Caring for patients with advanced COPD: beyond the inhalers…

Authors: Michelle A. Murray, Kathryn Mulryan, Maedhbh Ní Chléirigh, Karen C. Redmond, Emer Kelly

Abstract

COPD affects millions of people worldwide. Patients with advanced COPD have a high symptom burden. Breathlessness, cough and fatigue are frequent daily symptoms. Guidelines often focus on pharmacological treatment, especially inhaler therapy, but other approaches in combination with medications offer symptomatic benefit.

In this review, we take a multidisciplinary approach with contributions from pulmonary physicians, cardiothoracic surgeons and a physiotherapist. The following areas are oxygen therapy and noninvasive ventilation (NIV), dyspnoea management, surgical and bronchoscopic options, lung transplantation and palliative care. Oxygen therapy prescribed within guidelines improves mortality in patients with COPD. NIV guidelines offer only low-certainty instruction on the use of this therapy on the basis of the limited available evidence. Dyspnoea management can take place through pulmonary rehabilitation. Specific criteria aid decisions on referral for lung volume reduction treatments through surgical or bronchoscopic approaches. Lung transplantation requires precise disease severity assessment to determine which patients have the most urgent need for lung transplantation and are likely to have the longest survival. The palliative approach runs in parallel with these other treatments, focusing on symptoms and aiming to improve the quality of life of patients and their families facing the problems associated with life-threatening illness. In combination with appropriate medication and an individual approach to symptom management, patients' experiences can be optimised.

Educational aims

• To understand the multidisciplinary approach to management of patients with advanced COPD.
• To recognise the parallel approaches to oxygen, NIV and dyspnoea management with consideration of more interventional options with lung volume reduction therapy or lung transplantation.
• To understand the high level of symptomatology present in advanced COPD and the relevance of palliative care alongside optimal medical management.

Introduction

There are an estimated 65 million people with moderate-to-severe COPD worldwide [1]. Patients with advanced COPD can be very symptomatic. Despite optimisation with medical treatments, patients continue to experience a variety of symptoms, with breathlessness, fatigue and cough, resulting in a loss of capability that is consistently reflected in synthesised studies of the qualitative data [2]. This is associated with an unrelenting psychosocial impact of the disease. Multimorbidity adds to the symptoms. Anxiety and depression are also highly prevalent. Breathlessness can lead to a limit in function that leads to isolation and loneliness.

The medical treatment and management of COPD has been well categorised in an incremental, stepwise manner in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, with additional therapies added at each stage of the disease [3]. Smoking cessation, vaccination and pulmonary rehabilitation are first-line treatments and recommended for all. Indeed, smoking cessation is the most effective strategy for slowing down the progression of COPD, as well as increasing survival and reducing morbidity [4]. There are limitations to the treatment that we have to offer patients with COPD. From the TORCH study and many randomised controlled trials (RCTs), pharmacological therapy has been shown to have modest effects on airflow limitation and exacerbation rate but does not impact on survival [5]. Pulmonary rehabilitation and even transplant improve exercise capacity, exacerbation frequency and quality of life but not survival [6]. Apart from long-term oxygen therapy (LTOT) and surgery in a select few patients, survival is not altered [7].

In this article we aim to go beyond the pharmacological therapy and take a multidisciplinary approach to the patient with advanced COPD by addressing the areas Oxygen therapy and noninvasive ventilation (NIV)Dyspnoea managementLung volume reduction proceduresLung transplantationPalliative care

Oxygen therapy and NIV

Oxygen

The role of oxygen therapy has long been established in COPD and is supported by two landmark trials from over 40 years ago. The Nocturnal Oxygen Therapy Trial (NOTT) included 203 hypoxaemic COPD patients and showed that continuous oxygen therapy was superior to 12 h of nocturnal oxygen therapy with a mortality benefit at 1 year (11.9% mortality in the continuous group and 20.6% in the nocturnal oxygen group) [8]. The Medical Research Council (MRC) trial published a year later enrolled 87 COPD patients with COPD and severe hypoxaemia and carbon dioxide retention [9]. Subjects randomised to no supplemental oxygen had a mortality rate of 67%, while the study group on 2 L·min^−1^ for at least 15 h per day had a mortality rate of 45% over the 5 years of the study. On the basis of this convincing evidence, LTOT is prescribed for COPD patients with resting hypoxaemia; arterial oxygen tension (PaO2~~) <55 mmHg (7.3 kPa) or 59 mmHg (8 kPa) with evidence of right heart strain or polycythaemia (figure 1).

Some unanswered questions remain when it comes to prescribing oxygen outside of these strict parameters. The difference between evidence and practice was the motivation behind the Long-Term Oxygen Treatment Trial (LOTT) [10]. Subjects with moderate hypoxaemia (peripheral oxygen saturation (SpO2~~) 89–93%) and moderate exercise-induced desaturation SpO2~~ <90% for >10 s and SpO2~~ >80% for >5 min during the 6-min walk test were randomised to receive oxygen or no oxygen. A large cohort of 738 patients were enrolled and no differences were found between the oxygen and no oxygen groups in terms of time of death or first hospitalisation or the rates of hospitalisations or COPD exacerbations. There was also no difference in 6-min walk distance, lung function or health-related quality of life score (HRQL). This paper has been the subject of much discussion. Based on expert opinion, the evidence can be used not to instigate oxygen supplementation in patients who are not eager to pursue it [11] with an option to formally assess with a blinded exercise test while breathing either air or oxygen [12], although other interventions to target breathlessness should be the focus. Criticisms of the paper include selection bias and a lower duration of oxygen delivery time (13.6 h per day) compared with previous studies. Smaller studies have shown benefit from oxygen therapy in mildly hypoxaemic COPD patients in terms of quality of life, reduction in anxiety and depression scores, and 6-min walk distances [11].

Oxygen is sometimes considered as a palliative measure for the treatment of dyspnoea, but the assumption that oxygen can relieve dyspnoea is not based on fact and in the absence of hypoxaemia the use of oxygen to alleviate breathlessness is not supported by the literature. Campbell et al. [13] found no reduction in respiratory distress in subjects near death from respiratory failure. Addressing other approaches to dyspnoea is important in these patients.

NIV and high flow nasal oxygen

The long-term use of NIV is less clearly established. Noninvasive positive pressure ventilation administered by home ventilators is a bilevel positive airway pressure therapy.

On the basis that hypercapnia is known to be associated with increased mortality [14, 15], physiologically NIV would help reduce the impact of hyperinflation on respiratory muscle workload and ventilatory chemosensitivity to carbon dioxide would improve. In a study of 144 stable hypercapnic COPD patients, published in 2009, McEvoy et al. [16] found in favour of NIV plus LTOT compared with LTOT alone in terms of a survival benefit (28 months versus 20.5 months; mean inspiratory positive airway pressure (IPAP) was 13 cmH2O, expiratory positive airway pressure (EPAP) 5 cmH2O). In 2014, another RCT of 195 patients with COPD and stable chronic hypercapnia compared LTOT with long-term home NIV (LTH-NIV) but targeted carbon dioxide reduction (mean IPAP 22 cmH2O, mean EPAP 5 cmH2O used to decrease arterial carbon dioxide tension (PaCO2~~) by at least 20%) and showed a 1-year survival benefit (1-year mortality in the intervention group 12% versus 33% in the control group) [17]. Many studies followed and pooled analysis of 13 RCTs on the use of NIV in stable hypercapnic patients with COPD showed an overall minimal effect on mortality (RR 0.86) or hospitalisations (mean difference 1.26 fewer hospitalisations) [18–25].

NIV may improve exercise capacity and outcomes of pulmonary rehabilitation by resting fatigued muscles and improving mechanics and daytime gas exchange [20]. Seven RCTs evaluated HRQL and found that HRQL was higher with NIV [26]. Kohnlein et al. [17] found that HRQL was improved more with NIV plus LTOT than with LTOT alone.

Other trials investigated the use of LTH-NIV use after an episode of acute hypercapnic respiratory failure in patients with COPD. An initial smaller study showed no mortality benefit [27]. The RESCUE RCT included 201 COPD patients admitted with acute hypercapnic respiratory failure and prolonged hypercapnia with half randomised to NIV plus LTOT and the control group on LTOT. After 1 year there was no difference between the two groups in the primary outcome of time to readmission or death [28]. The HOT-HMV trial studied 116 COPD patients with persistent hypercapnia 2–4 weeks after a life-threatening episode of acute on chronic respiratory failure. This study found that NIV plus LTOT resulted in an increased time to readmission or death within 12 months (4.3 months versus 1.4 months) [29]. Data from a short-term trial focusing on physiological benefits, which was not an RCT, showed that delivery of higher levels of pressure support was associated with better compliance and a greater subjective benefit in chronically symptomatic patients [30]. Pooled data from five RCTs comparing higher levels of pressure support at 6 weeks compared to lower levels found no effect on HRQL [18].

Guidelines have been published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS) to aid clinical decision making in light of the data. The ERS guidelines on LTH-NIV for COPD offer conditional support for the use of NIV to improve health outcome by targeting a reduction in carbon dioxide in COPD patients with persistent hypercapnic respiratory failure [18]. The recommendation is prefaced by a statement that the evidence base is weak. On the question of whether NIV should be used in stable patients with COPD, a conditional “yes” is offered by the ERS guidelines. Further support is suggested for use of NIV after a patient has presented with an episode of acute hypercapnic respiratory failure. These patients are known to have a high risk of repeat admission and may traditionally be the patients considered for home NIV. On the basis that home NIV is not associated with a reduction in mortality in the setting of acute hypercapnic respiratory failure but is associated with some reduction in exacerbations, time to readmission and some parameters of dyspnoea and quality of life a low evidence recommendation in favour of NIV in this setting is made.

The suggestion that we should treat to normalise or to reduce PaCO2~~ is a conditional, very low-level evidence suggestion. High-intensity NIV with IPAP up to 30 cmH2O with a high back-up rate theoretically should correct nocturnal alveolar hypoventilation. Despite the low level of evidence, the reason given for the positive recommendation states the low risk of harm. Fixed pressure support is suggested as the first-choice mode for home NIV for COPD patients as opposed to volume-targeted NIV without any current established benefit from auto-titrating pressure modes [18].

The ATS guidelines on LTH-NIV in chronic stable hypercapnic COPD patients were published 1 year after the ERS guidelines and were largely based on the same evidence [31]. The guidelines reflected similar themes to the ERS document stating “conditional” and “very low” to “moderate” level certainty. The two main differences across the Atlantic 1) the suggestion that NIV would not be started during an admission with hypercapnic respiratory failure but deferred until 2–4 weeks after; and 2) obstructive sleep apnoea (OSA) screening was suggested prior to the NIV initiation. The ATS document suggests that the increased incidence of obesity in the USA may mean that OSA is a more frequent comorbidity.

The question of cost-effectiveness of LTH-NIV needs to be considered. A study with a Markov model-based cost-utility analysis from the UK National Health Service investigated cost-effectiveness for two advanced COPD patient those commenced on NIV who were stable without a recent admission and a group commenced on domiciliary NIV post-hospitalisation for an exacerbation [32]. Based on calculations, the authors concluded that NIV appears to be cost-effective when started immediately after or within 4–6 weeks of a hospital admission in which NIV was required (incremental cost-effectiveness ratio (ICER) GBP 11 318 per quality-adjusted life-year (QALY) gained) but uncertainty remained around the cost-effectiveness of domiciliary NIV (ICER GBP 27 380 per QALY, only 4% likely to be cost-effective at the GBP 20 000 per QALY threshold).

The evidence suggests that specific patients with advanced COPD and hypercapnic respiratory failure may benefit from LTH-NIV; however, individual patient characteristics and preferences, local infrastructure, cost and expertise need to be taken into account. Comorbidities such as malignancy, heart failure and OSA are exclusion criteria in most RCTs and the impact of age has not been evaluated. Considering the option of LTH-NIV should be reviewed in the context of the overall picture of the other treatment options in this patient group.

Frat et al. [33] showed that high flow nasal oxygen (HFNO) was non-inferior to standard oxygen therapy or NIV in preventing intubation with non-hypercapnic acute hypoxic respiratory failure. The use of HFNO is increasing in admitted COPD patients with acute exacerbations and could help with secretion removal and reduce the work of breathing especially in patients who do not require NIV management as part of their treatment, but have severe hypoxaemic respiratory failure [34]. There are a number of proposed benefits for this specific subgroup of patients, who have a significant degree of mucus burden but do not have severe acidotic respiratory failure. The humidification of air may help remove secretion burden and reduce airway inflammation. It also gives additional intrinsic positive end-expiratory pressure (PEEPi) and so may reduce the work of breathing [35]. The high-flow oxygen reduces dead space and this has been shown to reduce PaCO2~~ [36]. RCTs are needed to clarify the real efficacy of HFNO and the best target population during COPD exacerbation.

Dyspnoea management

Dyspnoea is a cardinal symptom of COPD and is subjectively described as a discomfort of breathing. Its severity increases as the underlying disease progresses and can lead to significant limitations and disability as the body becomes more deconditioned [37]. It is believed that dyspnoea occurs from the disruption of the normal relationship between the inspiratory neural drive to breathe and the dynamic response of the respiratory system [38]. The respiratory system is designed to maintain homeostasis in terms of gas exchange and normalising pH. If the expected airflow into the lungs is not achieved, or if the displacement of the lungs and chest wall is inadequate, then an imbalance occurs and can result in the development of dyspnoea [39].

There are different action plans for acute breathlessness and chronic breathlessness. In acute breathlessness the symptom is triggered. The patient may start to feel anxious or overwhelmed and experience physical changes such as muscle tightness and increased respiratory rate which in turn impact on the sensation of breathlessness. Using reliever inhalers, adopting positions-of-ease and doing breathing control and airway clearance exercises are the initial steps. Chronic breathlessness is breathlessness which persists despite optimal treatment of the underlying disease and its severity is increased with increasing airflow limitation [40]. Self-management techniques and lifestyle changes can be very helpful in this instance. Overall, the promotion of regular physical activity, particularly the participation in pulmonary rehabilitation programmes has proven efficacy in reducing dyspnoea and is recommended in international guidelines for patients with COPD and persistent dyspnoea [6].

Finding the right position-of-ease to relieve dyspnoea, reduce effort on accessory muscles and help with sputum clearance is best practised when the patient is stable. Commonly, the forward lean position (resting forearms on the thighs or a table) is most helpful for those with an obstructive pattern (figure 2). Those with restrictive patterns can respond best to sitting upright in a supported high-backed chair. A walking aid may help decrease the work of breathing by bracing the arms on the aid and adopting a forward-lean position which stabilises the ribcage, allowing the accessory muscles to better engage in respiration (figure 3). It may also be a consideration in the presence of portable oxygen.

Breathing techniques can help the patient feel confident that they have the knowledge and ability to tackle unexpected episodes of breathlessness. Controlled breathing is normal tidal breathing using the lower chest on inspiration while relaxing the upper chest, and then relaxing the stomach on expiration (rise, relax, rest). It can be used to promote slow regular breaths, focusing the mind on positive “I have experienced this before; I know it will subside, I need to adopt my position-of-ease, and I will be okay”.

For acute dyspnoea, techniques used start with pursed lip breathing which can decrease respiratory rate, increase vital capacity, and improve gas exchange. The patient can then proceed on to controlled breathing to normalise their respiratory rate. For exertional dyspnoea, the “blow-as-you-go” technique helps make tasks it uses the pursed lip breathing technique and times expiration with effort of the task. Paced breathing can be useful for when climbing stairs or walking (see www.blf.org.uk).

Dyspnoea can be provoked by bouts of coughing and retained sputum. The active cycle of breathing technique (ABCT) is a set of exercises which loosen secretions and helps with expectoration by using a forced expiration “huff”, which is less fatiguing than coughing. A breath is taken in, and with an open mouth and glottis the air is then squeezed out using the chest wall and abdominal muscles [41].

Neuromuscular transcutaneous electrical stimulation (NMES) has been linked to increased muscle strength, functional capacity and health status in COPD patients, and unlike physical exercise, does not evoke dyspnoea [42]. Vieira et al. [43] found that NMES in COPD patients significantly increased 6-min walk test distances by 87 m (p<0.01) and has potential to be considered as an adjunctive technique to exercise. However, the commitment on behalf of the participants and staff was significant, requiring sessions of 60 min, twice daily, five times per week for 8 weeks.

Another non-pharmacological strategy recommended by the ATS is the use of a hand-held fan to help modulate the perception of breathlessness and the person's response to it. The fan is thought to stimulate the upper airway receptors or trigeminal skin receptors. The draught of cool air directed 6 inches from the face, in the three clinical trials reviewed by Luckett et al. [44] resulted in a perceived benefit by 72% of participants in terms of a quicker recovery from breathlessness.

Reduced exercise tolerance in patients with COPD is multifactorial. Altered skeletal muscle function, strength and endurance are affected by systemic factors such as inflammation, medication and inactivity, and changes in protein expression can result in a reduction of muscle mass, depressing the contractile function of skeletal muscles [45]. Progressive dynamic hyperinflation and subsequent dyspnoea also play a significant role in reduced exercise capacity. To avoid exertional dyspnoea, patients often avoid exercise, leading to a “dyspnoea spiral” [46]. There is a known link between oxygen supply and muscle contraction; weaker muscles need more oxygen to work. Thus, exercising regularly can make muscles stronger so that less oxygen is required to do the same amount of activity.

Pulmonary rehabilitation is a 6–8-week structured exercise programme which establishes an environment that normalises the feeling of being short of breath and sees it as a positive reaction to keeping the body fit and strong [47]. The benefits include improved dyspnoea, health status and exercise in stable patients and it also reduces symptoms of anxiety and depression [6]. The modified BORG Dyspnoea Scale is an outcome measure scale which uses specific descriptors of dyspnoea and has been validated as a clinical tool to prescribe workload during muscle training and physical exercise [48]. During pulmonary rehabilitation, this scale helps to judge intensity at an individual level and exercises may be progressed or modified based on symptoms. Interval training at high intensities allows patients to tolerate higher training load with less dyspnoea and leg fatigue as it is interspersed with periods of active recovery or rest. Resistance training provides greater increases in muscle mass and strength and is less strenuous on the breathing system than endurance training, which can be a more positive feature when looking to improve overall activity. All of these factors are combined to deliver an individualised, group-based progressive exercise class with a structured multidisciplinary education programme [49].

The multidisciplinary team (MDT) focus on self-management education covering topics of breathlessness management, nutrition (to make the body stronger, help it fight infections and maintain a healthy weight), energy conservation (by prioritising what needs to be done, pacing techniques and using the BORG scale, planning to do tasks and timing them around when your energy levels are high, linking breathing and swallowing of food and saliva) and lifestyle behaviour changes such as smoking cessation, healthier eating and regular physical activity.

Lung volume reduction procedures

Lung volume reduction (LVR) is a treatment option for patients with end-stage COPD whose main complaint is dyspnoea. This encompasses endobronchial placement of valves (EBV-LVR) or minimally invasive keyhole surgery, such as robot-assisted LVR surgery (RATS-LVRS) or video-assisted LVRS (VATS-LVRS). Surgical LVR is an effective, established treatment for selected patients with severe emphysema and has been shown to provide improvements in health status and lung function outcomes [50–52].

LVRS was initially introduced in the 1930s and aims to remove diseased, hyperinflated lung; enhancing the remaining, more functional lung to improve exercise tolerance and breathlessness at rest [53]. Due to high morbidity, it fell out of routine use until the National Emphysema Treatment Trial (NETT) demonstrated the clinical benefit of LVRS in selected subgroups [7]. They concluded that patients with a low forced expiratory volume in 1 s (FEV1) of <20%, homogenous emphysema or a very low transfer factor for carbon monoxide (TLCO) of <20% were at increased risk for morbidity post-surgery [54]. More modern surgical techniques, such as VATS instead of midline sternotomies, have led to a decrease in the mortality associated with LVRS [55]. The mortality rate of 5.5% in NETT trial from 2003 is overstated compared with 2021 figures (2.2% in the post-operative period) [56]. Robotic LVRS has recently been introduced into practice as an alternative to VATS-LVRS, using real-time Firefly perfusion to identify perfusion defects [57]. Both VATS-LVRS and RATS-LVRS involve the resection of hypo-perfused lung using staples and are typically carried out unilaterally in a specialised thoracic centre. This directly reduces residual volumes, providing symptomatic relief for this dyspnoeic cohort.

Bronchoscopic interventions for the treatment of COPD, including EBV-LVR, have been developed to address the invasive and irreversible nature of surgical LVR. These one-way valves reduce lung hyperinflation by lobar collapse of the targeted site [58] and can be carried out under general anaesthesia or sedation. Other LVR interventions that are mentioned in literature include endobronchial coils, thermal vapour ablation (TVA), targeted lung denervation (TLD) and airway bypass stent (ABS) [12]. Improvement in quality-of-life metrics post-LVR has been established, with a mean reduction in St George's Respiratory Questionnaire of 19.61 units in an Irish cohort comparing EBV, RATS-LVRS and VATS-LVRS [59]. Gompelmann et al. [60] have reported on a long-term follow-up of EBV-LVR patients with lobar atelectasis who had a significant improvement in overall survival with a 5-year survival rate of 65.3% as compared to patients without lobar atelectasis, i.e. without a LVR effect, of 43.9% at 5 years. There was improvement in baseline pulmonary tests for patients with lobar collapse in this cohort [60].

LVR is a complex procedure, balancing medical optimisation, fitness to undergo a procedure and the patient's motivation to proceed involves a stringent screening process. Optimisation of overlapping phenotypes (small airways disease, malacia, bronchitis, bronchiectasis, sleep apnoea, pulmonary hypertension) and comorbidities (reflux, ischaemic heart disease) should be considered. As a general starting point, any patient with severe emphysema (defined as patient achieving an FEV1 ≤50%; GOLD Stage 3 or 4 [3]) who remains breathless on optimal pharmacological therapy and who has completed a course of pulmonary rehabilitation is referred for further assessment. The selection criteria for LVR are multifactorial, encompassing clinical factors, degree of hyperinflation, patient motivation and patient goals of care. The referral criteria are summarised in table 1.

LVR aims to reduce hyperinflation; this relieves dyspnoea on exertion, and at rest. A StratX report (based on a high-resolution, non-contrast computed tomography (CT) thorax) gives a report on fissure completeness and emphysema index (a measure of emphysematous destruction of lung tissue). A bronchoscopy is carried out routinely and a Pulmonx Chartis assessment is carried out to assess for inter-lobar collateral ventilation. If this is found, EBV-LVR will be unsuitable for this patient and RATS-LVRS or VATS-LVRS may be offered. A ventilation/perfusion scan identifies a target perfusion deficit. EBV-LVR patients must meet the above outlined criteria; however, as it is a minimally invasive procedure there is a reduced operability threshold. Therefore, patients who undergo EBV-LVR can have increased comorbidity which may render them unsuitable for VATS-LVRS or RATS-LVRS.

In UK general practice, it has been estimated that 8.1% of patients with COPD meet eligibility criteria to be assessed for a possible LVR procedure [61]. The complexity of this patient cohort's care necessitates input from a MDT. COPD, or hyperinflation, MDTs have been set up in different centres in the UK. They commonly include a respiratory consultant, thoracic surgeon, interventional bronchoscopist, clinical nurse specialist, physiotherapist, palliative care input and consultant radiologists [53].

Transplant in COPD

COPD remains one of the most common indications for lung transplantation worldwide. However, not everyone with severe COPD will derive a benefit from lung transplant and challenges remain in choosing the right candidates. The trajectory of the illness in patients with severe COPD is highly variable despite low lung function. Focusing on potential quality of life benefits post-transplant become important areas of discussion.

Lung transplantation can be a lifesaving treatment option for patients with severe lung disease, which is refractory to conventional treatments. However, there is a significant disparity between the number of donor organs available and the number of potential recipients. It is generally recommended to consider transplantation when the patient is symptomatic during daily living activities (New York Heart Association (NYHA) class III or IV) and survival is expected to be limited to 2–3 years, which represents the upper end of the usual waiting time [62]. The chance of surviving the waiting period will depend on the waiting time, the underlying disease and the existing system for allocation of donor organs [63].

It is important to control and optimise available therapies, including LVRS and pulmonary rehabilitation, but also to weigh the risks and benefits of lung transplantation to each individual patient prior to a lung transplant referral. Other pre-existing conditions may affect patients’ overall outcome and the long-term survival of the graft involves regular hospital reviews and surveillance bronchoscopies as well as taking a complex medicine regimen. Data from the International Society for Heart and Lung Transplantation (ISHLT) registry show a median survival of 6 years for patients who undergo lung transplantation for COPD [64]. The long-term success of lung transplant for the patient can often be reduced by opportunistic infection and rejection issues.

The ISHLT have published guidelines to aid referring teams on choosing the most appropriate patients for referral. It is important to define disease severity as precisely as possible in order to determine which patients have the most urgent need for lung transplantation and are likely to have the longest survival after transplantation.

Guidelines for timing a referral for a transplant assessment for patients with COPD and emphysema due to alpha-1 antitrypsin deficiency include the Progressive disease despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapyPatient is not a candidate for surgical or endoscopic LVRSBODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index 5 to 6Post-bronchodilator FEV1 20–25% of predictedResting hypoxaemia, defined as PaO2~~ <60 mmHg (8 kPa)Hypercapnia, defined as PaCO2~~ >50 mmHg (6.6 kPa)Increase in BODE index score >1 over past 24 months and pulmonary artery to aorta diameter >1 on CT scanWhile TLCO has not been shown to be an independent predictor of mortality in COPD, a low TLCO has been associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk, and thus, also may prompt consideration of referral [62, 65] Following an initial review at the transplant referral clinic, the transplant physician may decide that a formal lung transplant assessment is appropriate, if the disease is severe enough and if there is an absence of other end-organ dysfunction or significant comorbidities (table 2). The lung transplant assessment process involves a series of investigations focusing primarily on understanding the vascular disease and potential malignancy profile of the candidate that can increase with age. Following an assessment, candidates are discussed at a lung transplant MDT meeting to discuss appropriateness of listing for lung transplant.

The following are suggested criteria for placing a patient with COPD on the transplant list (presence of one criterion is sufficient) [62]: BODE index ≥7FEV1 <15 to 20% of predictedThree or more severe exacerbations (hospitalisations) in the preceding yearOne severe exacerbation with acute hypercapnic respiratory failureModerate-to-severe pulmonary hypertensionThe 2022 ISHLT Adult Lung Transplant Report has recently published its findings on recipients who received a lung transplant for COPD over time. Lung transplant recipients transplanted for COPD are now older and more likely to be hospitalised or on mechanical ventilation with more comorbidities pre-transplant than previously. Patients seem also in certain age groups to have better survival with a double lung transplant for COPD than a single lung transplant and the report showed that 5-year survival conditioned at 1 year showed lower survival for single versus double lung transplant recipients in the age groups 40–59 years and >60 years [66].

Many challenges remain with appropriate lung transplant recipient selection for patients with COPD. All possible modifiable barriers should be optimised prior to lung transplantation to ensure the most effective long-term outcome. Prognostic models to predict the appropriate timing for referral are unpredictable even with patients with advanced disease and a careful benefit versus risk assessment is required to see who will derive benefit and improve their quality of life.

Palliative care in COPD

Patients with COPD have a high level of symptomatology daily. Those who care for patients with this condition often focus on the “acute” of the acute-on-chronic breathlessness leaving the “chronic” untreated. Palliative care is defined as an approach that improves the quality of life of patients and their families, in the face of a life-threatening illness. It is an approach focused on the prevention and relief of suffering. It puts the person before the disease, affirms life and regards death as a normal process [67].

It can be difficult to know when to consider a palliative approach, but guidelines suggest it should begin at the time of diagnosis of a life-limiting illness [6, 68]. Despite these recommendations, there is low uptake of palliative care services for COPD patients within primary care. A large UK cohort study showed that only 16.7% of deceased COPD patients who did not have an accompanying cancer diagnosis received palliative care services compared with 56.5% of deceased patients with COPD and lung cancer [69]. In the USA, insurers do not support coverage of this service unless the physician certifies that the patient will die within 6 months if the disease to take its usual course [70]. This can be challenging as COPD has an unpredictable course, punctuated by exacerbations and often without a distinct terminal phase. Predicting the terminal phase is difficult [71] and physicians’ ability to assess this in their patients is limited.

The respiratory triad of symptoms are those of breathlessness, fatigue and cough. Dyspnoea is defined as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. Chronic breathlessness in advanced disease results from a number of pathophysiological processes, such as cachexia, deconditioning and airway narrowing.

The multidisciplinary approach addressing this complex symptom is addressed in the dyspnoea management section. The pharmacological approaches to managing dyspnoea come from three main drug opioids, benzodiazepines and antidepressants.

Morphine has the largest evidence base though this is not substantial. A helpful practical paper in Breathe suggests starting on the lowest possible dose, increasing when necessary to 20 mg daily modified-release form and titrate up, if needed to a maximum of 30 mg daily, treating adverse effects actively [67]. Most patients in clinical trials have required no more than 30 mg per day, but it should be noted that two thirds of patients had stopped morphine at 3 months because of adverse effects (constipation, dysphoria, myoclonus, nausea and sedation) or lack of response.

A recent study of the effect of morphine on breathlessness and exercise endurance in advanced COPD saw a randomised crossover trial investigate the acute effect of immediate release oral morphine versus placebo on physiological and perceptual responses during cardiopulmonary exercise test (CPET) in 20 adults with advanced COPD and chronic breathlessness syndrome [72]. In the morphine group breathlessness was reduced by 1.2 BORG units with exercise endurance time increased by 2.5 min. Breathing frequency during exercise was decreased by 2 breaths per min. CPET could be considered to separate responders from non-responders. A further trial of 111 participants investigated outcomes after 4 weeks of 10 mg sustained release morphine twice daily versus placebo [73]. The COPD Assessment Test score was 2.18 points lower in the morphine group and PaCO2~~ was 1.19 mmHg higher. Breathlessness, however, remained unchanged but “worst breathlessness” improved in participants with mMRC grades 3 to 4. Five participants in the morphine group withdrew compared with one in the placebo group.

There is no evidence for or against benzodiazepines for the relief of breathlessness in people with advanced cancer and COPD [74]. Benzodiazepines caused more drowsiness as an adverse effect compared with placebo, but less compared with morphine. Benzodiazepines may be considered as a second- or third-line treatment, when opioids and non-pharmacological measures have failed to control breathlessness.

Currently, there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease [75, 76]. Mirtazapine is a promising candidate to pursue, with a RCT underway to determine its efficacy and safety in this setting [77].

Fatigue is a highly prevalent symptom in advanced respiratory disease and often overlooked. This is not simply tiredness but “incorporates total body feelings ranging from tiredness to exhaustion, creating an overall body condition which is unrelenting and alters the person's ability to function” [67]. Characteristically it is not improved by sleep or rest. There is some overlap with the dyspnoea treatments with exercise, cognitive behavioural therapy, pacing and prioritising being key approaches. Pulmonary rehabilitation reduces fatigue in COPD [78].

Cough can be a very distressing symptom, and a precipitator and exacerbator of breathlessness, anxiety and poor sleep in both the sufferer and those closest to them. Non-pharmacological interventions based on speech and language therapy have been used in chronic (idiopathic) cough with some success [67]. Drug therapy is gabapentin, a central modulator of cough generation, is used but there is no guidance for its use in advanced respiratory diseases. Further information is outstanding on the use of gefapixant, a P2X3 receptor antagonist proven to have some benefit in refractory chronic cough and unexplained chronic cough [79]. This medication has not yet been licensed for use in the setting investigated and has not yet been investigated in cough associated with COPD. Taking 10 mg of oral modified release morphine has been shown to cause a statistically significant 40% reduction in cough scores in chronic cough compared with placebo but has not been tested for this symptom in COPD [80].

In terms of palliation, the holistic approach includes addressing comorbidities which may include anxiety (intrinsically linked with breathlessness), depression, nutritional deficits and inadequate sleep. Other important issues in community care include caring for the carers and optimising general health with advanced care planning. The pulmonary physician has a key role in recognising the requirement for palliative care in their patients but an integrated approach with the palliative team, with appropriate referral pathways in place, is optimal [81] (figure 4). Expert palliative input may be required Breathlessness having a very significant impact on the quality of life of the patient or familyMultiple hospital admissions or consultations irrelevant to disease managementExtra barriers exist to giving the patient and family excellent careInsufficient expertise within the respiratory service to provide adequate symptoms control

A large and growing body of evidence testifies to palliative care outcomes, that include improved patient satisfaction with care, decreased symptom burden and in some cases better survival [82]. Palliative care has been shown to create cost savings for health systems due to decreased hospital utilisation [83]. Incorporating palliative care earlier in the management of COPD patients and combining it with other therapy is suggested by the authors.

Areas for future research

There are areas for further research and service development within advanced COPD. More widespread support for oxygen therapy and NIV follow-up care may help with appropriate prescription and therapy compliance, to optimise this expensive resource for each patient. Studies are needed to clarify which patient cohorts may benefit from referral to transplant rather than LVR options. Within the area of lung transplant, work continues on donor organ preservation methods and reconditioning of lungs and a more focused approach is now being adopted with respect to the area of personalised medicine in immunosuppression treatments. Results are awaited from ongoing trials in the area of pharmacological management of dyspnoea. Ongoing collaboration with palliative care colleagues in combination with further training in this skill set for pulmonary specialists are likely to improve symptom management care for these patients.

Conclusions

Although the GOLD report offers an evidence-based guide to diagnosis and treatment in COPD, an individualised, multidisciplinary approach is required in patients with advanced COPD to address the chronic symptomatology associated with the condition. This should include assessment of oxygen requirement, review of the role of NIV, dyspnoea management coaching, and consideration of surgical or bronchoscopic options, up to and including lung transplantation, which can run in parallel with a palliative approach to chronic symptoms.