The non-exacerbator phenotype is characterized by having at most one moderate exacerbation in the previous year without requiring hospitalization. The initial treatment for a high-risk COPD patient with a non-exacerbator phenotype is dual bronchodilation (LABA/LAMA). This recommendation is based on the demonstrated greater bronchodilator efficacy compared with monotherapy, accompanied by significant improvements in dyspnea, quality of life, exercise capacity, and a reduction in the use of rescue medication [35–39] (Table 4, Fig. 2). No superior efficacy of triple therapy over LABA/LAMA has been demonstrated in patients with only one moderate exacerbation (PICO 3, Table 4). The available LABA/LAMA combinations are listed in Table 3.

The exacerbator phenotype is defined as any patient with COPD who, in the previous year, has experienced two or more moderate exacerbations requiring treatment with systemic corticosteroids and/or antibiotics, or at least one severe exacerbation requiring hospital care [7]. These exacerbations must be separated by at least 4 weeks from resolution of the previous exacerbation or 6 weeks from symptom onset, to differentiate a new event from a relapse or treatment failure [7]. Given the different responses to pharmacological treatments, it is important to distinguish those with a T1/T3 (non-eosinophilic) endotype from those with a T2 (eosinophilic) endotype. Patients who, in the stable phase, have>300eosinophils/mm3 in peripheral blood will be classified as eosinophilic exacerbators. Blood eosinophil concentration may vary [49,50]; therefore, in some cases, it may be useful to obtain several measurements, always during the stable phase and within the same period used to assess exacerbation frequency, in order to make a more reliable therapeutic decision. Large studies conducted in Spain show that approximately 15–25% of COPD patients have>300eosinophils/mm3 in the stable phase [50,51].

Exacerbator patients with elevated blood eosinophil counts (>300cells/mm3) are more likely to have a clinical response to ICS [46,48,52]; this response is graded according to eosinophil concentration, so ICS may also be useful at eosinophil levels<300cells/mm3, although efficacy will be progressively lower as peripheral eosinophilia decreases [46,53] (Table 3).

ICS cannot be used as monotherapy in COPD, and trials of combination therapy have only been conducted with LABA/ICS. This combination has been shown to be superior to LABA/LAMA in eosinophilic exacerbator patients and could be considered an alternative initial therapy in minimally symptomatic patients (mMRC dyspnea<2) and without severe obstruction.

Given the high efficacy and favorable safety profile of LAMAs, it is reasonable to initiate triple therapy (LABA/LAMA/ICS) when the patient presents a high symptom burden, defined by an mMRC dyspnea score of 2 or more or an FEV1 (%) below 50% of predicted. In all other cases, treatment can be initiated with LABA/ICS, and triple therapy will be the second therapeutic step in eosinophilic exacerbator patients (Table 3 and Fig. 2). Recent studies of single-inhaler fixed triple therapy have demonstrated greater efficacy in improving lung function and respiratory symptoms and a greater reduction in exacerbation risk than the LABA/ICS combination [54–56]. Triple therapy has also shown a greater reduction in exacerbation risk than the LABA/LAMA combination, especially in patients with higher blood eosinophil concentrations [54,55,57]. These studies included symptomatic patients with frequent and severe exacerbations despite regular COPD treatment; therefore, in most cases, triple therapy is considered continuation treatment rather than initial treatment for COPD [58].

Despite maximum inhaled treatment with triple therapy, a significant number of patients with severe COPD may continue to experience exacerbations [59,60]. In patients with a T2 endotype, biologic drugs initially developed for asthma have been tested [61]. Among them, dupilumab, a fully human monoclonal antibody that blocks the shared receptor for IL-4 and IL-13, has been shown to reduce the risk of moderate-to-severe exacerbations by 31% in COPD patients with mucus hypersecretion and >300eosinophils/mm3 who continued to experience exacerbations despite triple therapy [62]. For this reason, the European Medicines Agency (EMA) has authorized its use, and its commercialization in Spain for the COPD indication is forthcoming. Dupilumab represents the next step in the treatment of high-risk eosinophilic exacerbator patients who continue to exacerbate despite triple therapy, once good adherence and correct inhaler use have been verified (Table 4). Other biologic drugs for COPD are also in development, and new products are expected to be launched in the coming years [61].

This refers to a patient who meets the criteria for the exacerbator phenotype but presents with a predominantly T1 endotype, with <300eosinophils/mm3 in peripheral blood. In these patients, the efficacy of ICS is lower, although this does not exclude them from treatment, particularly if the eosinophil count is >100cells/mm3[53].

In this group, the LABA/LAMA combination has shown a modest improvement in preventing exacerbations compared with LAMA alone [63,64], while also providing the added benefit of improving symptoms, exercise capacity, and quality of life compared with monotherapy [31–34,39]. A systematic review and meta-analysis of the results of LABA/LAMA versus LABA/ICS combinations in exacerbation prevention revealed wide differences in effectiveness, mainly due to the varying inclusion criteria of clinical trials. Moreover, none of these studies compared LABA/LAMA with LABA/ICS as initial treatment [54,55,65]. Overall, the LABA/ICS combination shows better results when eosinophil counts are higher (closer to 300eosinophils/mm3), when exacerbation frequency is greater, and when previous exacerbations responded well to systemic corticosteroids [55,66], whereas LABA/LAMA shows better results than LABA/ICS when eosinophil counts are lower, exacerbations are less frequent or require antibiotic treatment, while also providing greater bronchodilator effect and a lower risk of pneumonia [65,66].

Because GesEPOC 2025 considers concomitant asthma as a comorbidity that should be treated, patients with >300eosinophils/mm3 are classified within the eosinophilic phenotype, and most exacerbator patients have only two moderate exacerbations or one hospitalization in the previous year, first-line treatment with LABA/LAMA is recommended for the majority of non-eosinophilic exacerbator patients (Table 4). The LABA/ICS combination (or triple therapy in more symptomatic patients) may be considered when exacerbation frequency is higher, exacerbations respond to systemic corticosteroids, there is no history of pneumonia, and eosinophil counts are closer to 300eosinophils/mm3.

The non-eosinophilic exacerbator patient who continues to experience frequent or severe exacerbations despite treatment with LABA/LAMA requires specialized care, and the presence of treatable traits should be investigated [67,68], as will be detailed in the corresponding section. Regarding inhaled therapy, ICS in the form of triple therapy may be useful in patients with eosinophil counts between 100 and 300cells/mm3[54,55,66]. In this situation, the indication for ICS should again consider factors associated with greater efficacy and safety of ICS, namely: (1) more frequent or severe exacerbations, (2) prior exacerbations responsive to oral corticosteroids, (3) non-active smokers, and (4) no history of pneumonia [69].

In contrast, there is no evidence supporting the efficacy of ICS in patients with eosinophil counts<100cells/mm3. In the meta-analysis conducted to evaluate the evidence for this PICO question, no differences were observed in the overall rate of exacerbations, moderate or severe exacerbations, or in the time to first exacerbation between patients receiving triple therapy versus LABA/LAMA, despite the fact that these were already moderate-to-severe patients who had been previously treated. However, there was a small but significant 16% increase in adverse event rates, most of them non-serious, in patients on triple therapy. For this reason, triple therapy is not recommended in patients with <100eosinophils/mm3[54,55,66,70,71] (Table 4). When initial treatment was started with LABA/ICS, escalation should be to triple therapy.

• V.

  Identification and management of treatable traits

The term “treatable trait” is used to refer to a clinical, physiological, radiological, or biological characteristic that can be identified through diagnostic tests or biomarkers and that has a specific treatment with clinical benefit for patients [67,68]. It is important to bear in mind that in a given patient, multiple treatable traits are likely to coexist, and all of them should be considered. In its definition, the essential objective is to improve clinical outcomes for individual patients while minimizing unnecessary side effects in those less likely to benefit from a specific treatment.

Based on their relevance and applicability, GesEPOC 2025 identifies the most important and frequent treatable traits that should be investigated in high-risk patients, with the exception of alpha-1 antitrypsin deficiency, which must be investigated in all COPD patients regardless of their risk level [72] (Table 5, Fig. 3). The details on non-pharmacological treatments for treatable traits have been addressed in other documents [15]; therefore, they will only be briefly mentioned here.

Fig. 3.

Main treatable traits in COPD.

Dyspnea should be considered a symptom; however, for organizational reasons it is included in this section on treatable traits. Patients who continue to experience significant dyspnea despite dual bronchodilation require an evaluation that includes the possibility of identifying treatable traits and ruling out comorbidities that may worsen dyspnea, such as heart failure. These high-risk patients should be assessed in specialized units and require comprehensive pulmonary function studies, as well as imaging, to determine the potential for non-pharmacological therapeutic alternatives such as pulmonary rehabilitation and/or lung volume reduction.

From a pharmacological perspective, the addition of theophylline may be considered. These are weak bronchodilators with a positive effect on diaphragmatic strength, improved respiratory muscle performance, reduced air trapping, and enhanced mucociliary clearance [73,74]. Although the usual dose is 200–300mg every 12h orally in sustained-release tablets [74], lower doses (100mg every 12h) have been shown to improve pre-bronchodilator FEV1[75], although no effect has been demonstrated on exacerbation prevention [76,77].

The toxicity of theophylline is dose-dependent. When administered long-term, plasma concentrations must be monitored, and the risk of interactions with other drugs such as allopurinol, ciprofloxacin, erythromycin, benzodiazepines, or cimetidine, among others, must be taken into account. In any case, its limited clinical efficacy, narrow therapeutic margin, and high potential for drug interactions relegate theophylline to a third-line option, mainly in high-risk patients who remain dyspneic after dual bronchodilator therapy [73].

Low-dose opioids are suggested in patients with refractory dyspnea despite optimized treatment, anticipating potential side effects (e.g., constipation). At low doses, opioids do not increase the risk of hospitalization or mortality, even in patients with advanced respiratory failure. Continuation of treatment should be individualized according to variability in patient response [16].

Alpha-1 antitrypsin deficiency (AATD) is a congenital cause of emphysema in adulthood [72]. Severe AATD affects approximately 1 in 4500 individuals of Caucasian descent and accounts for about 1 in every 700 COPD cases in southern Europe [78]. For accurate identification, every patient with COPD should undergo at least one measurement of serum AAT concentrations or a genotype determination using noninvasive techniques such as DNA analysis obtained from buccal mucosa cell swabs [79]. Once a patient with AATD has been identified, a family study should be conducted to detect possible undiagnosed cases [72]. Identified cases should be reported to the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, which is integrated into the European Alpha-1 Antitrypsin Deficiency Research Collaboration (EARCO) registry [80], and they should be referred to a reference center for comprehensive diagnosis, evaluation of potential replacement therapy, and family studies [81].

Augmentation therapy with purified AAT is indicated in patients with pulmonary emphysema associated with severe AATD because of its effect in slowing the loss of lung density [82] (Table 4). Early diagnosis is essential to avoid risk exposures—particularly smoking—and to initiate replacement therapy as soon as possible in order to preserve lung tissue [72]. However, due to the considerable variability in the progression of emphysema in AATD [83], treatment should be prescribed by experienced specialists in reference centers [81].

The presence of severe emphysema with hyperinflation leads to severe dyspnea and exercise intolerance. Its evaluation requires a detailed assessment with chest CT, lung volumes, DLco, and a 6-min walk test. Depending on the severity and distribution of emphysema, the patient may be a candidate for endoscopic or surgical lung volume reduction techniques, which are not addressed in this document [84].

This condition often presents with severe dyspnea that is disproportionate to the degree of bronchial obstruction, and with exercise intolerance accompanied by severe and early desaturation during the 6-min walk test [85]. Evaluation requires arterial blood gas analysis, walk test, echocardiography, natriuretic peptide measurement, and right heart catheterization. Treatment usually involves oxygen therapy in addition to management of the underlying disease [86]. A vascular phenotype of COPD has been described, characterized by hypoxemia with normocapnia or hypocapnia, very low diffusion capacity, and dyspnea with minimal exertion showing a cardiovascular exercise limitation pattern in the presence of only mild to moderate airflow obstruction [87,88].

In patients with COPD and severe hypoxemia (PaO2≤55mmHg) at rest, continuous oxygen therapy has been shown to provide survival and quality-of-life benefits. Continuous oxygen therapy (at least 15h per day, including sleeping hours) is indicated when PaO2 at rest is ≤55mmHg, and also when PaO2 at rest is between 56 and 59mmHg with evidence of hypoxia-induced organ damage (including right heart failure, pulmonary hypertension, or polycythemia). The oxygen flow rate must be sufficient to maintain a PaO2>60mmHg or a SpO2>90% [89,90].

Long-term home noninvasive mechanical ventilation is recommended in patients with stable hypercapnic COPD (PaCO2>52mmHg) due to its survival benefits, or in those who remain hypercapnic 2–4 weeks after an episode of hypercapnic respiratory failure requiring hospital ventilatory support, given its benefits in prolonging the time to hospital readmission or death [91,92]. Overlap syndrome with obstructive sleep apnea and obesity hypoventilation syndrome should be differentiated from chronic hypercapnia attributable solely to advanced COPD.

Chronic bronchitis is classically defined as the production of sputum for at least three consecutive months in two successive years, although in practical terms it may be considered as the habitual production of sputum during the stable phase of COPD. It is a risk factor for frequent exacerbations and has a significant impact on patients’ quality of life [93].

Patients who continue to experience exacerbations and have chronic bronchitis despite optimal inhaled therapy may benefit from treatment with mucolytics/antioxidants. Carbocisteine at a dose of 500mg every 8 or 12h [94] and high-dose N-acetylcysteine (NAC), considered to have antioxidant effects (600mg every 12h), have demonstrated a significant reduction in exacerbations, particularly in high-risk patients (those with FEV1<50% or with ≥2 exacerbations in the previous year, or both) [95–98] (Table 4).

A specific alternative for exacerbator patients with chronic bronchitis is roflumilast. Roflumilast is an oral anti-inflammatory drug and phosphodiesterase-4 inhibitor that has been shown to prevent exacerbations in patients with severe COPD who present with chronic cough and sputum production and also suffer frequent exacerbations [99]. The effect of roflumilast in preventing exacerbations has been observed when added to maintenance therapy with long-acting bronchodilators and even when added to triple therapy, particularly in more severe patients requiring hospital admission [100] (Table 4). The usual dose is 500μg orally once daily.

Adverse effects with roflumilast usually appear at the beginning of treatment, are quickly noticed by the patient, and generally resolve within the first four weeks, although in some cases they lead to discontinuation of the drug. The most frequent adverse effects are weight loss, gastrointestinal disturbances, nausea, headache, and loss of appetite. The safety profile of roflumilast is not modified by concomitant COPD treatments the patient may be receiving. The use of roflumilast should be avoided in combination with theophylline. GesEPOC suggests treatment with roflumilast in patients with COPD, severe obstruction, chronic bronchitis, and exacerbations despite adequate inhaled therapy [97].

The exacerbator phenotype may present with bronchiectasis in up to 70% of cases [101], which can contribute to perpetuating a vicious cycle by amplifying underlying inflammation and inducing frequent exacerbations and are even associated with increased mortality [102,103]. In patients with COPD and bronchiectasis, the infectious component and mucus hypersecretion should be managed in accordance with established bronchiectasis treatment guidelines [104].

Chronic bronchial infection (CBI) is defined as the isolation of the same potentially pathogenic microorganism in at least three sputum cultures within one year, separated by at least one month between samples [105]. The presence of CBI is associated with increased frequency and severity of exacerbations and poorer prognosis [106]. Treatment is indicated when CBI is associated with frequent exacerbations. There is no evidence supporting the effectiveness of treating CBI in the uncommon case of non-exacerbator patients.

In exacerbator patients, long-term macrolide therapy is indicated if they present with at least three exacerbations in the previous year despite adequate inhaled treatment [107]. Long-term administration of macrolides has been shown to significantly reduce the number of exacerbations [107,108]. The effectiveness of macrolides in COPD has been observed in patients both with and without associated bronchiectasis [107]. The recommended dosage is azithromycin 500mg/day, three days per week, or 250mg/day daily. This treatment should be restricted to reference centers with appropriate monitoring, including clinical assessment, hearing tests, ECG, liver function tests, and microbiological studies to rule out mycobacterial infection. There is limited evidence regarding the efficacy of this treatment beyond one year of follow-up; therefore, an annual evaluation of the potential risk–benefit ratio is recommended [109]. In line with other international guidelines, GesEPOC suggests long-term macrolide therapy in high-risk COPD patients with exacerbations despite adequate inhaled treatment [97] (Table 4).

There is very limited evidence regarding the efficacy and safety of inhaled antibiotic therapy, but it may be considered as an alternative in high-risk patients with frequent exacerbations and CBI, based on existing experience with CBI treatment in bronchiectasis [105,110,111]. It is important to note that tolerance to inhaled antibiotic therapy in COPD may be lower than that observed in bronchiectasis, particularly due to the reduced ventilatory reserve of COPD patients [112].

• VI.

  Treatment adjustment during follow-up

Treatment adjustment should be performed at each medical visit, during which possible changes in risk level, phenotype, or the appearance of new treatable traits should be assessed. GesEPOC proposes evaluating clinical control of COPD through the use of a scale specifically designed and validated to facilitate therapeutic decisions, based on a set of variables that are easy to obtain at each visit [113]. The combination of these variables indicates that the patient is well controlled when they present stability (no exacerbations in the previous 3 months) and a low-impact profile, defined as low levels of dyspnea, absence of sputum or presence of mucoid sputum, infrequent use of rescue medication, and an adequate level of physical activity [114]. The detailed criteria for assessing COPD control are presented in Fig. 4. Patients classified as uncontrolled have a higher risk of exacerbations in both the short term (within the next 6 months) and the long term, as well as a greater risk of deterioration in health-related quality of life [113,115]. Therefore, a detailed analysis of the possible causes of this lack of control is required, and it may be necessary to intensify treatment.

Fig. 4.

Criteria for COPD control.

A quantitative control scale, the RADAR scale, has recently been developed to classify three levels of control: uncontrolled, partially controlled, and controlled. This classification is based on the assessment of dyspnea, physical activity performed, exacerbations in the previous three months, and the use of rescue medication [116]. This scale is currently undergoing validation [117]. Fig. 5 provides a series of recommendations to follow when uncontrolled patients are identified during follow-up visits.

Fig. 5.

Follow-up of COPD patients according to their level of disease control.

In controlled patients, treatment de-escalation may be considered. With respect to bronchodilator therapy, it is well known that its effect lasts only during administration; therefore, the withdrawal of a bronchodilator, or its substitution with another of lower bronchodilator potency or shorter duration of action, is expected to result in functional or symptomatic worsening [118,119].

Conversely, GesEPOC suggests the withdrawal of ICS in patients without frequent exacerbations (no more than one moderate episode in the previous year) and <300eosinophils/mm3. However, in patients with frequent exacerbations, there is insufficient evidence to establish a recommendation for ICS withdrawal. ICS withdrawal studies have shown a significant increase in the risk of exacerbations when ICS are discontinued in patients with >300eosinophils/mm3, which supports a strong recommendation not to withdraw ICS in eosinophilic exacerbator patients [120] (Table 4). The purpose of ICS withdrawal is to avoid the potential occurrence of adverse effects [121] in patients for whom their efficacy has not been demonstrated.