New Frontiers of the Management of Chronic Obstructive Pulmonary Disease (COPD)
Chronic obstructive pulmonary disease (COPD) is a common respiratory condition. It is among the leading causes of mortality worldwide. This is expected to rise, due to ongoing exposure to COPD risk factors in developing countries and an aging population in developed countries.1, 2 Because of its high prevalence and chronicity, COPD exerts a substantial burden on the healthcare system and resources, due to the need for ongoing chronic therapy, outpatient appointments, and frequent hospitalisations.3
COPD is a heterogeneous lung condition characterised by persistent respiratory symptoms (dyspnoea, cough, sputum production) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema), that cause persistent, often progressive, airflow obstruction.4 COPD management aims to improve the quality of life via symptom control and prevention of exacerbations.5 Therefore, the optimal management of COPD requires an integrated pathway of care involving patients, family, care-givers, and healthcare professionals as patients move between stability and acute exacerbations.6
Diagnosis of COPD is based on a triad of causative exposure (particularly smoking), symptoms, and airflow obstruction (FEV1/ FVC <70%) on spirometry. The HSE Integrated Model of Care for the Prevention and Management of Chronic Disease includes COPD.7 This model of care supports people to live well within the community, with ready and equitable access to their GP, diagnostics, health and social care professional input and specialist opinion, as required. The focus is on keeping people well and on providing care as close to home as possible. The cornerstone of treatment for COPD is smoking cessation and must be stressed with those who continue to smoke at every encounter.7 The other key non pharmacological interventions are vaccinations and pulmonary rehabilitation. Approved pharmacological therapies include inhaled bronchodilators and corticosteroids, azithromycin, roflumilast and oxygen therapy.
There have been numerous research developments in the management of COPD patients who are still symptomatic, despite optimal treatment. These new frontiers include monoclonal antibodies (MAbs), hyaluronan, stem cells, new bronchoscopic interventions, and digital health.
Monoclonal antibodies (MAbs)
MAbs are immunoglobulins designed to specifically act on a target to produce desired therapeutic effects for patients.8 In respiratory medicine, omalizumab was the first MAb approved and used in severe asthma in the early 2000s. Since then, more targeted MAbs have been developed, such as mepolizumab and benralizumab, and offered to appropriate asthma populations. Numerous MAbs or biologic agents have been tried to target inflammatory pathways in COPD but most disappointingly failed to demonstrate significant findings. Interest in MAbs was re sparked from positive results in COPD patients with an eosinophilic phenotype using mepolizumab (anti-IL5) in METREO, a phase 3 clinical trial.9 However, the small yet significant results using mepolizumab in moderate-tosevere COPD in METREO were not demonstrated in its parallel phase 3 clinical trial, METREX, nor in two other phase 3 clinical trials for benralizumab (anti-IL5 receptor) (GALATHEA, TERANOVA).10 A systematic review integrating all of these results showed that these MAbs are safe but require high doses to reduce moderateto-severe exacerbations in highly selected eosinophilic COPD.11 For now, MAbs used in asthma show positive but limited proof of efficacy in eosinophilic COPD. In terms of cost-effective balance, they are not yet approved by the FDA.11 Nevertheless, there are more ongoing studies to delineate these effects (RESOLUTE trial for benralizumab, NCT04053634) and with different agents (dupilumab in NOTUS, NCT04456673) (tezepelumab in COURSE, NCT04039113). MAbs still have a long way to go in COPD management, but they remain a huge potential to be utilised in the personalised treatment of COPD, especially in a very selected group.12
Matrix Biologics: Hyaluronan
Hyaluronan is a high molecular mass polysaccharide found as a major component in extracellular matrix, especially of soft connective tissue.13 It has a key role in wound repair with tissue regeneration, inflammation response and angiogenesis.14 In the lung, a high concentration of hyaluronan can be found and detected on the airway surface.15, 16 Hyaluronan molecules could be degraded to smaller fragments in acute inflammation and these smaller fragments could exert strong pro-inflammatory effects.17 New evidence suggests that the imbalance between hyaluronan and its smaller fragments may contribute to the pathogenesis of chronic airway disease.18 In animal models, aerosolized hyaluronan was found to reverse emphysema induced by neutrophil elastase.19
A phase 2 clinical trial on hyaluronan in the form of highmolecular-weight in COPD exacerbation demonstrated significant findings clinically in terms of shortened duration of acute respiratory failure, need for non-invasive ventilation and length of stay in the hospital.20 This was only a pilot study with a small number of patients, but it has illustrated the safety and feasibility of further exploring hyaluronan as a potential agent in the management of COPD in the future.
Stem cells
Stem cells are a population of unspecialized cells with the potency to differentiate into different types of cells and with regenerative capability.21, 22 Stem cell therapy in regenerative medicine may have the potential to play a revolutionary role in the management of COPD or even in any other lung disease, moving away from treating symptoms and focusing more on regenerating damaged lung structures and restoring lung function.23
Based on preclinical research on COPD, stem cells may benefit patients in terms of improving airway inflammation, regenerating new lung tissues for ventilation, and angiogenesis of blood vessels to improve perfusion.24 Clinical trials of stem cells in COPD so far have not progressed from phase 2. A recent systematic review of stem cells in COPD patients demonstrated that whilst stem cells or its derivative product were safe, they only significantly improved the exercise capacity of COPD patients, with no improvement in lung function, pCO2 retention or hospitalisation from acute exacerbation.23 Thus, the success of stem cell therapy in animal models was not fully replicated and demonstrated in clinical trials, possibly due to the heterogeneity, small number of samples, and the severity of COPD patients enrolled.25
Larger, well-designed randomised controlled trials are required to quantify the beneficial effects of stem cells in COPD.
Bronchoscopic interventions
Lung hyperinflation occurs with advanced emphysema in COPD. It causes breathlessness as the diaphragm is unable to function properly. Surgical intervention may be indicated in a very carefully selected group of COPD patients if they are still symptomatic despite maximal medical therapy and pulmonary rehabilitation.26 The recognized surgical interventions for COPD are mainly giant bullectomy, lung volume reduction surgery (LVRS) and lung transplantation.27 LVRS, when performed on the right group, can improve both symptoms and mortality. However, open surgery is not without risk of severe complications, especially in the multimorbid COPD population. In the NETT trial, for example, LVRS is associated with high perioperative mortality and morbidity.28 This is one of the highest-risk procedures performed electively due to the fact that these patients generally have low lung function and increased age.29
Endoscopic Lung Volume Reduction (eLVR) is an alternative procedure which is less invasive and has better postoperative risk profiles compared to open surgery. Different techniques are available including an endobronchial oneway valve (EBV), self-activating coils, airway bypass stent, sealant, and thermal ablative techniques. The most widely studied and used technique in eLVR is EBV.30 Current literature shows a carefully selected group of patients who underwent EBV had significant improvement in exercise capacity and quality of life.31 These results are comparable to LVRS but with a lower rate of complications.32 An ongoing trial (CELEB) will further clarify which one is a better option; LVRS or eLVR. (ISRCTN19684749)
There are new procedures targeting the chronic bronchitis group of COPD; nitrogen cryospray, bronchial rheoplasty and lung denervation technology. These procedures use a similar concept, that is to deliver a specific substance endobronchially via bronchoscopy to reduce airway secretions. The nitrogen cryospray uses liquid nitrogen to induce extreme cold to freeze and destroy abnormal cells.33 It has two clinical trials ongoing currently (NCT03892694, NCT03893370). A study published in 2020 showed that it was safe, feasible and significant symptom improvement.34 Bronchial rheoplasty is a technique applying non-thermal pulsed electrical fields to the abnormal airway epithelium. A small clinical trial in COPD patients with chronic bronchitis demonstrated that it is feasible, safe and associated with significant symptomatic relief.35 An ongoing trial, RheSolve (NCT04677465), will further elucidate the effects of this intervention.
Lung denervation technology uses radiofrequency ablation via bronchoscopy to disrupt parasympathetic innervation of the lung. By doing this, cholinergic hyperactivity and subsequently mucous secretions can be reduced. A phase 2 trial, AIRFLOW-2, showed that this technology can reduce the risk of exacerbation and hospitalizations in patients with moderate to severe COPD with chronic bronchitis.36 An ongoing follow-up trial (AIRFLOW-3, NCT03639051) will further determine the effects of the technology on COPD exacerbation.
Digital health
Self-management is an essential part of chronic disease management as patients become more responsible for their healthcare and develop skills to manage their conditions more effectively.37 It is associated with an improvement in quality of life, reduction in hospitalisation, reduction in exacerbation duration, and lower healthcare costs.38 However, efforts to increase patients’ autonomy and active participation in their selfmanagement care can be difficult with barriers from both patients (motivation, ambivalence) and healthcare professionals (time, resources, skills).39
The recent rise of digital technologies and innovations during the COVID-19 pandemic has led to an emphasis on a different approach to address self-management and ultimately COPD care.40 The utilisation and medicalisation of digital technologies to make healthcare more enhanced, efficient, affordable, personalised and precise have been termed digital health.41 Examples are telemonitoring, telehealth, postdischarge care, hospital-at-home strategy, electronic records, big data analytics, environmentmonitoring applications and digital-technology-enabled homecare programmes.42
Digital health is an innovative solution to provide an integrated, patient-centred care model for the management of COPD and patients are perceptive to its role, especially with symptoms and anxiety management.43 In COPD management specifically, digital health technologies potentially can be used in a number of ways. These include pulmonary rehabilitation, inhaler technique training, adherence monitoring, recognition and early treatment of exacerbations, education about COPD and its management, remote monitoring and recognition of symptoms, feedback to patients and healthcare professionals, tools to avoid exacerbation triggers etc (Figure 1).40
Pulmonary rehabilitation (PR) is a vital component in managing breathless patients with COPD. Its use, especially postexacerbation, can provide better symptomatic relief and quality of life and improve mortality.44 However, barriers preventing full utilisation of this service include accessibility, inconvenience, lack of transportation and fewer PR centres.45 Using digital technologies, home PR could be an alternative to provide this key intervention. Current literature demonstrates that this is feasible and effective even in frail COPD populations.46, 47, 48 Digital health is projected to be the future of healthcare and therefore it will become the new frontier in how we manage patients with COPD.49
Summary
COPD is a heterogeneous condition that requires specific treatment for different types of phenotypes or endotypes. The pathogenesis needs further exploration to better understand this complex heterogeneity and the inflammatory pathway involved. There are numerous emerging therapies targeting different aspects of COPD, including monoclonal antibodies, matrix biologics (hyaluronan), stem cells, bronchoscopic interventions and digital health. Further research is still needed before they become mainstays of treatment, but the healthcare professionals and patients with COPD can look towards the future with optimism at the new frontiers of COPD management.
Figure 1: Potential opportunities for digital innovations to facilitate effective COPD management (from Watson, A. and T.M.A. Wilkinson, Digital healthcare in COPD management: a narrative review on the advantages, pitfalls, and need for further research. Therapeutic Advances in Respiratory Disease, 2022. 16: p. 17534666221075493).
References available on request
Written by
Dzufar Halim, Department of Respiratory Medicine, University Hospital Galway – University of Galway
and
Sinead Walsh, Department of Respiratory Medicine, University Hospital Galway – University of Galway
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