Inhaled therapy for chronic obstructive pulmonary disease

Airflow obstruction may be caused by bronchoconstriction and an abnormal inflammatory response, often the result of prolonged inhalation of noxious particles, such as through smoking. Overproduction of mucus is seen in chronic bronchitis, and permanent damage to lung tissue can be found in emphysema (McNee, 2006). Symptoms include progressive and persistent shortness of breath that is made worse with activity, a chronic cough that may be intermittent, regular sputum production, and wheezing (National Institute for Health and Care Excellence (NICE), 2019). Respiratory tract infections are common and can lead to exacerbations or attacks that can last days of even weeks, and often result in a decline in lung function (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2020). The aims of treatment strategies include reduction of disease progression, improving symptoms and quality of life, maintaining lung function, and reducing risk of exacerbation (NICE, 2019; GOLD, 2020).

Chronic obstructive pulmonary disease (COPD) describes conditions with chronic airflow obstruction, such as emphysema and chronic bronchitis (GOLD, 2020). Airflow obstruction is caused by a reduction in the diameter of the lumen of the airway, which reduces the speed of air exhaled from the lungs. It is best measured using quality assured spirometry, where various measurements can be taken, including the speed of air that can be forcibly exhaled in one second (forced expired volume in one second or FEV1) and the forced vital capacity (FVC) (Graham et al, 2019). The FEV1 can then be compared to the FVC and expressed as a ratio, known as the FEV1/FVC. When the ratio falls to 0.7 or below, this is known as airflow or airway obstruction (NICE, 2019). This can also occur in asthma, where the variable nature of the disease can cause airflow obstruction to come and go (British Thoracic Society / Scottish Intercollegiate Guideline Network (BTS/SIGN), 2019). When airflow obstruction becomes permanent or chronic in the presence of appropriate signs and symptoms, a diagnosis of COPD may be given.

While the aim of inhaled therapy for both COPD and asthma is to treat bronchospasm and inflammation, the way they are prescribed and administered is quite different.

Flu vaccination

Pharmacological treatment includes ensuring that all patients with COPD are offered pneumococcal and annual influenza vaccination (NICE, 2019). Although not exclusive to COPD, the London Respiratory Network (2014) found that the cost per quality adjusted life year was lower for flu vaccination than any other treatment.

Smoking cessation

Smoking cessation should be offered at every opportunity. A measurement of smoking history as the number of ‘pack years' (number of cigarettes smoked per day, divided by 20, multiplied by the number of years smoked) should be taken (NICE, 2019). Patients should be referred to smoking cessation services and offered nicotine replacement therapy where appropriate.

Bronchodilation

Two types of inhaled bronchodilators are available, beta-2 agonists and muscarinic antagonists. Both can also be categorised as short- or long-acting bronchodilators. Bronchodilators may improve certain parameters of lung function, such as the FEV1. They have also been shown to reduce exacerbations and hospitalisations (Kew et al, 2013).

Beta-2 agonists

Beta-2 agonists work by stimulating the beta-2 adrenergic receptors, which relax the smooth muscle surrounding the airways, making them wider (Bourke and Burns, 2011). This allows air to flow with a greater degree of freedom and increased speed. Beta-2 agonists reduce symptoms such as breathlessness, and also prevent occurrence of symptoms. Side effects include peripheral tremor, tachycardia, anxiety, headache and cramps (Bourke and Burns, 2011).

Short-acting bronchodilators are the first-line of inhaled therapy for people with COPD, and short acting beta-2 agonists (SABAs) are usually prescribed in the first instance (NICE, 2019; GOLD, 2020). SABAs, such as salbutamol and terbutaline, can be prescribed ‘as required’ and work within a few minutes to dilate the airways and ease breathlessness (Seberova and Anderson, 2000).

Long-acting beta-2 agonists (LABAs), such as formoterol, salmeterol, olodaterol, vilanterol, and indacaterol, can be prescribed if symptoms persist despite regular SABA use.

Muscarinic antagonists

Muscarinic antagonists block the M3 muscarinic receptors in airway smooth muscle, thus inhibiting bronchoconstriction (GOLD, 2020). Also known as anticholinergics, common side effects include dry mouth (GOLD, 2020), cough, throat irritation, headache, dizziness and cramps (Simonsen et al, 2006).

Short-acting muscarinic antagonists (SAMAs) generally have a slower onset of action, and are usually no longer recommended, having been replaced by the long-acting muscarinic antagonists (LAMAs), which have better clinical outcomes (Cheyne, 2015).

LAMAs, including tiotropium, aclidinium, glycopyrronium, and umeclidinium, can also be administered for persistant symptoms, and may have a greater effect on reducing exacerbation rate than LABAs (Vogelmeier et al, 2011).

Combination bronchodilators

Although SABAs and LABAs may be administered together, SAMAs and LAMAs should not be. If LAMAs are commenced, then SAMAs should be discontinued because of the increased risk of anticholinergic side effects (Cole et al, 2012; Medicines.org.uk, 2019). Combinations of LABAs and LAMAs have been shown to be more clinically effective than using either LABAs or LAMAs alone (Oba et al, 2018).

When commencing inhaled bronchodilator therapy, an assessment should be made of the patient's symptoms, exercise capacity, activities of living, exacerbation history, and lung function. The impact of breathlessness and quality of life should be assessed using the Medical Research Council (MRC) dyspnoea score or the COPD Assessment Test (CAT) (Fletcher, 1960; Jones et al, 2009). Exacerbation history and number of hospital admissions can help to indicate the severity of disease, and thus the type of treatment. Lung function, specifically FEV1, can be useful in understanding the risk of exacerbation, although it is not a good indicator of the severity of symptoms, and should not be used alone to assess effectiveness of treatment (NICE, 2019).

Patients are commenced usually on a SABA (Wirral University Teaching Hospital, 2015; Leeds Integrated COPD Service, 2018). If symptoms are persistent and short-acting bronchodilators are required frequently, it is legitimate to commence long-acting bronchodilator therapy straight away.

The decision to add a single long-acting bronchodilator or a LABA/LAMA combination can be assessed using the GOLD (2020) Initial Pharmacological Treatment model. This classifies people with COPD according to symptom severity (using MRC or CAT) and exacerbation frequency. Ideally, each exacerbation should be recorded or coded in the patient's medical records, but if this is not available, then the number of courses of oral steroids could be used as a proxy measure of exacerbation rate. The GOLD classification provides four groups of patients, with SABA for immediate symptom relief for all patients.

Group A classifies people who have had one or fewer exacerbations in the past year, and who have low symptom severity. The recommended treatment is ‘a bronchodilator’, which is clarified as either a SABA, LABA or LAMA.

Group B classifies people who have more severe symptoms, but who have had one or fewer exacerbations in the past year. The suggested treatment is either a LABA or LAMA, which are more clinically effective than SABAs (Cheyne et al, 2015).

Group C is for patients who have had two or more exacerbations (or who have been admitted to hospital) in the past year, but who still have low symptom scores. The recommendation here is for LAMAs, which are more effective at reducing risk of exacerbation than LABAs in moderate to severe patients (Vogelmeier et al, 2011; Decramer et al, 2013).

At this stage, it is worth noting that the GOLD (2020) guidelines differ from the NICE (2019) guidelines, in that NICE do not advocate the use of long-acting bronchodilator monotherapy. NICE (2019) suggests that treatment should proceed directly to LAMA/LABA combination, as some studies have shown this to have advantages over either LAMA or LABA therapy alone, and may be more cost-effective in the long-term (Oba et al, 2018). Table 1 shows currently available bronchodilators and combinations.

Group D of the GOLD (2020) model classifies patients with both two or more exacerbations (or one hospitalisation) and high symptom scores. Three treatment options are recommended from LAMA alone, LAMA/LABA combination, or triple combination therapy of LAMA/LABA plus inhaled corticosteroids (ICSs).

Inhaled corticosteroids

The decision to prescribe ICSs is, perhaps, a difficult one. In asthma, inhaled steroids are the mainstay of therapy, as they directly improve the type of eosinophillic inflammation found in the majority of people with asthma (BTS/SIGN, 2019). However, the type of inflammation found in COPD is different, and it has a more limited response to ICSs (Suissa and Barnes, 2009). The most common unwanted effects from ICSs include horse voice, oral candida, skin bruising, palpitations, and pneumonia (Yang et al, 2012). Other adverse effects include reduced bone mineral density, increased risk of diabetes, cataracts, adrenal suppression and growth retardation (Medicines.org.uk, 2018; GOLD, 2020).

Although airway inflammation is present in COPD (Hogg at al, 2004), the use of ICSs alone has shown to be of minimal clinical benefit in COPD (Suissa and Barnes, 2009), as ICSs do not reduce the decline in lung function or improve mortality (Yang et al, 2012). For this reason ICSs alone are not licensed for COPD.

However, when used in combination as LABA/ICS, the exacerbation rate in moderate and severe disease can be reduced (Calverley et al, 2003; Barnes, 2010). The landmark ‘TORCH’ study, showed that LABA/ICS reduced the risk of exacerbation, but did not reduce mortality (Calverley et al, 2007). TORCH also showed there was a significant increase in non-fatal pneumonia, a finding that has been replicated in the UPLIFT study to demonstrate a >20% increase in pneumonia, mainly associated with those patients receiving fluticasone (Morjaria et al, 2017). Although this study reported on non-fatal pneumonia, people with COPD are at greater risk from dying if they contract pneumonia (Restrepo et al, 2006).

Combination bronchodilator with or without inhaled corticosteroid

In mild and moderate COPD, there is no indication for prescribing inhaled steroids, and early escalation of treatment focuses around long-acting bronchodilator therapy. The decision to increase to either LAMA/LABA therapy or to LABA/ICS, may therefore depend on whether or not the patient has either a tendency to breathlessness or exacerbation (GOLD, 2020). Differentiation between the COPD phenotype of breathlessness and that of exacerbations has been reported for many years (Marsh et al, 2008) and it can be helpful to consider into which treatment trait an individual may sit. This can be a very subjective matter, often with overlap between the two phenotypes and with other respiratory diseases, such as asthma. Patients who have high MRC dysnpnoea scores (>3), poor lung function (FEV1 <30%), and with comorbidities of cardiovascular disease, depression, or osteoperosis, are more likely to be at risk from exacerbation (McGarvey et al, 2015), and possibly more likely to sustain clinical benefit from an ICS and long-acting bronchodilator.

Until recently, LABA/ICS combinations of budesonide and formoterol (Calverley et al, 2003), and fluticasone and salmeterol (Calverley et al, 2007) were thought to provide significant risk-reduction of exacerbation. The INSPIRE study (Wedzicha et al, 2008) showed that there was no difference in exacerbation rate between the LAMA tiotropium and the LABA/ICS salmeterol/fluticasone. LABA/ICS showed a decrease in mortality, but conversely an increase in pneumonia. However, the landmark FLAME study showed that combination LAMA/LABA was superior to LABA/ICS in exacerbation reduction in all severities of disease (Wedzicha et al, 2016). In addition, this study showed that patients taking LAMA/LABA took less rescue medication, had better quality of life, and improved lung function. A further systematic review supported the findings that LAMA/LABA combinations reduced exacerbations, improved lung function and quality of life, and had a lower risk of pneumonia, when compared to LABA/ICS (Horita et al, 2017).

Triple therapy of LAMA/LAMA/ICS exists in the form of glycopyrronium/formoterol/beclometasone (Singh et al, 2016) and umeclidinium/vilanterol/fluticasone furoate (Lipson et al, 2018). These have been shown to improve exacerbation rate, lung function, and breathlessness when compared to LAMA monotherapy (Vestbo et al, 2017), LABA/ICS therapy (Singh et al, 2016), and they have also been shown to have a lower rate of hospital admission for COPD when compared to LAMA/LABA (Lipson et al, 2018). There was no difference in adverse events, including pneumonia, for the beclometasone-based triple therapy, but a significant increase in pneumonia with the fluticasone-based triple therapy.

Perhaps the most significant indicator of ICS therapy in COPD that is relatively easy to obtain is peripheral blood eosinophil (Ernst et al, 2014). An eosinophil level ≥ 300 cells/μL is useful in determining if a patient may respond to ICS therapy (Bafadhel et al, 2018). Eosinophil levels <100 cells/μL may predict a low likelihood of positive response to ICS (GOLD, 2020). ICS therapy may also be beneficial in those patients with comorbid asthma, or who have FEV1 or PEF >20% of predicted, or who show signs of atopy, heyfever, or asthma (NICE, 2019).

Therefore, the decision to prescribe ICSs in COPD must be undertaken with concomitant long-acting bronchodilators, and needs to be made following assessment and identification of the patient phenotype, along with careful consideration of the risks and benefits to the individual patient (Table 2). The cost-effectiveness of triple-therapy must also be taken into consideration (London Respiratory Network, 2014).

A pragmatic and easy to understand view of both the NICE (2019) and GOLD (2020) guidelines has recently been published by the Primary Care Respiratory Society (PCRS, 2019), which helps to unpick the complexities and subtle differences between the two guidelines. This excellent guide describes the ‘keeping it simple’ approach to COPD management, and reminds prescribers to check basics such as medication adherence and inhaler technique, as well as referral to specialist services.

Withdrawl of inhaled corticosteroids

There is evidence to suggest that ICS therapy is overprescribed in COPD, and there are instances where it has been introduced too early for clinical benefit to outweigh clinical risk, leading to the overtreatment of some patients who may be taking ICSs inappropriately (Chalmers et al, 2017). Withdrawl for ICSs is possible, and has been seen in clinical studies. Chapman et al (2018) examined moving patients from LAMA/LABA/ICS triple therapy to LAMA/LABA, and reported only a small loss of lung function. The GOLD (2020) guidelines report on further studies with differing results. Advice from local COPD formularies includes a gradual withdrawl of ICS by halving the dose, where possible (Leeds Integrated COPD Service, 2018). This strategy may include the short-term prescribing of ICSs outside license, and clear documentation is needed to avoid continued unlicensed treatment.

Inhaler devices

Although it is not the intention of this paper to discuss inhaler devices in detail, a working knowledge of delivery devices and inhaler technique is essential, as both the drug and the device need to be prescribed (Capstick et al, 2015; BTS/SIGN, 2019). The ability to use an inhaler device is fundamental if a patient is to be able to self-administer their treatment. Choice of device should be made by a health professional who is competent to do so, taking into consideration the patient's ability to use the device, their preference, and their inspiratory flow rate (Capstick and Clifton, 2012).

Inhaler devices can be split into either aerosol or dry powder, commonly known as metered dose inhalers (MDIs) or dry powder inhalers (DPIs) (Booth, 2016; Sanders, 2017). MDIs require a low inspiratory flow, while DPIs require a higher inspiratory flow rate (Haidl et al, 2016). With an MDI, patients should be taught to inhale ‘slow and steady’ and with DPIs ‘quick and deep’ (UK Inhaler Group, 2019).

Inhaler devices are a unique and specialist subject, and familiarity with these devices used on local formularies is essential when prescribing inhaled therapy. Patients should be shown how to use the device, and then their technique checked at every available opportunity (Scullion, 2020).

Oral steroids

Steroid tablets are not routinely recommended for COPD as there is no evidence to support their use. However, in clinical practice there are patients who have been commenced on low-dose daily prednisolone. However, in clinical practice, the author's experience has shown there may be patients who have been commenced on low-dose daily prednisolone outside of guideline recommendation Oral steroids may be used as rescue therapy for patients having an exacerbation (often with concomitant antibiotics) and have been shown to improve symptoms of breathlessness and lung function (NICE, 2019; GOLD, 2020).

Antibiotics

Antibiotics may be prescribed for acute exacerbations, or as prophylaxis. An acute exacerbation of COPD can be described as a sustained worsening of symptoms from a person's stable state (NICE, 2019). Many exacerbations are not caused by bacterial infections, and therefore will not respond to antibiotics. Change of sputum colour, to a dark green or yellow, has been found to be a better predictor of bacterial presence in chronic bronchitis than sputum viscosity or dyspnoea (Miravitlles et al, 2011).

Prophylactic antibiotics, in the form of azithromycin, may be offered for people experiencing more than four exacerbations per year with sputum production, or hospitalisations, and who do not smoke (NICE, 2019). It is recommended that these patients have sputum cultures to exclude pseudomonas and non-tuberculous mycobacteria, and have had a CT scan to rule out bronchiectasis and other pathologies. For these reasons, prophylactic antimicrobial therapy is usually initiated within specialist care.

Mucolytic

Medications such as carbocysteine may be helpful in those patients who experience tenacious sputum and difficulty clearing from their airway, but clinical evidence is lacking to support regular use (GOLD, 2020). Personal experience of the author has shown that it can have a significant effect on improving quality of life in some patients, yet have no benefit in others. A trial of treatment is useful, with discontinuation of therapy if there are no obvious benefits.

Methylxanthines

Oral methylxanthines, such as theophylline, have a bronchodilation effect and are sometimes used in people with COPD. They can improve FEV1 slightly when added to LABA, although the evidence is limited and the potential for toxicity is high (GOLD, 2020). NICE (2019) recommends their use only after long-acting bronchodilators have been prescribed and in patients who are unable to use inhaled therapy, as there is a need to monitor blood levels to reduce risk of toxicity.

Roflumilast

PDE4 inhibitors, such as Roflumilast, reduce inflammation and exacerbations in patients with severe COPD (NICE, 2017). They may also improve lung function when added to bronchodilator therapy, and may be useful for people with COPD who have more severe disease and a history of admission to hospital with acute exacerbation (GOLD, 2020). Romflumilast is currently recommend only for people with severe COPD, who have been hospiatalised despite triple therapy, and should only be commenced by specialist respiratory services (NICE, 2017).

Conclusions

Inhaled therapy remains the mainstay of treatment for people with COPD. There are a variety of different inhaler devices available, and every patient should have their inhaler technique checked to ensure they are using the device correctly.

Long-acting bronchodilators in the form of beta-2 agonists and muscarinic antagonists are recommended by local formularies, national guidelines, and international consensus documents, and are regarded as safe and effective ways of improving symptoms and reducing risk of exacerbation. The addition of inhaled steroids to long-acting bronchodilator therapy can be additionally beneficial, if the right patient is selected, and the benefits of treatment are considered to outweigh the not insignificant risks.

Other treatments, including flu vaccination, smoking cessation, and pulmonary rehabilitation, have been shown to be of greater clinical benefit and have greater cost effectiveness, and these must be offered to all patients before the consideration of triple therapy.

Key Points

• Inhaled long-acting bronchodilators are used either on their own, or in combination to improve symptoms and reduce exacerbations
• Long-acting muscarinic antagonists are more effective at reducing exacerbation risk than long-acting Beta-2 agonists
• In more severe COPD, inhaled steroids can help to reduce risk of exacerbation, but are not without potential complications that include pneumonia
• Inhaled steroids can only be given in combination with either a long-acting Beta-2 agonist, or as triple therapy with long-acting muscarinic antagonist
• Other treatments such as those for seasonal influenza, smoking cessation, and pulmonary rehabilitation should be offered before triple therapy

CPD reflective questions

• How many people with COPD in your practice have been offered the flu jab and smoking cessation
• What does your local respiratory formulary say about dual-bronchodilation with long-acting muscarinic antagonists and long-acting Beta-2 agonists?
• How many patients on your COPD register are taking inhaled steroids without long-acting Beta-2 agonists (excluding those on your asthma register)?
• Can you locate the blood eosinophil counts for your patients who are prescribed inhaled steroids?