No type of oral or anti-inflammatory treatment is indicated in the low-risk patient, and pharmacological treatment will consist of long-acting bronchodilators (LABD). In the rare case of mild obstruction with few or intermittent symptoms, short-acting bronchodilators (SABD) on demand may be indicated.

SABD can be of 2 types: anti-cholinergics (SAMA, short-acting muscarinic antagonists) such as ipratropium bromide, and short-acting beta-2 agonists (SABA) such as salbutamol or terbutaline. In patients with occasional symptoms, SABD treatment reduces symptoms and improves exercise tolerance.11 Because of their rapid onset of action, these drugs, added to the baseline treatment, are preferred for on-demand treatment of symptoms, regardless of the level of disease severity. In patients with persistent symptoms or limitations in their daily activities as a result of their respiratory problem, regular baseline treatment with a LABD will be required.

LABD can be beta-2 adrenergics (LABA, long-acting beta-agonists) or anticholinergics (LAMA, long-acting muscarinic antagonists). The LABA available in Spain are salmeterol, formoterol, indacaterol, olodaterol and vilanterol, and the LAMA are tiotropium, aclidinium, glycopyrronium and umeclidinium (Table 3). LABD should be used as a first step in the treatment of all patients with persistent symptoms who require regular treatment, because they enable better control of symptoms than can be achieved with SABD and improve lung function, exercise capacity and QoL.12,13 Furthermore, LABD – both LABA and LAMA – have been shown to reduce the number of exacerbations.14

There are differences between the different LABD; some have a duration of action of 12 h (aclidinium, salmeterol and formoterol) and others 24 h (tiotropium, umeclidinium, glycopyrronium, indacaterol, olodaterol and vilanterol). In terms of preventing exacerbations, tiotropium has been shown to be more effective than salmeterol or indacaterol15,16; for this reason, when choosing an LABD as monotherapy, a LAMA is recommended as first choice over a LABA (Table 4).

LABD are generally well tolerated and have few adverse effects. Nevertheless, the following should be considered: LABA has been associated with fine tremor of the extremities, muscle cramps, tachycardia, high blood pressure, peripheral vasodilatation, headache, hyperglycemia, hypokalemia, cough, bronchospasm, oropharyngeal irritation and dyspepsia, while LAMA may be associated with dry mouth, urinary retention, increased ocular pressure, and pharyngeal irritation. It should be noted that clinical trials exclude patients with significant heart disease, so clinicians should be vigilant with the use of bronchodilators in these patients.12,13

In symptomatic patients or those with clear exercise limitation despite bronchodilator monotherapy, treatment compliance and proper inhalation technique must be verified; there is also the possibility of switching LABD, for example, from a LAMA to a LABA.17 The next therapeutic step is dual bronchodilator therapy; the combination of LABA and LAMA offers an added functional benefit, with less need for rescue medication and improvement in symptoms and QoL compared to monotherapy.12,13,18,19

In the next treatment step in low-risk patients, two LABDs can be combined to optimize the bronchodilator effect (Fig. 2, Table 3).

Fig. 2.

Treatment of COPD guided by risk level and phenotype.

(*) Second-line in patients with blood eosinophils >100 cells/mm3, according to the frequency, severity and etiology of the exacerbations, assessing the risk of pneumonia.

(0.29MB).

In high-risk patients, GesEPOC 2021 recognizes three phenotypes in the pharmacological treatment scheme: 1) non-exacerbator; 2) eosinophilic exacerbator; and 3) non-eosinophilic exacerbator.

This distribution of phenotypes differs from that of GesEPOC 2017,4 and is led by several pieces of evidence. First, the so-called mixed asthma-COPD phenotype (ACO, asthma-COPD overlap) was defined by GesEPOC and the Spanish Guidelines on the Management of Asthma (GEMA) as a patient with COPD and a concomitant diagnosis of asthma or with peripheral eosinophilia or a strongly positive bronchodilator test.20,21 Evidence has accumulated in recent years on the predictive role of peripheral eosinophilia in the clinical response to inhaled corticosteroids (ICS) in COPD. However, it has been found that a strongly positive bronchodilator test rarely occurs in isolation and has little diagnostic value.24,25 For this reason, GesEPOC proposes separating the two main clinical forms of ACO,26 reserving the name ACO for the coexistence of asthma as a comorbidity in a patient with COPD, requiring both diseases to be treated. In contrast, the presence of peripheral eosinophilia (>300 cells/μL) in a patient with a history of repeated exacerbations (2 or more in the last year or 1 with hospital admission) will define the eosinophilic exacerbator COPD patient.

In terms of the emphysema and chronic bronchitis phenotypes, both are well defined.1 However, there is no difference between them with regard to inhaled treatment of COPD. For this reason, we will include emphysema, as well as chronic cough and expectoration, in the list of treatable traits, as they will be useful in severe patients for the indication of other specific non-inhaled or non-pharmacological treatments. Thus, the GesEPOC 2021 phenotypes are defined as:

The non-exacerbator phenotype is characterized by a maximum of 1 exacerbation in the previous year without requiring inpatient care. Initial treatment in a patient with high-risk non-exacerbator COPD is dual bronchodilation (Table 4). This recommendation is based on evidence of superior bronchodilator efficacy compared to monotherapy, accompanied by a significant improvement in dyspnea and QoL and a reduction in the use of rescue medication18,27; this has even been demonstrated in patients not receiving concomitant ICS.28 Existing combinations of LABD (LABA/LAMA) are presented in Table 3.

An exacerbator phenotype is defined as any patient with COPD who presents 2 or more outpatient exacerbations, or 1 or more severe exacerbations requiring inpatient care in the previous year.29 To differentiate the new event from relapse or therapeutic failure, these exacerbations must be separated by at least 4 weeks from the resolution of the previous exacerbation, or 6 weeks from the onset of symptoms.29 Due to the different response to pharmacological treatments, it is important to differentiate patients with an eosinophilic or non-eosinophilic phenotype. Patients with >300 eosinophils/mm3 in a stable phase will be classified as eosinophilic exacerbators. The blood eosinophil count can vary,30,31 so it will be preferable to have different determinations from the same period in which the frequency of exacerbations is evaluated in order to make a more reliable therapeutic decision. Extensive studies in Spain show that approximately 15%–25% of patients with stable COPD have >300 eosinophils/mm3.31,32

Exacerbator patients with an elevated blood eosinophil count (>300 cells/mm3) experience a better clinical response to ICS and justify the use of ICS combined with a LABA as a first option to reduce the risk of exacerbations22,23,33 (Table 3). The response gradient to ICS depends on the blood eosinophil count, so while these compounds may also be useful in patients with values <300 cells/mm3, they will become less effective as peripheral eosinophilia decreases.22,34

The next therapeutic step in eosinophilic exacerbator patients is triple ICS/LABA/LAMA therapy (Table 3 and Fig. 2). Recent studies of fixed triple therapy have shown greater efficacy in improving lung function and respiratory symptoms and a greater reduction in the risk of exacerbations than the LABA/ICS combination.35–37 Triple therapy has also shown a greater reduction in the risk of exacerbations than the LABA/LAMA combination, especially in patients who had a higher blood eosinophil count.35,36,38 These studies included symptomatic patients with frequent severe exacerbations despite regular treatment for their COPD; triple therapy is therefore considered a continuation treatment and not an initial treatment for COPD.39

This is a patient who meets the criteria for the exacerbator phenotype, but at the same time has <300 eosinophils/mm3 in peripheral blood. ICS are less effective in these patients, although this does not exclude them from treatment, particularly if the eosinophil count is >100 cells/mm.3,34

In these patients, the LABA/LAMA combination has shown a modest improvement in the prevention of exacerbations compared to LAMA,40,41 but offers the added benefit of improving symptoms and QoL compared to monotherapy.12,13,18,19 The systematic review and meta-analysis of the results of LABA/LAMA versus LABA/ICS combinations in the prevention of exacerbations show large differences in effectiveness, mainly due to the different inclusion criteria in the clinical trials. Moreover, none of these studies compared LABA/LAMA with LABA/ICS as initial treatment35,36,42 (Supplement 1). The LABA/ICS combination generally provides better results when eosinophil counts are higher (closer to 300 eosinophils/mm3), when the frequency of exacerbations is higher, and when previous exacerbations responded well to systemic corticosteroids.36,43 The LABA/LAMA combination, on the other hand, offers better results than LABA/ICS when eosinophil counts are lower and exacerbations are less frequent or require treatment with antibiotics; it also has a greater bronchodilator effect and a lower risk of pneumonia.42,43 Since GesEPOC 2021 considers concomitant asthma as a comorbidity that must be treated, since patients with >300 eosinophils/mm3 are classified as eosinophilic phenotypes and, furthermore, since most exacerbator patients have a low frequency of exacerbations, first-line treatment with LABA/LAMA is recommended in most non-eosinophilic exacerbator patients (Table 4). The LABA/ICS combination may be indicated when the frequency of exacerbations is higher, the exacerbations respond to systemic corticosteroids, there is no history of pneumonia, and the eosinophil count is closer to 300 eosinophils/mm3.

The non-eosinophilic exacerbator patient who presents frequent or severe exacerbations despite treatment with LABA/LAMA requires specialized care, and the presence of treatable traits should be investigated,44,45 as indicated in the corresponding section. In relation to inhaled treatment, ICS in the form of triple therapy may be useful if the patient has eosinophil counts between 100 and 300 cells/mm.3,35,36,43 In this case, the indication for ICS should reconsider the factors associated with greater effectiveness and safety of ICS, such as: 1) more frequent or severe exacerbations, 2) previous exacerbations that respond to oral corticosteroids, 3) no current smokers, and 4) no history of pneumonia.46 In contrast, the efficacy of ICS in patients with eosinophil counts <100 cells/mm3 is very limited and their use is not recommended to avoid adverse effects35,36,43,47 (Table 4). When treatment was initiated with LABA/ICS, escalation will be to triple therapy.

Dyspnea should be regarded as a symptom, but for reasons of text organization, we have included the treatment of severe dyspnea in this section. Patients who continue to have significant dyspnea despite dual bronchodilation require an evaluation that includes the possibility of identifying treatable traits and ruling out comorbidities that may increase dyspnea, such as heart failure. In particular, the need for a pulmonary rehabilitation program and a chest computed tomography (CT) to evaluate the indication for lung volume reduction techniques should be assessed.

From a pharmacological point of view, the addition of theophyllines may be attempted. These are weak bronchodilators that have a positive effect on diaphragm strength, increase performance of the respiratory muscles, reduce air trapping and improve mucociliary clearance.49,50 Although the usual dose is 200–300 mg/12 h orally in sustained-release tablets, good results have been obtained with doses of 200 or 300 mg/day in 24 h extended-release preparations.50 Lower doses (100 mg/12 h) have shown beneficial effects on pre-bronchodilator FEV1,51 although they have not demonstrated an effect on the prevention of exacerbations.52,53

Theophylline toxicity is dose-dependent. When administered on a long-term basis, plasma concentrations should be checked, and clinicians must take into account the risk of interactions with other drugs such as allopurinol, ciprofloxacin, erythromycin, benzodiazepines and cimetidine, among others. In any case, their limited clinical efficacy and narrow therapeutic margin relegate them to third-line therapy, mainly in high-risk patients if dyspnea persists after dual bronchodilator therapy.49

Alpha-1 antitrypsin (AAT) deficiency is a congenital cause of emphysema in adulthood.48 Severe AAT deficiency affects 1/4500 Caucasian people and is responsible for approximately 1 in every 700 cases of COPD in southern Europe.54 For correct identification, all patients with COPD should have at least 1 measurement of their serum AAT levels or determination of their genotype using non-invasive techniques such as DNA analysis obtained by buccal swabs.55 After a patient with AAT deficiency is identified, a family study should be carried out to identify possible undiagnosed cases.48 Any cases identified should be reported to the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, part of the EARCO (European Alpha-1 Research Collaboration) European registry,56 and the patient should be referred to a reference center for complete diagnosis and assessment for possible augmentation therapy and a family study.57

Augmentation therapy with purified AAT is indicated in patients with pulmonary emphysema associated with severe AAT deficiency, due to its effect in slowing down the loss of lung density58 (Table 4). Early diagnosis is important to avoid risk exposures, especially smoking, and to initiate specific treatment as soon as possible to preserve lung tissue.48

The presence of severe emphysema with hyperinflation leads to severe dyspnea and exercise intolerance. Its evaluation requires detailed analysis with chest CT, lung volumes, CO diffusing capacity test and 6-minute walk test. Depending on the severity and distribution of emphysema, the patient may be eligible for endoscopic or surgical lung volume reduction techniques.59

Pulmonary arterial hypertension also usually presents with severe dyspnea or dyspnea disproportionate to the degree of bronchial obstruction, and exercise intolerance with severe early desaturation during the 6-minute walk test (6MWT). It requires assessment with arterial blood gases, 6MWT, echocardiography, natriuretic peptide determination, and cardiac catheterization. Treatment usually involves oxygen therapy in addition to treatment of the underlying disease.60 A vascular phenotype has been described in COPD, characterized by hypoxemia with normocapnia or hypocapnia, very low diffusing capacity and dyspnea on minimal exertion, and a cardiovascular exercise limitation pattern in the presence of mild or moderate airflow limitation.61,62

In patients with COPD and severe hypoxemia (PaO2 ≤ 55 mmHg) at rest, continuous oxygen therapy has shown a benefit in survival and QoL. Continuous oxygen therapy (at least 15 h a day, including sleep hours) is indicated when resting PaO2 is ≤55 mmHg, and also when resting PaO2 is 56–59 mmHg with evidence of organ damage due to hypoxia (including right-sided heart failure, pulmonary hypertension and polycythemia). Oxygen flow should be sufficient to maintain a PaO2 >60 mmHg or SpO2 >90%.63

Long-term high-intensity home mechanical ventilation is recommended in patients with stable hypercapnic COPD, given its survival benefits, or in patients who remain hypercapnic 2–4 weeks after an episode of hypercapnic respiratory failure who require in-hospital ventilatory support due to its benefits in prolonging time to hospital readmission or death.64,65 Overlap syndrome and obesity hypoventilation syndrome should be differentiated from chronic respiratory failure attributable only to advanced COPD.

Chronic bronchitis is classically defined as the production of sputum for at least 3 months of the year in 2 consecutive years, although for practical purposes, it can be considered as the regular production of sputum in stable COPD. It is a risk factor for frequent exacerbations and has a significant impact on patient QoL.66

Patients with exacerbations and chronic bronchitis despite optimal inhaled treatment may benefit from treatment with mucolytics/antioxidants. Carbocysteine67 and high doses of N-acetylcysteine (NAC), considered antioxidant (600 mg/12 h), have shown a significant reduction in exacerbations, especially in high-risk patients (those with FEV1 <50% or 2 or more exacerbations in the previous year, or both)68–70 (Table 4).

A specific alternative for exacerbators with chronic bronchitis is roflumilast. This is an oral anti-inflammatory drug, a phosphodiesterase-4 inhibitor, that has been shown to prevent exacerbations in patients with severe COPD who have chronic cough and sputum production, and frequent exacerbations.71 This effect is maintained when roflumilast is added to maintenance treatment with an LABD, either LABA or LAMA. The effect of roflumilast in the prevention of exacerbations has been observed even when added to triple therapy, and especially in patients with more severe COPD who require hospital admission72 (Table 4). The usual dose is 500 µg orally once daily.

Adverse effects with roflumilast usually appear at the start of treatment, are rapidly detected by the patient, and usually resolve within the first four weeks, although they may occasionally lead to discontinuation of the drug. The most common adverse effects are weight loss, gastrointestinal disturbances, nausea, headache and loss of appetite. The safety profile of roflumilast is not modified by any concomitant treatment that the patient may be taking for COPD. The use of roflumilast with theophyllines should be avoided. Ges-EPOC suggests treatment with roflumilast in patients with COPD and severe obstruction, chronic bronchitis and exacerbations despite adequate inhaled treatment.70

The exacerbator phenotype can present bronchiectasis in up to 70% of cases,73 which can help perpetuate a vicious circle, amplifying the underlying inflammation and inducing the presence of frequent exacerbations, and is even associated with higher mortality.74 In patients with COPD and bronchiectasis, the infectious component and mucus hypersecretion should be treated according to bronchiectasis treatment guidelines.75

Chronic bronchial infection (CBI) is defined as the isolation of the same potentially pathogenic microorganism in at least 3 sputum cultures in 1 year, at least 1 month apart.76 The presence of CBI is associated with more frequent and more severe exacerbations and worse prognosis.77 Treatment will be indicated if it is associated with frequent exacerbations. There is no evidence of the effectiveness of treatment for CBI if it occurs in the rare case of non-exacerbator patients.

Long-term treatment with macrolides is indicated in exacerbator patients if they present at least 3 exacerbations in the previous year despite adequate inhaled therapy.78 Macrolides administered on a long-term basis have been shown to significantly reduce the number of exacerbations.78,79 The effectiveness of macrolides in COPD has been observed in patients with and without associated bronchiectasis.68 The recommended dose is azithromycin 500 mg/day, 3 days per week. This treatment should be reserved for reference centers with clinical, auditory, ECG, liver biochemistry and microbiological monitoring to rule out mycobacterial infection. There is little evidence on the efficacy of this treatment beyond 1 year of follow-up, so the possible risk-benefit should be evaluated annually.80 Like other international guidelines, GesEPOC suggests long-term macrolide treatment in patients with moderate to very severe COPD and exacerbations despite adequate inhaled therapy70 (Table 4).

There is very little evidence on the efficacy and safety of treatment with inhaled antibiotics, but it can be considered as an alternative in patients with severe COPD with frequent exacerbations and CBI, based on experience in the treatment of CBI in bronchiectasis.76,81

Treatment should be adjusted at each medical visit, when possible changes in the risk level, phenotype or the appearance of new treatable traits should be evaluated. GesEPOC proposes to use COPD control as a therapeutic target by applying a scale designed and validated to facilitate therapeutic decisions, which is based on a series of variables easily obtained at each visit.82 The combination of these variables indicates that the patient has good control when he is in a situation of stability (no exacerbations in the previous 3 months) and low impact, defined by a low level of dyspnea, with no expectoration or mucus expectoration, infrequent use of rescue medication and an adequate level of physical activity.83 Detailed criteria for evaluating COPD control are presented in Fig. 3. Patients classified as uncontrolled have a higher risk of exacerbations both in the short term in the next 6 months, and in the long term, and a higher risk of deterioration in their health-related QoL84,85; detailed analysis of the possible causes of this lack of control is therefore necessary, and an increase in the intensity of treatment may be required.

Fig. 3.

COPD control criteria.

(0.66MB).

The previous section on pharmacological treatment described successive steps for increasing the intensity of treatment according to the increase in symptoms or the frequency of exacerbations; conversely, de-escalation may also be considered in treatment in controlled patients. Bronchodilator treatment is known to exert its effect only during administration, so it is very likely that withdrawing a bronchodilator or replacing it with another with lower bronchodilator potency or shorter duration of action will cause functional or symptomatic worsening.86,87 Instead, GesEPOC suggests withdrawing ICS in patients who do not have frequent exacerbations (no more than 1 moderate exacerbation in the previous year) and <300 eosinophils/mm3. However, in patients with frequent exacerbations, there is insufficient evidence to establish a recommendation for withdrawal of ICS. Studies on withdrawal of ICS have shown a significant increase in the risk of exacerbations when ICS are withdrawn in patients with >300 eosinophils/mm3, so it is strongly recommended not to withdraw ICS in eosinophilic exacerbator patients88 (Table 4). The aim of ICS withdrawal is to avoid the possible appearance of adverse effects89 in patients in whom their efficacy is not proven.