COPD is defined by the presence of chronic respiratory symptoms, among which exertional dyspnoea, cough and sputum production are the most frequent [35]. Although more severe patients present a higher intensity of symptoms, there is not always a clear relationship between the degree of airflow obstruction and the presence and impact of respiratory symptoms in a patient with COPD [35, 36]. The observational study ASSESS characterised the symptoms of COPD during 24 h and assessed their relationship with patient-reported outcomes [37]. The analysis showed that the frequency of symptom occurrence was high for any degree of bronchial obstruction, with a prevalence of symptoms in GOLD stages I-II of 84–88%.

The presence of respiratory symptoms in patients with early COPD may modify long-term FEV1 decline and health-related quality of life. Symptomatic subjects with GOLD I COPD have a more rapid long-term decline in lung function than asymptomatic subjects [38, 39].

Despite referring fewer symptoms, mild COPD patients present exercise limitation that leads to changes in lifestyle and deconditioning, with an increasing burden of the disease beyond the degree of airflow obstruction. Indeed, around two thirds of GOLD stage II patients may have significant lung hyperinflation [40]. This hyperinflation is manifested as exertional dyspnoea, and furthermore, dyspnoea significantly contributes to a worse quality of life due to the high impact on their daily activities [41]. Even mild patients may have severe dyspnoea; a study carried out in 5299 subjects found that 7.5 and 18.3% of subjects with GOLD stages I and II, respectively, had a Medical Research Council (MRC) score ≥ 3 [42]. Similarly, a large European observational study conducted in 1817 patients in PC showed a high prevalence of symptoms in GOLD II patients (cough 76.6%, sputum 64.1%, and dyspnoea 67.3%). Moreover, 31% had a MRC dyspnoea grade ≥ 3. [43]. In a recent analysis carried out in 49,438 COPD patients, 50.2% were GOLD stage II, and 37.1% had a MRC dyspnoea grade ≥ 3, demonstrating that significant dyspnoea can be present in early stages of the disease [44]. In addition to being the most frequent symptom, dyspnoea has proven to be a better predictor of death at 5 years than airway obstruction in patients with COPD [45].

Concerning quality of life, the study by Jones et al. [43] using the St. George’s Respiratory Questionnaire [SGRQ] and the 12-Item Short Form Survey [SF-12] demonstrated that GOLD I and II patients had an impaired quality of life compared with healthy individuals. These results are similar to those obtained in the EPI-SCAN study, which observed a significant impairment of health-related quality of life in all severities of COPD, even GOLD I and II and undiagnosed COPD patients [18].

Physical activity significantly deteriorates in patients with COPD as the disease progresses [46], and the reduction in physical activity is one of the best predictors for COPD survival [47]. In addition, physical inactivity is strongly associated with the presence of comorbidities [48]. In contrast, regular physical activity reduces hospitalisation and the risk of death in COPD [49]. However, even in early stages of the disease, most patients with COPD spend less time walking (and walking more slowly) and standing, and more time sitting and lying compared with sedentary healthy elderly subjects [50].

The main objectives for the treatment of COPD are the reduction of symptoms, the reduction of frequency and severity of the exacerbations and the improvement of prognosis [3, 51]. Non-pharmacological treatment, especially smoking cessation, is essential for every COPD patient and ha sproven to be the most efficient and cost-effective therapeutic strategy [3, 51]. Smoking cessation slows the loss of lung function and improves survival. Indeed, the benefits may be more evident in milder patients than in individuals with a more established disease [52]. Psychotherapy might be beneficial in addition to exercise and medication. Other non-pharmacological approaches include regular physical activity, an adequate nutrition status, management of comorbidities, and vaccination against pneumococcal and influenza viruses is also recommended for all patients. Pulmonary rehabilitation has shown to improve symptoms, exercise tolerance and health-related quality of life, and to reduce the risk of morbidity from acute exacerbations of COPD [53]. Both a meta-analysis and a systematic review concluded that patients with mild to moderate COPD also benefit from short- and long-term rehabilitation [54, 55]. Hence, considering the benefits of physical activity, patients with COPD should be encouraged to increase their level of exercise from early stages.

Since the decline in lung function is faster in early stages of the disease, early intervention is required to prevent functional impairment [71]. However, there are only a few large-scale clinical trials on long-term interventions in patients in early stages of COPD. The Lung Health Study, carried out in 3926 smokers with mild to moderate airway obstruction for a period of 5 years showed that participants who stopped smoking experienced an improvement in FEV1 in the year after quitting (average of 47 ml or 2%), and that the subsequent rate of decline in FEV1 among sustained quitters was half the rate of that of continuing smokers (31 ml versus 62 ml, respectively), and comparable to that of never-smokers [72]. A post hoc analysis of the UPLIFT study that included only GOLD II patients observed that the rate of decline for postbronchodilator FEV1 was lower in the tiotropium group than in the control group (43 ml per year [SE 2] vs. 49 ml per year [SE 2], p = 0.024) [66]. Another sub-analysis from UPLIFT assessed the efficacy of treatment with tiotropium in patients without previous maintenance treatment (naïve patients) and included a majority of GOLD II (60%). The annual FEV1 decline was slower in the tiotropium group (35 ml (SD 3) in the tioptropium arm vs. 45 ml (SD 4) in the placebo arm) [73].

More recently, in a randomised placebo-controlled trial which included 841 mild to moderate COPD patients, Zhou et al. [74] observed that the annual FEV1 decline in early stage COPD was lower in patients treated with tiotropium (29 ml ±5) than in the placebo group (51 ml ± 6; difference 22 ml (95% CI 6 to 37). In the TORCH study, SFC also showed a reduction in the rate of decline in FEV1 versus placebo in the GOLD II group (difference 16 ml/year, 95% CI: 0, 32) [63]. These results were confirmed in the SUMMIT study, in which GOLD II patients also had a lower rate of decline in FEV1 in the fluticasone furoate/vilanterol arm compared to placebo (38 ml (2.4) vs. -46 ml (2.5) respectively, p = 0.019) [75]. These results should be considered in the context of both studies failing to reach their primary outcome of mortality (Table 3).

With regard to mortality, the TORCH study showed a 33% reduction in the risk of death in GOLD stage II COPD patients (HR 0.67; 95% CI: 0.45, 0.98) with SFC compared with placebo [63]. In UPLIFT, there was a non significant reduction in mortality with tiotropium compared to placebo (hazard ratio [HR], 0.89; 95% CI, 0.79 to 1.02, p = 0.09) [76]. More recently, treatment with fluticasone furoate/vilanterol showed no effect on mortality in COPD patients with FEV1 > 50% and cardiovascular risk (HR 0·88 [95% CI 0·74–1·04]; 12% relative reduction; p = 0.137) [77].

A recent review of COPD treatment guidelines published in Europe and Russia in the last 7 years found that although there were differences in some recommended treatments, there was a general agreement on treatment goals and the use of LABD as the cornerstone of COPD treatment [85].

The GOLD strategy establishes pharmacologic treatment algorithms by groups of different risk and intensity of symptoms. For patients in GOLD group A (low risk and low symptom burden), a bronchodilator should be offered to reduce breathlessness. For patients in GOLD group B (low risk and high symptom burden), the preferred initial therapy should be a LABD. If the symptoms persist, therapy with two bronchodilators may be considered [3].

The National Institute for Health and Care Excellence (NICE) guidelines updated in 2010 recommended that patients with FEV1 > 50% predicted with exacerbations or persistent airflow obstruction should be offered LABDs, and in the case of persistence of symptoms, patients should receive either LABA/ICS or LAMA/LABA [86].

The Spanish COPD guidelines (GesEPOC) were developed based on risk stratification and clinical phenotypes [51]. They use an easy risk classification (low or high risk) based on lung function, dyspnoea grade, and history of exacerbations. The four clinical phenotypes identified were: non-exacerbator, ACO, exacerbator with emphysema, and exacerbator with chronic bronchitis. However, they only recommend the determination of clinical phenotype in high-risk patients. Pharmacological recommendations for low-risk patients consist of LABD without any type of anti-inflammatory treatment, and the initial treatment for most high risk patients consists of LAMA/LABA [51].

The newest position statement of the Canadian Thoracic Society in COPD gives more weight to symptoms and exacerbations when it comes to increasing or decreasing therapy. In symptomatic patients with stable COPD without frequent exacerbations, treatment should be started with a LABD, and if experiencing persistent or increased dyspnoea, exercise intolerance, and/or reduced health status despite the use of monotherapy, patients should be considered for “step up” treatment with a LAMA/LABA. In patients with stable COPD experiencing exacerbations despite the use of LAMA or LABA monotherapy, “step up” treatment with inhaled LAMA/LABA should be considered. If a patient is still experiencing exacerbations despite the use of LAMA/LABA, “step up” treatment with LAMA plus LABA/ICS can be considered. Since inhaled triple or dual therapy may not prove to be superior in every patient, the notion of “step down” treatment may be a consideration in some patients. For patients with suspected ACO, a combination of LABA/ICS is recommended [87]. Figure 1 presents a treatment algorithm for mild-moderate COPD patients.

Although patients with mild to moderate disease represent the majority of patients with COPD, most studies and in particular RCTs are focused on severe COPD patients. Moreover, mild to moderate patients tend to be underdiagnosed and undertreated, affecting their prognosis and quality of life. Since COPD is progressive, it is important to identify and treat patients at early stages in order to prevent further deterioration, even more considering that patients with mild COPD already have measurable physiological impairment that leads to changes in lifestyle and deconditioning.

Smoking cessation, management of symptoms and treating activity limitations and exacerbations by appropriate pharmacologic and non-pharmacologic management at the earliest possible stage could positively affect the impact and progression of the disease, symptoms, exacerbations, and quality of life. These benefits may be more evident in milder patients than in COPD individuals with a more established disease. Non-pharmacological management includes regular physical activity, pulmonary rehabilitation, an adequate nutrition status, and management of comorbidities, and vaccination against pneumococcal and influenza viruses is also recommended for all patients. On the other hand, early treatment with one LABD or the combination of two bronchodilators has shown to produce a slightly greater improvement in lung function in patients with GOLD stage II than in those with more advanced stages of COPD, and this improvement was associated with an improvement of symptoms, health-related quality of life and a reduction in the risk of exacerbations.

New studies suggest that early treatment with dual bronchodilators may prevent disease deterioration, but this interesting concept should be tested in large clinical trials specifically designed for this objective.