Approach

The ultimate goals of treatment of COPD are to prevent and control symptoms, to reduce the severity and number of exacerbations, to improve respiratory capacity for increased exercise tolerance, and to reduce mortality. [1] There is a stepwise approach to therapy, but it is important to remember that treatment should be individualised for general health status and comorbid conditions.

The therapeutic approach involves reducing risk factor exposure, appropriate assessment of disease, patient education, pharmacological and non-pharmacological management of stable COPD, and prevention and treatment of acute COPD exacerbations.

Continuous assessment and monitoring of disease

Ongoing monitoring and assessment in COPD ensures that the goals of treatment are being met. Quality of life and patients' sense of well-being will improve, and hospital admissions will be significantly decreased in cases where self- or professional monitoring of disease is being utilised. [29] Such assessment of the medical history should include:

Exposure to risk factors and preventative measures:

  • Tobacco smoke

  • Occupational exposures (fumes, dust, etc.)

  • Influenza and pneumococcal vaccination.

Disease progression and development of complications:

  • Decline in exercise tolerance

  • Increased symptoms

  • Worsened sleep quality

  • Missed work or other activities.

Pharmacotherapy and other medical treatment:

  • How often rescue inhaler is used

  • Any new medicines

  • Compliance with medical regimen

  • Ability to use inhalers properly

  • Adverse effects.

Exacerbation history

  • Urgent care or emergency department visits

  • Recent oral corticosteroid bursts

  • Frequency, severity, and likely causes of exacerbations should be evaluated.

Comorbidities:

  • Assessment of co-existing medical problems (e.g., heart failure).

In addition, objective assessment of lung function should be obtained yearly or more frequently if there is a substantial increase in symptoms.

Integrated disease management (IDM) in which several healthcare providers (physiotherapist, respiratory physician, nurse, etc.) worked together with patients has been shown to improve quality of life and decrease hospital admissions. [30] [ Cochrane Clinical Answers logo ]

Acute exacerbations

An exacerbation of COPD is defined as an event characterised by a change in the patient's baseline dyspnoea, cough, and/or sputum that is beyond normal day-to-day variations and is acute in onset.

Patients can be treated either as inpatients or as outpatients, depending on severity of symptoms and comorbidities. Indications for hospitalisation include significant comorbidities (heart failure, arrhythmias, kidney disease), failure of outpatient treatment, worsening gas exchange, or an inability to cope at home. [1]

Intensive care unit (ICU) admission is considered for patients with worsening respiratory function (hypoxaemia or hypercapnia), severe respiratory acidosis, or haemodynamic instability, and those requiring mechanical ventilation. [1] Use of non-invasive positive airway pressure (NIPAP) and/or mechanical ventilation may be inevitable in severe cases of COPD exacerbations. [31] [32]

Infections are among the most common causes of COPD exacerbation. The use of empirical antibiotics in suspected cases of infection is usually warranted because it has beneficial effects on lung function and duration of disease, as well as potential benefit for dyspnoea, cough, and sputum purulence, especially for patients admitted to the ICU. [33] [34] Choice of antibiotic should be made according to severity of exacerbation and whether or not the patient is being treated in hospital. [33] [35] [36] [37]

Bronchodilators are indicated, with or without supplemental oxygen. Oral corticosteroids should also be considered. [1] A short course (i.e., usually 5 days) of corticosteroid therapy appears to be as effective as a 10- to 14-day course. [38] [39] [ Cochrane Clinical Answers logo ] When needed for treatment of an exacerbation, oral or parenteral therapy is superior to inhaled corticosteroids. [40] [41] A 5-day course of oral prednisolone (40 mg/day) is recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. [1] There is no evidence that parenteral treatment is better than oral therapy with regards to relapse, treatment failure, or mortality. There is a greater risk of side effects with parenteral therapy. [41]

Chronic management: stepwise therapy according to GOLD class

GOLD guidelines [1] recommend a stepwise approach to pharmacological therapy:

  • For group A patients (few symptoms and low risk of exacerbations), a bronchodilator is offered first-line. This can be either a short- or a long-acting bronchodilator. This should be continued if symptomatic benefit is documented.

  • For group B patients (more symptoms and low risk of exacerbations), a long-acting bronchodilator should be offered first-line. If the patient has persistent symptoms when taking one long-acting bronchodilator, then the use of two bronchodilators is recommended. For patients with severe breathlessness, initial treatment with two bronchodilators may be warranted. Evidence A

  • For group C patients (few symptoms but higher risk of exacerbations), first-line treatment should be a long-acting bronchodilator, and GOLD recommends starting a long-acting muscarinic antagonist (LAMA) in this group. [ Cochrane Clinical Answers logo ] Patients who experience further exacerbations may benefit from adding a second long-acting bronchodilator (long-acting beta-2 agonist [LABA] or LAMA) or using a combination of a LABA and an inhaled corticosteroid (ICS). GOLD recommends a LABA/LAMA combination over LABA/ICS, as ICS increases the risk of developing pneumonia in some patients. [ Cochrane Clinical Answers logo ]

  • For group D patients (more symptoms and high risk of exacerbations), GOLD recommends starting therapy with a LABA/LAMA combination. If patients experience further exacerbations when on LABA/LAMA, they can either try escalation to LABA/LAMA/ICS, or they can switch to LABA/ICS. If patients treated with LABA/LAMA/ICS still have exacerbations, then additional options include adding roflumilast, or a macrolide, or stopping the ICS.

All patients are candidates for education, vaccination, and smoking cessation interventions. Evidence A

Bronchodilator therapy options

Beta agonists are widely used in the treatment of COPD. Evidence A They increase intracellular cAMP, leading to respiratory smooth muscle relaxation and reduced airway resistance. They are available as short-acting and long-acting preparations. Short-acting beta-2 agonists improve lung function and breathlessness and quality of life. These agents can be used as rescue therapy when the patient is using long-acting beta-2 agonist therapy. [42] LABAs improve lung function, breathlessness, exacerbation rate, and number of hospitalisations, but do not affect mortality or rate of decline of lung function. [1]

A muscarinic antagonist is a type of anticholinergic agent that acts as a bronchodilator by blocking the cholinergic receptors on the respiratory smooth muscle. This causes muscle relaxation and reduces airflow limitation. Evidence B Inhaled muscarinic antagonists are available as both short- and long-acting preparations. [ Cochrane Clinical Answers logo ] Tiotropium, a LAMA, has been shown to reduce risk of exacerbation versus placebo or other maintenance treatments. [43] [ Cochrane Clinical Answers logo ]  Newer LAMAs, such as aclidinium, glycopyrronium, and umeclidinium, have at least comparable efficacy to tiotropium, in terms of change from baseline in trough forced expiratory volume in 1 second (FEV1), transitional dyspnoea index focal score, St George's Respiratory Questionnaire score, and rescue medication use. [44]  There is a suggestion of increased cardiovascular-related mortality in some studies of patients taking short-acting muscarinic antagonists and in some studies of patients taking LAMAs. [45] [46]  A population-based cohort study found that older men with COPD newly started on LAMAs are at increased risk of urinary tract infections. [47]

Beta agonists and muscarinic antagonists, therefore, provide bronchodilator effects through different pathways. Their combination may provide a better therapeutic effect without increasing the adverse effects of each class. [48] [49] [50] [51] Evidence A Compared to LABA/ICS, a LABA/LAMA combination has fewer exacerbations, a larger improvement of FEV1, a lower risk of pneumonia, and more frequent improvement in quality of life. [52]  A systematic review and network meta-analysis found that all LABA/LAMA fixed-dose combinations had a similar efficacy and safety. [53]

In cases of stable COPD, if the decision is made to use single-agent therapy, LAMA may be superior to LABA agents. [48] Clinical trials have shown that LAMA have a greater effect on reducing rates of exacerbations compared with LABA. [54] [55] The long-term safety of LAMA was demonstrated in the UPLIFT trial. [56] As outlined above, GOLD makes recommendations on the initial agent based on the patient’s risk group (A, B, C, or D). [1]

Theophylline (a methylxanthine agent) is a bronchodilator that acts by increasing cAMP and subsequent respiratory smooth muscle relaxation. It is not commonly used because of limited potency, narrow therapeutic window, high-risk profile, and frequent drug-drug interactions. Theophylline is indicated for persistent symptoms if inhaled therapy is insufficient to relieve airflow obstruction. Evidence A Theophylline has modest effects on lung function in moderate-to-severe COPD. [57]

Umeclidinium/vilanterol is a LABA/LAMA approved for use in COPD. [58] Glycopyrronium/formoterol fumarate is another LABA/LAMA combination approved for COPD patients, [59] as is indacaterol/glycopyrronium. [60] [61] This once-daily inhaler showed superior efficacy compared with glycopyrronium plus tiotropium in patients with moderate to severe COPD, [62] and compared with salmeterol/fluticasone in preventing COPD exacerbation. [63]

Inhaled corticosteroids

Inhaled corticosteroids are indicated in patients with advanced stages of COPD who suffer from frequent exacerbations. [64] They should be added to the patient's existing bronchodilator therapy and should not be used as monotherapy. [1] Inhaled corticosteroids are believed to be effective because of their anti-inflammatory effects. Long-term inhaled corticosteroid use reduces the need to use rescue therapy and reduces exacerbations, and may also decrease mortality. [65] [66] [ Cochrane Clinical Answers logo ] Several studies have pointed to an increased risk of pneumonia in COPD patients taking inhaled corticosteroids. [67] This risk is slightly higher for fluticasone in comparison with budesonide. [68] A systematic review and meta-analysis found that, despite a significant increase in unadjusted risk of pneumonia associated with use of inhaled corticosteroids, pneumonia fatality and overall mortality were not increased in randomised controlled trials and were decreased in observational studies. [69]  Therefore, an individualised treatment approach that assesses a patient's risk of pneumonia versus the benefit of decreased exacerbations should be implemented. [67] [70] [71] Concern is also raised with regards to increased risk of tuberculosis and influenza in adult patients with COPD who are on inhaled corticosteroid therapy. [72]

According to the GOLD guidelines, inhaled corticosteroids are not recommended as first-line therapy in any of the patient groups A to D. They are only recommended as part of escalation of therapy if patients continue to experience exacerbations despite taking a long-acting bronchodilator. [1]

Phosphodiesterase-4 inhibitors

Roflumilast is an oral phosphodiesterase-4 inhibitor that may reduce exacerbations in group D patients at risk for frequent exacerbations when not adequately controlled by long-acting bronchodilators. [1] This agent offers benefit in improving lung function and reducing the likelihood of exacerbations. However, it has little impact on quality of life or symptoms. [73]

Combined bronchodilator and corticosteroid preparations

A combination preparation of long-acting bronchodilator and inhaled corticosteroid may be used for patients who require both these agents. This is convenient and may help with compliance in some patients. The choice of therapy in this class is based on availability and individual response and preference. [74] Combination therapy with inhaled corticosteroid and a long-acting beta agonist is superior to use of either agent alone. [75] [76] [ Cochrane Clinical Answers logo ] The combination may be provided in separate inhalers or a combination inhaler.

Multiple studies support triple therapy with LABA/LAMA/ICS as being superior to single- or double-agent therapy with LABA/LAMA or LABA/ICS regarding rate of moderate to severe COPD exacerbations [77] [78] [79] [80]  and rate of hospitalisation. [81] [82]

Patient education and self-management

All patients should be well educated about the disease course and symptoms of exacerbation or decompensation. Their expectation of the disease, treatment, and prognosis should be realistic. It is important to remember that no medicine has been shown to modify the long-term decline in lung function, and the primary goal of pharmacotherapy is to control symptoms and prevent complications.

One Cochrane review found that self-management interventions that include an action plan for acute exacerbations of COPD are associated with improvements in health-related quality of life and fewer admissions to hospital for respiratory problems. An exploratory analysis found a small, but significantly higher, respiratory-related mortality rate for self-management compared to usual care, although no excess risk of all-cause mortality was seen. [83]

One randomised controlled trial found that a telephone health coaching intervention to promote behaviour change in patients with mild COPD in primary care led to improvements in self-management activities, but did not improve health-related quality of life. [84]

Physical activity is recommended for all patients with COPD. [1]  One systematic review and meta-analysis of randomised controlled trials found that exercise training on its own can improve physical activity in COPD, and greater improvements can be made with the addition of physical activity counselling. [85]  Another systematic review and meta-analysis found that a combination of aerobic exercise and strength training was more effective than strength training or endurance training alone in increasing the 6-minute walking distance. [86]

Smoking cessation and vaccination

Smoking cessation should be encouraged in all patients, in addition to guidance on avoiding occupational or environmental tobacco smoke exposures.

Usual smoking-cessation programmes include counselling, group meetings, and drug therapy. [87] Some patients may need frequent referrals to achieve success. Smoking cessation significantly reduces the rate of progression of COPD and risk of malignancies. Evidence A It also reduces risk of coronary and cerebrovascular diseases. Smoking cessation that includes pharmacotherapy and intensive counselling has a higher success rate and is cost effective in COPD, with low costs per quality-adjusted life year. [88] [89] [90]

Patients should be vaccinated against influenza virus and Streptococcus pneumoniae . [1] [91] Vaccination against influenza is associated with fewer exacerbations of COPD. [91] [92] [ Cochrane Clinical Answers logo ]

Mucolytics

Patients with the chronic bronchitis phenotype of COPD often produce thick sputum on a frequent basis. Mucolytic agents are not associated with an increase in adverse effects and may be beneficial during exacerbations of COPD. They result in a small reduction in the frequency of acute exacerbations, but do not improve lung function or quality of life. Mucolytic agents may be most beneficial for patients not on inhaled corticosteroids. [93] [ Cochrane Clinical Answers logo ] The use of positive expiratory pressure (PEP) therapy to clear secretions during acute exacerbations has been found to improve subjective feelings of breathlessness but was not associated with decreased hospitalisations or rate of exacerbations. [94]

Pulmonary rehabilitation

Pulmonary rehabilitation should be initiated for patients who remain symptomatic despite bronchodilator therapy and is recommended to start early in the course of the disease, when they start feeling shortness of breath with regular activity and walking on a level surface. Its effect is beneficial in improving exercise capacity and quality of life. [ Cochrane Clinical Answers logo ] It also decreases the depression and anxiety related to this disease, and reduces hospitalisation in COPD patients. [95] The benefit appears to subside after termination of the course unless patients follow a home exercise schedule. [96] Benefits of home- or community-based pulmonary rehabilitation on respiratory symptoms and quality of life in patients with COPD could match those of the hospital-based rehabilitation programmes. [97] [98] Although pulmonary rehabilitation relieves dyspnoea and fatigue, improves emotional function, and enhances a sense of control to a moderately large and clinically significant extent, [99] it is important to remember that early progressive exercise rehabilitation beyond current standard physiotherapy practice during hospital admission for COPD is not recommended and could be associated with a higher 12-month mortality. [100] There is evidence to support starting pulmonary rehabilitation within 1 month of an acute exacerbation. [101] [102]

GOLD guidelines recommend pulmonary rehabilitation for patient groups B to D. [1]

Oxygen therapy

GOLD guidelines recommend long-term oxygen therapy in stable patients who have: [1]

  • PaO₂ ≤7.3 kPa (55 mmHg) or SaO₂ ≤88%, with or without hypercapnia confirmed twice over a 3-week period; or

  • PaO₂ between 7.3 kPa (55 mmHg) and 8.0 kPa (60 mmHg), or SaO₂ of 88%, if there is evidence of pulmonary hypertension, peripheral oedema suggesting congestive cardiac failure, or polycythaemia (haematocrit > 55%).

Oxygen therapy helps to minimise pulmonary hypertension by decreasing pulmonary artery pressure, and improves exercise tolerance and quality of life. It has been shown to improve survival. [1] [103] [104] Evidence B

Oxygen is suggested for patients in whom the predicted PaO₂ during air travel is <6.7 kPa (<50 mmHg). [1] These patients usually have a saturation of <92% in room air at sea level. If in doubt, patients could undergo testing to be evaluated for their predicted PaO₂ during flight.

There is some evidence that oxygen can relieve breathlessness when given during exercise to mildly hypoxaemic and non-hypoxaemic people with COPD who do not otherwise qualify for home oxygen therapy. [105]

Surgery

Surgical interventions (bullectomy, lung volume reduction surgery, [106] [107] [ Cochrane Clinical Answers logo ] and lung transplant) are the last step in the management of COPD. They are used to improve lung dynamics, exercise adherence, and quality of life. [108] Endobronchial valve insertion can produce clinically meaningful improvements in appropriately selected COPD patients. [109]

Criteria for referral for lung transplantation include: [110]

  • Progressive disease, despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy.

  • Patient is not a candidate for endoscopic or surgical lung volume reduction surgery (LVRS). Simultaneous referral of patients with COPD for both lung transplant and LVRS evaluation is appropriate.

  • Body mass index, airflow Obstruction, Dyspnoea, and Exercise (BODE) index of 5 to 6.

  • PaCO₂ >50 mmHg or 6.6 kPa and/or PaO₂ <60 mmHg or 8 kPa.

  • FEV1 <25% predicted.

BODE Index for COPD Survival Prediction

Palliative care

For some patients with very advanced end-stage COPD, palliative care and hospice admission should be considered. Patient and family should be well educated about the process, and it is suggested that discussions should be held early in the course of the disease before acute respiratory failure develops. [111] One study has suggested that low doses of an opioid analgesic and a benzodiazepine are safe and are not associated with increased hospital admissions or mortality. [112]

One Cochrane review concluded that there is no evidence for or against benzodiazepines for the relief of breathlessness in people with advanced cancer and COPD. [113]

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