Traditionally, spirometry has been used to assess Chronic Obstructive Pulmonary Disease (COPD) severity and guide treatment, but a growing body of evidence documenting a poor correlation between forced expiratory volume in 1 second (FEV1) and symptoms or Quality of Life (QoL) in COPD patients,1–5 raises doubts as to the real effectiveness of spirometry as an instrument for assessing COPD control. Currently, several tools are recommended for a comprehensive evaluation of COPD, and although some are objective measurements, many remain subjective, such as questionnaires for symptoms or QoL assessment.5–12 This hampers COPD control: how can we define a well-controlled patient if a proper assessment, encompassing all its dimensions, is not currently attainable? Despite the existence of several pharmacological and non-pharmacological approaches to the management of COPD, there is a clear need to bridge the gap between disease assessment and disease control. This paper discusses several objective and subjective parameters that may make part of that bridge.

The first reference to COPD dates back to the XVII century, in the writings of Theophile Bonet, where he described the effects of lung emphysema as “voluminous lungs”.13 However, only almost three centuries later, in 1944, Ronald Christie wrote in the British Medical Journal that “[…] the diagnosis (of emphysema) should only be considered certain when dyspnoea on exertion, of insidious onset, not due to bronchospasm or left ventricular failure, appears in a patient who has some of the physical signs of emphysema together with chronic bronchitis or asthma.”.14 The CIBA Guest Symposium in 195915 and the American Thoracic Society Committee on Diagnostic Standards in 1962,16 were two landmark meetings that defined the components of COPD. In the 70s the risks of smoking, the accelerated rate of decline in FEV1 in susceptible smokers, and the effects of smoking cessation on lung function were elegantly described by Fletcher et al.17 During the 80s, focus was given to exacerbations, prophylactic antibiotic therapy and prevention. The standards for oxygen use in patients with advanced COPD and chronic respiratory failure were also defined in this decade. During the late 90s there was a marked evolution in COPD concepts, individual and social approaches, and guideline development. There was the emergence of old and new inhaled drugs, such as short- and long-acting β2-agonists (SABAs and LABAs), and the recognition of the role of corticosteroids, smoking cessation and pulmonary rehabilitation in the treatment of COPD, when there was still clinical confusion between asthma and COPD in terms of diagnosis and treatment.

It was not until the early XXI century that asthma and COPD were recognized as distinct pulmonary obstructive diseases, although the Asthma-COPD Overlap Syndrome (ACOS) has features of both pathologies. During the first decade of the XXI century, the role of each pharmacological class, namely long-acting muscarinic antagonists (LAMAs) and inhaled corticosteroids (ICSs), in COPD was established.18 LABAs were recognized as efficient in symptom relief, in improving quality of life and exercise tolerance, and in preventing exacerbations. Corticosteroids, on the other hand, have been considered to have a modest global effect on COPD, and their use remains controversial in stable patients, in particular due to evidence of increased risk of pneumonia.19 The central role of tobacco on COPD was strengthened, and widespread smoking cessation campaigns and programs were implemented. Techniques such as lung volume reduction (surgical or endoscopic) and transplantation were established for a small number of COPD patients. After 2000, the understanding of the social costs of COPD and the elevated disease-associated morbidity and mortality – higher than in asthma – led to population-based studies to determine its prevalence worldwide and its impact on mortality in developed countries. Although COPD prevalence varies across countries, ranging from 7.8% to 19.7%, and across different groups within countries, it is one of the most important causes of morbidity and mortality worldwide.10 Like hypertension or type 2 diabetes, COPD is a chronic disease, associated to modifiable risk factors, high morbidity and increased healthcare costs, and should thus be a target for disease control strategies. However, and contrary to hypertension or type 2 diabetes, these strategies are more difficult to implement in COPD given the difficulty in establishing objective criteria that may predict outcomes or decrease disease risk. Moreover, indicators of disease control and modifiers of disease progression are still to be defined.

After 2010, a considerable effort was made to establish different COPD phenotypes,20 and GOLD 2011 proposed different COPD stages.21 Recently, and in contrast with GOLD guidelines, it has been suggested that COPD management needs to be centered on disease stratification based on the risk of exacerbations and dyspnea symptoms.22 ICS finally found their niche in COPD, and are currently recommended for patients at high risk of exacerbation, whilst the addition of a second bronchodilator is recommended for symptomatic patients.10,22

COPD in now recognized as a systemic disease with pulmonary, cardiovascular, metabolic and musculoskeletal implications.

There are currently no biomarkers to assess the onset of COPD, determine disease activity or severity or predict prognosis. Given the documented poor correlation between FEV1 and symptoms/QoL in COPD patients,1–5 several guidelines have recognized the need to incorporate non-spirometric measures in COPD assessment and in determining therapeutic options.6,7 Current GOLD guidelines recommend a comprehensive assessment of COPD, including symptoms, using validated questionnaires such as the modified Medical Research Council Dyspnea Scale (mMRC), the Clinical COPD Questionnaire (CCQ)8 and the COPD Assessment Test (CAT),9 degree of airflow limitation, risk of exacerbations and existence of co-morbidities.10 Other variables that should be taken into account in a comprehensive assessment of COPD are physical activity restrictions,5 particularly important because exercise capacity and functional status predict exacerbations, hospitalizations, and mortality.11 The overall impact of COPD in a patient's QoL should also be assessed. Some authors suggest that for the assessment of symptom control, clinical history, symptoms and spirometry should all be used.23

Recommended non-pharmacologic management of COPD depends on the individualized assessment of symptoms and exacerbation risk. GOLD proposes as essential smoking cessation, physical activity, influenza and pneumococcal vaccination for all patient groups, and pulmonary rehabilitation for B, C and D patients.10 Additional non-pharmacological measures include patient education, an appropriate diet,12,47 oxygen therapy and ventilatory support.47

Recommendations for therapy are set forth by international guidelines.6,7,10,24 There are three main therapeutic goals in COPD: (1) reduce symptoms; (2) reduce risk, and (3) improve prognosis.10 Beyond the already discussed non-pharmacological measures, several pharmacological approaches are currently available to manage stable COPD. The choice of pharmacotherapy should be based on symptoms, exacerbations and severity of obstruction. Inadequately controlled symptoms or the presence of exacerbations may modify therapeutic stratification.

Bronchodilators are the pivotal therapy in the control of COPD. According to the GOLD guidelines, inhaled formulations are preferable to systemic formulations due to less adverse events and increased efficacy. Also, long acting bronchodilators are preferable to short acting ones. The choice between a LABA or a LAMA depends on availability and individual response to therapy. The association of bronchodilators of different classes, e.g. LABA+LAMA, may improve efficacy and safety compared to dose adjustment of a bronchodilator in monotherapy. Indeed, a recently approved fixed-dose LABA/LAMA combination was associated with the concept of disease control.68–71 ICS should only be used in patients at higher risk of exacerbations and never as monotherapy, only added after trials of one or more long-acting bronchodilators, and only in frequent exacerbators (≥2 exacerbations per year or 1 exacerbation with hospitalization).10 In addition, and according to some data, a FEV1<60% should also be taken into consideration.18

However, the recognized heterogeneity of COPD has therapeutic implications. The distribution of variables such as severity of airflow limitation, degree of breathlessness, health status, presence of co-morbidities, exercise capacity, and number of exacerbations in the previous year has been reported to be highly variable within each GOLD stage.1 Also, classification of disease severity by airflow obstruction has been challenged not only by GOLD guidelines10 but also by other studies.72,73 This variability precludes a general therapeutic approach for COPD patients. Indeed, the Spanish guidelines for treatment of COPD proposes four clinical phenotypes on which pharmacological treatment should be based, and recommends different treatment options depending on these four phenotypes.74,75 These guidelines have been recently updated, with some modifications.20

We suggest a pharmacological therapeutic approach based on GOLD stages Table 2.

Pharmacological treatment should not be given to asymptomatic GOLD A patients, but a SABA or a short-acting muscarinic antagonist (SAMA) can be used as rescue medication, if needed. However, if patients have a low FEV1 (50%≤FEV1≤80% predicted), evidence of hyperinflation, and mMRC=1, a long acting bronchodilator for symptom relief is recommended.10 For GOLD B patients, the choice of LABA or LAMA should be made according to efficacy in each individual patient. However, since previous exacerbations are the most reliable predictors of future exacerbations, the choice of a single long-acting bronchodilator should take into account the decreased risk of exacerbations,76 and, in this context, a LAMA should be the first choice. The combination LABA+LAMA is recommended for more symptomatic patients. Maintenance of monotherapy before switching to dual bronchodilation should be based on symptoms, risk factors, and possibility of improving non-pharmacological measures. There is no evidence concerning ICS treatment in patients with FEV1>60% predicted.10 For GOLD C and D patients, the combination LABA+LAMA should be the first choice; for those patients with frequent exacerbations (≥2 exacerbations/year, or 1 exacerbation with hospitalization), the ICS/LABA combination should be preferred. Triple therapy with ICS+LAMA+LABA should be considered for patients with frequent exacerbations who continue to have symptoms. Although there have been some developments on the inclusion of eosinophilic counts in the decision tree to prescribe ICS, this paper does not discuss this issue, which is duly addressed elsewhere.77

There are some additional therapies not mentioned in Table 2 that are available and may be useful in certain patients. In patients with severe hereditary α-1 antitrypsin deficiency (ZZ genotype), α-1 antitrypsin replacement therapy may be considered for young patients with established emphysema who meet the established laboratory criteria.10 However, this therapy is very expensive and is not available in most countries.10 The National Institute for Health and Care Excellence (NICE) guidelines do not recommend replacement therapy in patients with α-1 antitrypsin deficiency.6 Another class of potentially useful drugs is mucolytic agents, such as N-acetylcysteine (NAC) or carbocysteine, but their effect on reducing exacerbations have not been consistent across studies,78–85 and seem to depend on dose and COPD severity. Therefore, their generalized use is not recommended. Erdosteine seems to be associated with a significant benefit in terms of symptom amelioration,86 but larger long-term studies with fully validated endpoints are required87 before a clear recommendation can be offered. Theophylline, a methylxanthine, should only be considered if other long-term treatment bronchodilators are unavailable or unaffordable, or in patients who are unable to use inhaled therapy. Intravenous methylxanthines (theophylline or aminophylline) should only be used in the management of exacerbations when there is insufficient response to short-acting bronchodilators.6,10,24 The available evidence on the efficacy of immunostimulating agents is currently not supportive of a recommendation.10

We agree that bronchodilation is the cornerstone of COPD treatment. COPD is a highly variable disease, and each individual patient will have different therapeutic needs. Therefore, it is imperative to tailor therapy to each patient, given an optimized therapeutic approach will not only improve symptoms but also increase compliance. We further propose that exacerbator phenotypes modulate COPD severity within each GOLD stage and should therefore have a more aggressive treatment approach.

Several key points have been proposed to be included on the follow-up of COPD patients.12 One important aspect is that COPD patients often underestimate their symptoms, namely dyspnea, since they adapt their lifestyle to cope with it, which may lead to undertreatment. Therefore, measuring symptoms in a routine manner using questionnaires, can lead to a better understanding of the patient's overall clinical status and hence to the adjustment of treatment accordingly. In recent years, the goal of COPD management has shifted toward optimizing symptom control and reducing future risk, such as exacerbations, mortality, and co-morbidities, as well as the long-term consequences of COPD. While prevention and treatment of symptoms may not preclude long-term lung function decline, symptom control could provide measurable improvements in other key outcomes.11

There are no clear recommendations concerning when COPD patients should be referred to a pulmonology outpatient department, but some guidelines suggest reasons for referral, e.g. FEV1<50% predicted, frequent exacerbators, α-1 antitrypsin deficiency, ACOS, or uncertain diagnosis.6,7,24

In the absence of clear recommendations, we propose that a key aspect of COPD monitoring resides in a multidisciplinary approach, with Primary Care having a central role in the monitoring and follow-up of the majority of stable COPD patients. Primary Care should be responsible for recognizing when a patient should be referred to a specific specialty, e.g. Pulmonology, Cardiology, Internal Medicine or Physical Rehabilitation, and henceforth the coordinated and integrated management of comorbities should be achieved.

There is no established time interval between follow-up consultations, and this should be guided by clinical judgment. We recommend that a stable COPD patient, with no exacerbations and who complies with therapy, may have a follow-up consultation every 6 months. In all follow-up consultations questionnaires should be completed, especially mMRC. Annual spirometric assessment is recommended, especially in poorly controlled patients and frequent exacerbators. Although oximetry is useful, it is conditioned by availability.

Presently, it is not possible to reach a consensus regarding COPD control, which will probably be difficult to attain until a consensus definition of “well-controlled disease” is achieved. However, this definition depends not only on a thorough assessment of COPD severity and symptoms, but also their individual and social impact, which, again, are lacking. Initial assessment, monitoring and follow-up of COPD patients do not yet have clear recommendations, and new, more accurate, instruments to assess disease control are missing. Consensus about COPD control will probably not be attainable before the gap between disease assessment and disease control is bridged. Once this is achieved, it may pave the way for new avenues of research that will eventually answer the current questions.

Funding for this paper was provided by Novartis Portugal. Funding was used to access all necessary scientific bibliography and cover meeting expenses. Novartis Portugal had no role in the collection, analysis and interpretation of data, in the writing of the paper and in the decision to submit the paper for publication.

The authors declare collaborating and receiving fees from pharmaceutical companies other than Novartis either through participation in advisory board or consultancy meetings, congress symposia, clinical trial conduct or investigator-initiated trials.