The relationship between COPD and cardiovascular disease is clearly relevant, since it affects the clinical presentation of COPD, alters diagnostic tests, and has therapeutic implications. The main cardiological diseases associated with COPD are heart failure of different etiologies, rhythm disorders, primarily atrial fibrillation, ischemic heart disease, systemic arterial hypertension, sudden death, peripheral arterial disease, and cerebrovascular disease.6

In terms of the impact of cardiovascular disease on the clinical presentation of COPD, whether stable phase disease or exacerbations, when the primary clinical expression is dyspnea, concomitant cardiovascular disease must be considered in a patient who is persistently poorly controlled despite correct inhaled treatment (Table 2).7 In these cases, an electrocardiogram and echocardiography are recommended as a first approach, while a exercise test should be considered if the contribution of each organ to exercise tolerance needs to be determined. Furthermore, COPD patients who attend the emergency department for dyspnea often have heart disease,8,9 so it would be reasonable to recommend a cardiological clinical evaluation along with the determination of markers of heart failure (pro-BNP) or acute myocardial damage (troponin) as part of the study of acute dyspnea.

From a diagnostic point of view, the presence of hyperinflation has been associated with impaired cardiac function.10 Heart failure may also be associated with a restrictive component in spirometry.11 COPD patients should, therefore, be examined for clinical signs of heart failure if spirometry shows a mixed pattern.

From a therapeutic point of view, 3 factors should be taken into consideration. First, although the cardiovascular safety of bronchodilator drugs has been demonstrated,12 it is also that one of the most common adverse effects is an elevated heart rate, especially with short-acting bronchodilators, seems reasonable to avoid their excessive use and to ensure the correct dosing of long-acting compounds. Second, if beta-blockers are necessary, cardioselective drugs (acebutolol, atenolol, bisoprolol, celiprolol, metropolol, nebivolol and esmolol)13 should be used. Third, although systemic corticosteroids are only recommended in COPD exacerbations, we should remember that the main adverse effects of glucocorticoids on the cardiovascular system include dyslipidemia and hypertension. These effects may predispose to coronary artery disease if high doses and prolonged courses are administered.14

The relationship of COPD with various gastrointestinal conditions has been discussed in the literature, but 2 comorbidities of particular significance emerge: periodontal disease and gastroesophageal reflux. Several papers have described a higher frequency of periodontal disease in COPD patients.15 Although COPD patients are at increased risk for periodontal disease, the impact of the disease on clinical presentation, diagnostic techniques, and COPD treatment has not been conclusively demonstrated. Its impact on self-reported quality of life has been noted, but no effect on the frequency of exacerbations has been observed.16,17 COPD patients should therefore be advised to maintain good oral health, especially if they are symptomatic.

Numerous studies exploring the relationship between gastroesophageal reflux and COPD have consistently shown an increased risk of exacerbations.18 This relationship has two controversial aspects. The first is that gastroesophageal reflux can be asymptomatic19 and the effect of asymptomatic reflux on COPD exacerbations has not been sufficiently explored. Secondly, the efficacy of reflux treatment in reducing the risk of exacerbations is under debate.20–23 Despite these limitations, it seems reasonable to recommend active screening for the presence of gastroesophageal reflux in patients with persistent exacerbations and to start appropriate treatment, if available.

Although the data are conflicting,24–27 an association has been described between treatment with inhaled antimuscarinic drugs and episodes of urinary retention.28 The risk may be greater in patients who use both SAMA and LAMA simultaneously25,29,30 and in subjects with benign prostatic hyperplasia25,29,31 during the first months of treatment.25,31 Therefore, urinary symptoms should be monitored in patients with COPD and prostatic hyperplasia during the first few months of treatment, especially if they are receiving a SAMA-LAMA combination.

The musculoskeletal system includes the joints, bones, and muscles. The most relevant comorbidities to consider are osteoporosis and muscle disorders. There is evidence on the association between COPD and osteoporosis.32 COPD patients have a higher prevalence of vertebral fractures and a low bone mineral density, which in turn is associated with COPD severity and prognosis.33 The risk of osteoporosis is multifactorial and appears to be related to treatment with inhaled corticosteroids (ICS), the appearance of emphysema, and a reduction in bone mineral density. However, evidence on the relationship between osteoporosis and ICS is controversial and conflicting. The results of clinical trials with ICS do not show a relationship,34 while observational studies describe a clear association, probably because most clinical trials have a duration of 1 year, which is insufficient time for the development of osteoporosis.35,36 Until this relationship is clarified, if ICS treatment is necessary, it is advisable to use the lowest possible dose in patients with a diagnosis of osteoporosis or other risk factors for osteoporosis (greater age, smoking habit, lower body mass index, sarcopenia, low level of physical activity, and vitamin D deficiency, among others).

Muscle dysfunction is a significant systemic consequence of COPD and affects both ventilatory and non-ventilatory muscle groups. This a very important comorbidity associated with poor quality of life and reduced survival.37 It is the result of a complex combination of functional, metabolic, and anatomical changes that lead to suboptimal muscle force.38 Muscle function should therefore be evaluated in symptomatic patients, since it can identify patients who have an increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality.39 In these cases, the recommended therapeutic approach is exercise training. Other therapies, such as neuromuscular electrical stimulation, may be useful in specific cases.

It has been reported that COPD patients are at increased risk of sexual dysfunction,40 and that this is associated with poorer quality of life and episodes of depression and other comorbidities,41 generating a complex spiral of interrelationships between comorbidities and COPD. This is therefore another comorbidity that may need to be explored and treated in patients with a high disease impact.

Many respiratory comorbidities have been studied in the setting of COPD. The most relevant are bronchial asthma, obstructive sleep apnea syndrome, bronchiectasis, pulmonary hypertension, lung cancer, chest wall disorders, pulmonary fibrosis, and chronic rhinitis (Table 2). These comorbidities have three important repercussions in COPD, affecting the impact of the disease, the risk of exacerbations, and prognosis. The presence of any of these comorbidities should be explored in COPD patients with poor disease control by taking a comprehensive medical history and performing specific complementary tests.

The concomitant presence of bronchial asthma and COPD, known as asthma-COPD overlap (ACO), is currently under debate.42 It seems reasonable that if a patient is diagnosed with asthma, this comorbidity should guide the pharmacological treatment,43,44 including the evaluation of biological therapy, where indicated. Other interventions including rehabilitation, roflumilast, or antibiotics, should also be considered as part of an individualized approach for COPD. Because each disease has its own assessment scales and severity criteria, it seems more reasonable to establish both diagnoses, COPD and asthma, and to determine the severity criteria for each one separately.

The presence of bronchiectasis also affects clinical presentation, the risk of exacerbations, and the prognosis. Specific guidelines are available for the diagnosis and treatment of this comorbidity.45,46

Pulmonary hypertension is usually mild, but in some cases it has a clear impact on patients’ symptoms, on their prognosis, and on the performance of some complementary tests. These patients are defined by a vascular phenotype consisting of less severe airflow limitation, more intense arterial hypoxemia with normocapnia or hypocapnia, very low diffusion capacity, severe dyspnea during exercise, and a cardiovascular exercise limitation pattern.47 Unfortunately, no specific treatment is currently recommended,48 but a thorough investigation can help clarify the origin of the symptoms to establish individualized measures in cases of severe pulmonary hypertension.49

COPD and lung cancer not only share the main risk factor, smoking, but they also mutually affect the clinical expression and prognosis of each disease. The risk of lung cancer is most common in patients with an emphysema phenotype, irrespective of airflow obstruction.50 Although the treatment of COPD does not vary in cancer patients, cancer treatment may vary in the presence of COPD. On the other hand, the clinical challenge lies in cancer screening by computed axial tomography, for which specific guidelines are available.51

Chest wall alterations, and in particular kyphoscoliosis, are usually associated with a restrictive component in respiratory function tests and a greater likelihood of developing chronic global respiratory failure with a specific response to pulmonary rehabilitation.52

The emphysema-fibrosis complex is a rare combination, but one that has a great impact on clinical presentation and prognosis. Its clinical and functional presentation and progression are marked by the pulmonary fibrosis component.53 At present, antifibrotic treatment is not indicated in this setting, although some trials are ongoing.

Few studies have evaluated the COPD-rhinitis association, but all data indicate that this association exists from the early stages of COPD54 and its presence suggests involvement of the entire airway.55 Its impact on COPD is associated with bronchial obstruction and respiratory symptoms. Consequently, the diagnosis and treatment concomitant rhinitis should be considered as part of the evaluation of COPD patients.

Vitamin D deficiency is associated with worse lung function, accelerated deterioration of lung function, and increased COPD exacerbations. Studies have identified 25-OH-vitamin D levels as a potentially useful marker of COPD-related adverse outcomes.56 It appears that supplementing this vitamin in patients with very severe deficiency (10ng/ml or 25nmol/l) might contribute to improving the clinical presentation of COPD patients in this situation.57,58 Therefore, the recommendation in patients with high clinical impact, especially if they are persistent exacerbators, is to determine 25-OH-vitamin D levels in blood and to correct any deficiency below 10ng/ml or 25nmol/l.

The most relevant comorbidity, other than cerebrovascular disease, is cognitive impairment associated with COPD. Although this condition is common and has a clear impact on clinical presentation and quality of life,59 there is no specific treatment for COPD patients beyond choosing an appropriate inhalation device that the patient can manage correctly.

The most relevant of the sensory organ diseases is ocular hypertension. Although this comorbidity does not affect clinical presentation or diagnostic tests, treatments have a bidirectional impact. For example, it is well known that topical ophthalmic drugs can cause systemic side effects by absorption through the nasal mucosa. Thus, timolol, a beta-blocker commonly used in the treatment of ocular hypertension, can produce bronchospasm.60 Moreover, the preservatives present in some eye-drops, including benzalkonium chloride, are potent bronchoconstrictors and may cause respiratory compromise in some susceptible patients.61,62 This interaction should, then, be considered in the evaluation of patients with symptomatic COPD despite treatment. On the other side, anticholinergics may worsen intraocular pressures in patients with ocular hypertension. This association can occur when the anticholinergic drug is deposited directly on the eyeball in two circumstances: during nebulization of the anticholinergic or by touching the eyes after handling dry powder and not washing hands afterwards. Although pressure elevations may not be very marked, they can contribute to a worse control of long-term ocular hypertension. Therefore, patients with COPD and ocular hypertension should be warned of this possible effect and instructed to wash their hands after the use of inhalers with anticholinergics. The effect of ICS on glaucoma has not been consistently demonstrated.63

Although COPD is associated with various psychiatric conditions, the most relevant are probably mood and anxiety disorders, given their frequency and impact on the disease. These syndromes are not only related to the clinical presentation of COPD,64 but can also impact prognosis.65 For these reasons, clinicians should know how to identify them and treat them appropriately,66 since currently available neuropsychiatric drugs at the recommended doses are safe from a respiratory point of view. Extremely simple questionnaires that allow rapid assessment in routine clinical practice are now available.67

Nutritional changes, obesity, and low body weight should be addressed in the COPD patient. Obesity is related to COPD and other comorbidities and has a greater impact on symptoms and greater functional alteration with a restrictive component or bronchial hyperresponsiveness.68,69 It may also be associated with obstructive sleep apnea and hypoventilation.70 This clinical presentation can be corrected by weight loss.71

Low body weight associated with sarcopenia has a profound impact on patients with COPD in terms of both clinical presentation and prognosis.72,73 A particular presentation with a significant impact on COPD is sarcopenic obesity, which must be identified by bioimpedence analysis.74 Patients with poor COPD control should undergo a nutritional assessment with evaluation of the lean and fatty compartments, at least by bioimpedence, and pulmonary rehabilitation programs should be recommended, if indicated.

Anemia is another comorbidity that increases the impact of COPD by increasing symptoms.75 High-risk patients should undergo a complete blood count to detect this comorbidity, determine its origin, and start appropriate treatment in each case.

From the above sections, it seems clear that concomitant complaints can affect the clinical presentation of poorly controlled COPD patients, so comorbidities should be addressed in a protocolized manner in high-risk patients. The initial diagnostic evaluations to be conducted are summarized in Table 3. This approach will help identify which comorbidities may be at play before a more specialized assessment is made.

A comprehensive COPD treatment strategy must select the appropriate patients who can benefit from self-management programs. However, it is still difficult to find a consensus on the best model for comparing the outcomes of the different studies, patients and interventions, professionals involved, and health models.77

In the last decade, self-management studies have assessed the multiple COPD components that are essential to achieve integrated care. The main components included in a self-management program should be treatment education programs to proactively promote self-care and health literacy, exercise training, and telemedicine.78 These components all form part of the multidisciplinary actions that constitute respiratory rehabilitation.79

Interestingly, the results of various clinical trials that have evaluated each of these components vary considerably, to the extent that in some cases they are contradictory, most likely due to variations in the intensity, duration, implementation and content of programs, and highly heterogeneous interventions, patient types, follow-up periods,80–84 and settings.85,86 For this reason, self-management interventions in COPD must be structured and personalized, they must include multiple components, and be coordinated between levels of care. These integrated healthcare models that are based on interactions between patients and health professionals are useful tools for addressing complex clinical problems,87–90 but the latest systematic reviews do not yet provide us with clear evidence as to whether self-management interventions with action plans can improve outcomes in COPD.81,91 This makes it difficult to propose clear recommendations regarding the most effective implementation of self-management plans92–94 and the most appropriate selection of candidates.

Palliative care seeks to prevent or treat the symptoms of a disease, the side effects of treatment, and the psychological, social, and spiritual problems of patients and their caregivers in the face of a serious or life-threatening disease or its treatment.95

The aim of such care is not to prolong life expectancy, but to improve its quality. Unfortunately, palliative care in Spain is wanting and medical training and protocols and strategies for COPD are insufficient,96 and our patients are less like to receive this specialized attention than cancer patients.97,98

It is difficult to establish the point in terms of lung function, physical limitation, or degree of dyspnea at which a palliative care strategy should be established in a COPD patient. We are probably talking about a clinical situation in which a patient who is receiving optimized pharmacological (with 3 or more drugs) and non-pharmacological treatment, perhaps even within a respiratory rehabilitation program, presents persistent symptoms and is not a candidate for surgical therapeutic measures or when this approach has not been effective.

The most prevalent symptoms associated with advanced COPD are dyspnea (present in 97% of patients), fatigue (68%), and pain (43%). Depression can be detected in between 50% to 90% of patients, while the prevalence of anxiety can be as high as 25%.97 In many cases, symptoms coexist and may go unnoticed if patients do not undergo a targeted interview.99

Opioids. For this section of the guidelines, we developed a PICO question (Patient, Intervention, Comparison, and Outcomes) on opioids (Supplement 1).

For the analysis, 14 randomized trials (RCTs) using placebo as comparator in a total of 642 patients were selected. The characteristics of the participants and the interventions varied widely. Most included outpatients, except one study that included hospitalized patients100 and another that studied mixed-type patients.101 All studies had a crossover design except one that had a parallel group design.101 In 4 studies, participants had not previously been treated with morphine.102–105 The endpoint assessment also ranged from 1h to 6 weeks. The variables analyzed were dyspnea (measured with the visual analog scale or the Borg scale), exercise tolerance, and quality of life (using different instruments). To assess dyspnea, 3 secondary analyses were conducted, evaluating route of administration, dyspnea scales, and type of morphine used.

In terms of intensity of dyspnea measured at the end of the trial, opioid therapy showed a significant reduction in the dyspnea score compared to placebo, with a standardized mean difference of −0.27 points (95% confidence interval of −0.50 to −0.04 points) on the visual scale analog or Borg scale (10 RCTs, 302 participants). However, the mean change from baseline in the dyspnea score between the groups was not significant. When both results were analyzed together, the administration of opioids showed a reduction in dyspnea intensity with a standardized mean difference of 0.18 points (95% confidence interval from 0.34 to 0.03; 14 RCTs; 642 participants). Subanalyses according to the type of opioid or route of administration are not useful for making recommendations in this regard. Exercise capacity and quality of life outcomes showed no significant differences, but the studies are limited by heterogeneous measurements and small sample sizes. Adverse effects significantly associated with opioid use were constipation, nausea, vomiting, and drowsiness.

Recommendation: Opioids are suggested for the treatment of refractory dyspnea in COPD (weak recommendation; low quality of evidence).

Specifications: Morphine should be used at low oral or transdermal doses (Table 5). The administration of low-dose opiates does not increase the risk of hospital admission or death, even in patients receiving home oxygen therapy.106 Analysis by morphine type shows a more marked effect for dihydrocodeine.

Benzodiazepines. Although no strong evidence is available on the use of benzodiazepines,107 the combination of opioids and anxiolytics is often used to treat end-of-life dyspnea and anxiety as second- or third-line treatment when opioids and other non-pharmacological treatments do not provide adequate control.107 Compounds that can be added to opioid therapy include oral or sublingual lorazepam (0.5–1mg), subcutaneous or intravenous midazolam (1.25mg), or, in very anxious patients, continuous subcutaneous or intravenous infusion of midazolam (10–20mg in 24h), if the patient is hospitalized. These doses must be progressively titrated to achieve the desired effect.108

Systemic corticosteroids. Corticosteroid use in these patients is justified by the need to reduce airway inflammation and edema. However, efficacy in this clinical setting remains controversial109–111 and use must be individualized.

Continuous standard oxygen therapy. Mechanisms that justify the use of palliative oxygen to relieve dyspnea include reduced respiratory center demand, reduced hypoxemia and serum lactic acid, decreased pulmonary arterial pressure, and stimulation of upper airway receptors that decrease the respiratory impulse and minute ventilation, irrespective of the effect on hypoxemia.112,113 However, while many COPD patients report improved dyspnea when they receive oxygen, the evidence supporting its use in patients with dyspnea in this clinical setting is inconclusive.114–116 At present, a supplemental oxygen trial should be performed in these patients, and it should be discontinued if they do not tolerate treatment or do not benefit symptomatically.

High-flow nasal therapy. This consists of a mixture of heated and humidified gas with adjustable FiO2 from 0.21 to 1.0 that is delivered at flow rates up to 60L/min through a specially modified soft, loose-fitting nasal cannula. Benefits include reducing labored breathing in patients with respiratory failure.117,118 Preliminary studies on the use of high-flow nasal therapy in the treatment of dyspnea in terminal patients suggest that it might provide more respite and relief of dyspnea than standard oxygen.118,119

Non-invasive mechanical ventilation. Non-invasive ventilation can help reduce breathing difficulty by improving oxygenation, ventilation, respiratory muscle resistive load, dynamic hyperinflation, and labored breathing. It is currently considered a ceiling of treatment in the pursuit of symptomatic relief, primarily of dyspnea.120 If it is well tolerated, it is a non-aggressive therapy with a patient acceptance rate similar to oxygen therapy. However, due to differences in tolerance and accessibility, oxygen therapy is recommended as the first therapeutic approach in this clinical context.

The prognosis of COPD is uncertain,121 so palliative care should be incorporated in a stepwise fashion throughout the course of the disease, without waiting for life expectancy to be considered limited in the short term. Planning should be based on a process of communication with the patient, taking into account his or her opinions, preferences, values and beliefs.122 Unfortunately, communication of this type between healthcare professionals and patients with advanced COPD is not as frequent.123 Healthcare professionals who care for these patients should be trained in palliative care and a palliative care support team should be at hand.

In summary, the medical treatment of dyspnea should start with a trial of progressive opioid titration, with or without anxiolytics, and patients’ responses, side effects, and preferences should be taken into account. Non-pharmacological treatments can include respiratory rehabilitation and oxygen therapy can be attempted. Each case must be evaluated individually to assess the need to escalate to a high-flow system or the use of non-invasive ventilation.

One concern often raised about palliative care is that it can shorten life. However, this possibility is extremely rare at the usually recommended drug doses, and in any case, the use of these interventions is ethically justified by the principle of double effect, which dictates that shortening of life is acceptable if the main objective is to alleviate suffering.