The Unmet Need in Chronic Obstructive Pulmonary Disease
and Call to Change
Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease that is characterised by persistent respiratory symptoms (including chronic cough, shortness of breath and sputum production), airflow limitation[i]. COPD affects an estimated 384 million people worldwide[ii] and is the third leading cause of death globally,[iii] but it is significantly under-reported and undertreated.[iv],[v]
The global burden of COPD is growing.
· COPD is the third leading cause of death, after ischaemic heart disease and stroke and before cancers[vi]
· COPD is the most prevalent chronic respiratory disease and most common cause of chronic respiratory disease attributable deaths7. In 2017, 3.2 million people died from COPD worldwide - an increase of 23 per cent compared to 1990[vii],[viii]
And the personal and economic burdens are significant:
· COPD-related costs are estimated to be >$100 billion per year globally, which is mainly attributable to the cost of exacerbations, also known as ‘flare ups’1,[ix],[x]. This mirrors other leading causes of mortality worldwide such as heart failure (estimated to cost $108 billion per year globally)[xi]. Despite this, COPD does not receive the same global recognition and prioritisation
· COPD is associated with significant reductions in quality of life in all stages of disease severity, which worsens during an exacerbation[xii]
A group of leading clinical experts and patient advocates have identified three policy priorities that have the greatest potential to impact on COPD patients and global healthcare systems. These are:
1. Earlier and accurate diagnosis
2. Access to therapies (pharmacological & non-pharmacological)
3. Awareness of exacerbations as an opportunity for optimised management
This consensus paper summarises policy priorities and provides the evidence base detailing the current standards of care that supports our call to change.
Earlier and accurate diagnosis
· Universal criteria for the diagnosis of COPD and identifying those at risk must be adopted globally to reduce variation in diagnosis rates. This includes in both national and regional healthcare system policies.
· Public health bodies should increase awareness of the common COPD risk factors and symptoms in the general public, so patients are informed and empowered to seek diagnosis.
· Governments must provide the resources necessary to educate healthcare professionals about effective COPD diagnosis and management.
· Access to appropriate spirometry and other diagnostic equipment must be prioritised alongside healthcare professional upskilling to properly perform and interpret diagnostic results.
Access to therapies (pharmacological & non-pharmacological)
· The use of pharmacological therapies in line with the latest global treatment guidelines published by GOLD, including maintenance therapy, must be prioritised by healthcare systems to improve clinical outcomes, health related quality of life and slow disease progression.
· Variation in access to pulmonary rehabilitation and specialist respiratory reviews must be addressed in local and national health service provision plans and should be prioritised as part of wider strategies to address health inequalities.
· Public health bodies must renew efforts to raise awareness of the benefits of smoking cessation and physical activity, as well as minimising exposure to indoor and outdoor pollutants, to both prevent and better manage COPD alongside other health benefit associated with co-morbidities like cardio-vascular conditions.
· Guidance on global quality standards of care for COPD management, to support improved access to and delivery of quality care, must be developed to guide health systems reform. This should be grounded in published evidence and clinical guidelines available.
· COPD patients should receive a personalised care approach, with a tailored action plan including pharmacological and non-pharmacological therapies based on their specific circumstances and preference.
Awareness of acute exacerbations as an opportunity for accelerated management
· Exacerbation and mortality targets associated with COPD must be set in national and regional healthcare system policies and should be audited for performance.
· Healthcare systems and providers should provide prompt personalised pharmacological and non-pharmacological treatment reviews post-exacerbation in order to prevent further exacerbations and irreversible lung deterioration. This should include the use of maintenance therapy to prevent or reduce further symptoms following an exacerbation.
· COPD patients must be given easy access to the tools and resources to better understand and recognise exacerbations in order to feel empowered to take immediate action and report their experience to their healthcare team.
Current standards of care
Earlier and accurate diagnosis
There is a lack of awareness of both COPD risk factors and symptoms among the public and patients. The resulting late diagnosis can significantly impact health outcomes and increase healthcare costs.
· Globally, there is large variation in rates of diagnosis, with 10-95% of COPD patients under-diagnosed and 5-60% over-diagnosed. A major reason for this variation is the different criteria used to diagnose COPD globally[xiii],[xiv]
· Opportunities to diagnose are missed in:
o 85% of patients in the 5 years preceding diagnosis
o 58% of patients in the 6-10 years preceding diagnosis
o 42% in the 11-15 years preceding diagnosis
o 8% in the 16-20 years preceding diagnosis[xv]
· COPD often remains undiagnosed until the disease has increased in severity15,[xvi] , which is associated with poor clinical outcomes[xvii] as lung damage is not reversible15
The reasons for late or inaccurate diagnosis:
· Because of a lack of knowledge of COPD and its symptoms, individuals often attribute early COPD symptoms to ‘just getting older’14,[xviii] . Additionally, due to the stigma associated with COPD and smoking, patients may ignore symptoms, dismiss them as self-inflicted[xix] or delay presentation to a clinician for fear of judgement because of previous or continued smoking[xx]
· Patients who over- or under-perceive their symptoms, and those who have comorbidities, may experience over diagnosis leading to excessive treatment, or a misdiagnosis14
· Accurate diagnosis of COPD can only be made using quality assured post-bronchodilator spirometry, however, access to spirometry results and skills to perform and interpret the tests vary greatly across health care settings[xxi]. Primary care physicians may decide not to incur the cost of spirometry equipment, or may be unfamiliar with the complex technology[xxii]
· Current diagnostic procedures may lead to misdiagnosis, such as errors made in the performance and interpretation of spirometry tests 13. Errors made in primary care, due to insufficient resources or a lack of knowledge of COPD and the differentiation between other diseases, have also been noted as reasons for misdiagnosis[xxiii]
The impact of late diagnosis:
· COPD is frequently diagnosed late when the disease has already progressed17. This is associated with higher exacerbation rates, increased comorbidities and costs17
· Rate of FEV1 decline, or airflow limitation, is greater in patients with a less severe disease than those with a more severe disease22 . If the disease were diagnosed and treatment begun sooner, lung function decline would be better controlled
· Health care utilisation and cost to health services and wider economy. Moderate-to-very severe COPD represents a considerable economic burden for healthcare providers despite the availability of efficacious treatments and comprehensive guidelines on their use[xxiv]. More severe COPD was significantly associated with higher healthcare utilization through hospitalisation, as well as higher work absence, and premature retirement[xxv]
Access to therapies (pharmacological / non-pharmacological)
Non-pharmacological and pharmacological therapies are clinically proven to reduce mortality, symptoms and the frequency of acute exacerbations. However, there are barriers in health systems which impact timely and appropriate access to therapies. Delayed access to therapies has a negative impact on disease progression and healthcare costs.
· COPD is a heterogenous disease1 and is associated with a number of co-morbidities which further contribute to disease severity, reduced quality of life, and poor clinical outcomes[xxvi],[xxvii] These factors highlight the need for a combination of pharmacological and non-pharmacological therapies to manage this condition1
· Results from recent trials have demonstrated that reducing the risk of all-cause mortality from pharmacological therapy is an achievable treatment goal in COPD[xxviii]
Healthcare system barriers to delivering earlier and better management:
· Non-adherence to guidelines in primary, community and acute care, leading to missed diagnostic opportunities and inappropriate management[xxix],[xxx] such as variation in the use of maintenance treatment[xxxi],[xxxii]
· As there are no adequate follow up guidelines on discharge21, patients discharged from the emergency department (ED) were less likely to have short-term treatment for their acute exacerbation compared to those being discharged from in-patient care hospital (44% versus 68%)32. This lack of standardisation means that clinical outcomes can vary significantly
· There is limited availability, capacity and variation in the quality of service[xxxiii] of pulmonary rehabilitation (PR). Access to PR is often dependent on location and therefore patients living in rural areas must travel further[xxxiv], further exacerbating health inequalities facing rural communities.[xxxv]
· Staffing levels and the availability of specialist respiratory review are linked to mortality and quality of service21, [xxxvi] – patients who received specialist review when admitted to hospital for a COPD exacerbation were 14% less likely to die as an inpatient than those who did not receive specialist review21
The need for timely access to pharmacological therapies:
· Pharmacological intervention in early COPD is likely to improve clinical outcomes[xxxvii]. Early initiation of treatment has been shown to slow disease progression and improve Health-Related Quality of Life (HRQoL)[xxxviii]
· Inability to access maintenance therapy (MT) dramatically increases the risk of future exacerbations[xxxix]. Prompt initiation of maintenance therapy after a COPD-related hospitalisation or visit to the ED is associated with a reduction in the likelihood of another exacerbation the following year40. If MT is delayed, there is a 68% increased likelihood of an exacerbation resulting in hospitalisation, an ED visit or physician visit plus prescription within 5 days, and increased COPD-related costs (US$3,931 compared to US$4,857 for prompt initiation of MT)[xl]
· There is limited data on the effects of earlier pharmacological intervention for COPD. Further studies are needed to assess the impact on not only lung function, but also breathlessness, symptoms and quality of life38
· National flu and pneumococcal vaccines. Vaccinating against commons viruses is important for COPD patients as the flu puts extra strain on the lungs and there is evidence that respiratory failure happens more often during or immediately after an acute inflammatory illness, such as flu[xli]
Alongside therapies, patient self-management is important:
· Self-management is linked to improved HRQoL, a lower probability of respiratory-related hospitalisation, and a reduction in breathlessness[xlii],[xliii]
· Patient adherence to their written action plan, which is a set of instructions to follow when symptoms deteriorate, is associated with a reduction in exacerbation recovery time[xliv]
· Additionally, caregivers of individuals with COPD have a key role in maintaining patient adherence and optimizing patient function[xlv]
Non-pharmacological therapies include:
· Smoking cessation. This therapy has been shown to reduce lung function decline at all stages of COPD, reduce morbidity and mortality38,[xlvi],[xlvii]. Compared to current smokers, former smokers are at a significantly decreased risk of exacerbations[xlviii]
· Physical activity. More frequent and longer low-intensity physical activity reduces the risk of COPD hospitalisations and mortality[xlix],[l]
· Pulmonary rehabilitation. PR should be considered a foundational intervention in the management of COPD given that is an important indicator of clinical outcomes and is associated with health benefits, including a reduced rate of exacerbations33and mortality[li]
Awareness of acute exacerbations as an opportunity for accelerated management
Exacerbations are linked to mortality, lung function decline and psychological deterioration. As well as the personal burden, most COPD-related costs are associated with hospitalisations and therefore the impact on healthcare system utilisation is substantial. Some patients do not receive appropriate therapies after an exacerbation, meaning their disease management is not optimised and this places them at greater risk of recurring events.
The burden of exacerbations:
· Acute exacerbations are a worsening or “flare up” of COPD symptoms, which may be triggered by a bacterial or viral infection in the lungs, exposure to environmental pollutants, or an unknown trigger[lii]
· Between 49%-~74% of patients will have at least 1 exacerbation within 3 years of diagnosis[liii],[liv],[lv]
· Acute exacerbations can occur at all stages of disease severity, however, they are more frequent in patients with a more advanced disease1. However, irreversible lung function decline following an exacerbation is greatest in patients with mild COPD[lvi]
· Hospitalisations resulting from severe exacerbations account for approximately 60-70% of all healthcare costs associated with COPD[lvii]
· Exacerbations appear to have a significant impact on patient well-being, including psychological well-being[lviii],[lix]
· One exacerbation increases frequency of exacerbations and decreases the time between these events or death[lx]
· The best predictor of future exacerbations is a history of exacerbations and therefore this history identifies a high-risk group[lxi]
Examples of poor exacerbation management:
· The current global treatment paradigm is one of failure-driven escalation, whereby escalation in treatment is only considered following a worsening of symptoms, such as severe breathlessness (dyspnea) or exacerbations1
· On average globally, over 1 in 3 patients receive no maintenance therapy, treatments offered to prevent or reduce symptoms, after an exacerbation:
o US – between 36% and 75% are not on appropriate therapy post-exacerbation32,[lxii]
o Canada – ~50% are not on appropriate therapy post-exacerbation[lxiii]
o China – 53% are not on appropriate therapy post-exacerbation[lxiv]
· Approximately 40% of COPD patients take no immediate action when having an exacerbation[lxv]
· Exacerbations are often not reported by patients[lxvi],[lxvii] . There may be many reasons for this. Some patients make the decision to self-manage, meaning that they are not subsequently treated with the appropriate medication[lxviii]
Exacerbations and poor exacerbation management can result in:
· An increased risk of mortality as even a single exacerbation can significantly reduce life expectancy and increases the risk of death[lxix],[lxx]
· Long-term decline and disease progression39,56,[lxxi]. Symptoms may not return to pre-exacerbation baseline if not reported to a clinician66
· Lung function decline: patients with milder disease levels have a greater rate of decline after each event56and some patients will not recover from the effects of an exacerbation71. Given that GOLD recommends escalation of treatment after >2 severe exacerbations, it is reasonable to suggest that the patient has already experienced significant and perhaps irreversible decline
· An increased risk of cardiovascular complications, such as myocardial infarctions (MI) and strokes. The risk of MI doubles within 5 days of the start of an exacerbation, and then returns to baseline over time, and the risk of stoke increases by 40% within 10 days[lxxii]
· A societal burden, with a significant increase in healthcare resource utilisation for COPD patients who have experienced an exacerbation compared with those who have not10,57
· A worsening of quality of life in the short- and long-term[lxxiii], related to a number of factors including anxiety, dystopia, depression and decreased exercise capacity59
COVID-19 and COPD
COVID-19 has intensified this unmet need even further, with the disease causing a significant impact on risk of poor outcomes[lxxiv]. COPD patients infected with COVID-19 may have up to 60% increased mortality risk versus non-COPD patients[lxxv].
COVID-19 has not only impacted those COPD patients who have contracted the illness, but all patients, who are not receiving the same type or regularity of care they previously did, despite efforts with virtual consultations and telehealth. Pulmonary rehabilitation, which improves health outcomes, including hospitalisations33, was in some cases not carried out during the pandemic. Patients who may have normally presented to the hospital during an exacerbation might choose to stay home for fear of exposure, resulting in delayed care and potentially death[lxxvi].Inability to carry out spirometry at pre-pandemic levels, due to it being an aerosol emitting equipment, will most likely have created a backlog of undiagnosed patients[lxxvii]. The long-term impacts of this pause or significant reduction in diagnostic services and routine care are yet to be fully understood.
 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) develops annual evidence-based strategy documents for COPD management. Classification of severity is based on airflow limitation and falls into four categories based on FEV1 (forced expiratory volume) (% predicted): GOLD 1 (>80 FEV1 - mild), GOLD 2 (50 – 79 FEV1 - moderate), GOLD 3 (30-49 FEV1 - severe) and GOLD 4 (<30 FEV1 – very severe). Classification of severity is separated from assessment of symptoms/ risk of exacerbations and does not inform therapeutic decisions
 FEV1 (forced expiratory volume) is the amount of air that can be forced from the lungs in 1 second, measured through a spirometry test. FEV1 score is used to classify COPD severity.
 A PR course, which usually lasts between six to eight weeks, consists of a physical exercise programme, and information and advice on managing COPD
[i] Global Initiative for Chronic Obstructive Lung Disease. Global strategy for diagnosis, management and prevention of COPD. 2020. Accessible here: https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf [Last accessed: January 2021]
[ii] Adeloye D, Chua S, Lee C et al. Global and regional estimates of COPD prevalence: Systematic review and meta–analysis. J of Glob Heath. 2015; 5(2):020415.
[iii] Quaderi S and Hurst J. The unmet global burden of COPD. Glob Health Epidemiol Genom. 2018; 3:e4.
[iv] Ho T, Cusack R, Chaudhary N et al. Under- and over-diagnosis of COPD: a global perspective. Breathe. 2019; 15: 24-35.
[v] Diette G, Dalal A, D’Souza A et al. Treatment pattern of chronic obstructive pulmonary disease in employed adults in the United States. Int J Chron Obstruct Pulmon Dis. 2015; 10:415 – 22.
[vi] Murray CJ and Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet. 1997; 349:1498 – 1504.
[vii]GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020; 8(6):585-596.
[viii]Li X, Cao X, Guo M et al. Trends and risk factors of mortality and disability adjusted life years for chronic respiratory diseases from 1990 to 2017: systematic analysis for the Global Burden of Disease Study 2017. BMJ. 2020; 368:m237.
[ix] Chen X, Wang N, Chen Y, et al. Costs of chronic obstructive pulmonary disease in urban areas of China: a cross-sectional study in four cities. Int J COPD. 2016; 11(5):2625-2632.
[x] Blasi F, Cesana G, Conti S, et al. The clinical and economic impact of exacerbations of chronic obstructive pulmonary disease: a cohort of hospitalized patients. PLoS One. 2014; 9(6): e101228.
[xi] Lesyuk W, Kriza C and Kolominsky-Rabas P. Cost-of-illness studies in heart failure: a systematic review 2004-2016. BMC CV Disorders. 2018: 74.
[xii] Jones PW, Brusselle G, Dal Negro RW, et al. Health-related quality of life in patients by COPD severity within primary care in Europe. Respir Med. 2011; 105(1):57-66.
[xiii] Diab N, Gershon AS, Sin DD et al. Underdiagnosis and overdiagnosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018; 198(9):1130―9.
[xiv] Ho T, Cusack R, Chaudhary N et al. Under- and over-diagnosis of COPD: a global perspective. Breathe. 2019; 15: 24-35.
[xv] Jones RC, Price D, Ryan D et al. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med. 2014; 2(4): 267–76.
[xvi] Mapel DW, Dalal AA, Blanchette CM, et al. Severity of COPD at initial spirometry-confirmed diagnosis: data from medical charts and administrative claims. Int J Chron Obstruct Pulmon Dis. 2011; 6: 573–581.
[xvii] Larsson K, Janson C, Stallberg B et al. Impact of COPD diagnosis timing on clinical and economic outcomes: the ARCTIC observational cohort study. Int J Chron Obstruct Pulmon Dis. 2019; 14: 995 – 1008.
[xviii] Leidy, N, Kim K, Bacci E et al. Identifying cases of undiagnosed, clinically significant COPD in primary care: qualitative insight from patients in the target population. NPJ Prim Care Respir Med. 2015, 25: 15024.
[xix] Shahab L, Jarvis MJ, Britton J et al. Prevalence, diagnosis and relation to tobacco dependence of chronic obstructive pulmonary disease in a nation-ally representative population sample. Thorax. 2006; 61:1043–7.
[xx] Russell S, Ogunbayo O, Newham J et al. Qualitative systematic review of barriers and facilitators to self-management of chronic obstructive pulmonary disease: views of patients and healthcare professionals. NPJ Prim Care Respir Med. 2018; 28(1):1-3.
[xxi] Royal College of Physicians. National Asthma and COPD Audit Programme (NACAP). COPD clinical Audit 2017/18.. Available at: https://www.rcplondon.ac.uk/projects/outputs/national-asthma-and-copd-audit-programme-nacap-copd-clinical-audit-201718 [Accessed: January 2021]
[xxii] Price D, Freeman D, Cleland J et al. Earlier diagnosis and earlier treatment of COPD in primary care. Prim Care Respir J. 2011; 20:1(15-22).
[xxiii] Hangaard S, Helle T, Nielsen C et al. Causes of misdiagnosis of chronic obstructive pulmonary disease: A systematic scoping review. Respir Med. 2017; 129:63-84.
[xxiv] Iheanacho I, Zhang S, King D et al. Economic Burden of Chronic Obstructive Pulmonary Disease (COPD): A Systematic Literature Review. Int J Chron Obstruct Pulmon Dis. 2020;15:439-460.
[xxv] Kirsch F, Schramm A, Schwarzkopf L et al. Direct and indirect costs of COPD progression and its comorbidities in a structured disease management program: results from the LQ-DMP study. Respir Res. 2019; 20, 215.
[xxvi] Westerik J, Metting E, van Boven J et al. Associations between chronic comorbidity and exacerbation risk in primary care patients with COPD. Respir Research. 2017; 18(1):31.
[xxvii] Negewo N, McDonald V and Gibson P. Comorbidity in chronic obstructive pulmonary disease. Respir Investig. 2015; 53(6):249-58.
[xxviii] Rabe K, Martinez F, Ferguson G et al. Inhaled Triple Therapy at Two Glucocorticoid Doses in Moderate-to-Very Severe COPD. N Engl J Med. 2020. 383: 35-48.
[xxix] Price D, West D, Brusselle G et al. Management of COPD in the UK primary-care setting: an analysis of real-life prescribing patterns. Int J Chron Obstruct Pulmon Dis. 2014; 9:889–905.
[xxx] Seys D, Bruyneel L, Decramer M et al. An International Study of Adherence to Guidelines for Patients Hospitalised with a COPD Exacerbation. J of COPD. 2017; 14: 156-163.
[xxxi] Barrecheguren M, Monteagudo, Ferrer J et al. Treatment patterns in COPD patients newly diagnosed in primary care. A population-based study. Resp Med. 2016; 111:47–53.
[xxxii] Diette GB, Dalal AA, et al. Treatment pattern of chronic obstructive pulmonary disease in employed adults in the United States. Int J Chron Obstruct Pulmon Dis. 2015; 10:415 – 22.
[xxxiii] Royal College of Physicians. National COPD Audit Programme. Pulmonary rehabilitation: An exercise in improvement – combined clinical and organisational audit 2017.. 2018. Available at: https://www.rcplondon.ac.uk/projects/outputs/pulmonary-rehabilitation-exercise-improvement-combined-clinical-and-organisational [Accessed: January 2021]
[xxxiv] EFA. Minimum Standards of Care for COPD Patients in Europe. Available at: https://www.efanet.org/images/2014/10/EFA-Book-Minimum-Standards-of-Care-for-COPD-Patients-in-Europe_ENGLISH.pdf. [Accessed: January 2021]
[xxxv] Richman L, Pearson J, Beasley C et al. Addressing health inequalities in diverse rural communities: An unmet need. SSM – Population Health. 2019; 7(100398).
[xxxvi] Hartl S, Lopez-Campos JL, Pozo-Rodriguez F et al. Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD Audit. Eur Respir J. 2016; 47(1): 113 – 21.
[xxxvii] Sun Y and Zhou, J. New insights into early intervention of chronic obstructive pulmonary disease with mild airflow limitation. J Int Chron Obstruct Pulmon Dis. 2019; 14:1119–25.
[xxxviii] Welte T, Vogelmeier C, Papi A et al. COPD: early diagnosis and treatment to slow disease progression. Int J Clin Pract. 2015; 69(3): 336-349.
[xxxix] Bollmeier S and Hartmann A. Management of chronic obstructive pulmonary disease: A review focusing on exacerbations. Am J Health Syst Pharm. 2020;77(4):259–268. 6
[xl] Coutinho A, Lokhandwala T, Boggs R et al.Prompt initiation of maintenance treatment following a COPD exacerbation: outcomes in a large insured population. Int J Chron Obstruct Pulmon Dis. 2016; 11:1223-1231.
[xli] NHS England. Flu Vaccinations And Long Term Respiratory Conditions. 2019. Available at: <https://www.england.nhs.uk/south/wp-content/uploads/sites/6/2019/10/Respiratory-Conditions-and-Flu-Vaccine-Importance.pdf> [Accessed: January 2021].
[xlii]Zwerink M, Brusse-Keizer M, van der Valk P et al. Self Management for Patients with Chronic Obstructive Pulmonary Disease. Cochrane Database Syst Rev. 2014;19(3):CD002990.
[xliii] Collinsworth A, Brown R, James Cet al. The impact of patient education and shared decision making on hospital readmissions for COPD. Int J Chron Obstruct Pulmon Dis. 2018.24; 13:1325-1332..
[xliv] Bischoff E, Hamd D, Sedeno M et al. Effects of written action plan adherence on COPD exacerbation recovery. Thorax. 2011; 66:26-31.
[xlv] Bryant J, Mansfield E, Boyes AW et al. Involvement of informal caregivers in supporting patients with COPD: a review of intervention studies. Int J Chron Obstruct Pulmon Dis. 2016.14; 11:1587-96.
[xlvi] Tønnesen P. Smoking cessation and COPD. Eur Respir J. 2013;22:37-43.
[xlvii]Wu J and Sin DD. Improved patient outcome with smoking cessation: when is it too late? Int J Chron Obstruct Pulmon Dis. 2011;6:259-267.
[xlviii]Au D, Bryson CL, Chien JW et al. The Effects of Smoking Cessation on the Risk of Chronic Obstructive Pulmonary Disease Exacerbations. J Gen Intern Med. 2009; 24:457-463.
[xlix]Donaire-Gonzalez D, Gimeno-Santos E, Balcells E et al. Benefits of physical acitivity on COPD hospitalisation depends on intensity. Eur Respir J. 2015;46:1281-1289.
[l] Hansen GM, Marott JL, Holtermann A et al. Midlife cardiorespiratory fitness and the long-term risk of chronic obstructive pulmonary disease. Thorax. 2019; 74:843-848.
[li] Ryrsø CK, Godtfredsen NS, Kofod LM et al. Lower Mortality After Early Supervised Pulmonary Rehabilitation Following COPD-exacerbations: A systematic Review and Meta-Analysis. BMC Pulm Med. 2018; 18(1):154.
[lii] Global Initiative for Chronic Obstructive Lung Disease. GOLD Global Strategy for the Diagnosis, Management and Prevention of COPD. 2018. Available at: https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf [Last accessed: January 2021].
[liii]Han M, Quibrera P, Carretta E et al. Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017; 5(8): 619 – 626.
[liv] Hoogendoorn M, Feenstra TL, Boland M et al. Prediction models for exacerbations in different COPD patient population: comparing results from five large data sources. Int J Chron Obstruct Pulmon Dis. 2017; 12:3183 – 3194.
[lv] Tashkin DP, Celli B, Senn S et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008; 369:1543 – 54.
[lvi] Dransfield M, Kunisaki K, Strand M et al. Acute exacerbations and lung function loss in smokers with and without Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017; 195:324 – 30.
[lvii] Halpin D, Miravitlles M, Metzdorf N et al. Impact and Prevention of Severe Exacerbations of COPD: A Review of the Evidence. Int J Chron Obstruct Pulmon Dis. 2017; 12:2891–2908.
[lviii] Kessler R, Ståhl E, Vogelmeier C et al. Patient understanding, detection, and experience of COPD exacerbations: an observational, interview-based study. Chest. 2006; 130(1):133-142.
[lix] Tsiligianni I, Kocks J, Tzanakis N et al. Factors that influence disease-specific quality of life or health status in patients with COPD: a review and meta-analysis of Pearson correlations. Prim Care Respir J. 2011; 20(3):257 – 68.
[lx] Suissa S, Dell’Aniello S and Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012; 67 (11): 957 – 63.
[lxi] Kerkhof M, Freeman D, Jones R et al. Predicting frequent COPD exacerbations using primary care data. Int J Chron Obstruct Pulmon Dis. 2015; 10: 2439-2450.
[lxii] Dalal A, Shah M, D’Souza A et al. Observational study of the outcomes and costs of initiating maintenance therapies in patients with moderate exacerbations of COPD. Respir Res. 2012; 13:41.
[lxiii] Bartels W, Adamson S, Leung L et al. Emergency department management of acute exacerbations of chronic obstructive pulmonary disease: factors predicting readmission. Int J Chron Obstruct Pulmon Dis. 2018;13:1647 – 1654.
[lxiv] Zhang J, Zhou JB, Lin XF et al. Prevalence of undiagnosed and undertreated chronic obstructive pulmonary disease in lung cancer population. Respirology. 2013; 18(2):297 – 302.
[lxv] Barnes N, Calverley P, Kaplan A et al. Chronic obstructive pulmonary disease and exacerbations: Patient insights from the global Hidden Depths of COPD survey. BMC Pulm Med. 2013; 13:54.
[lxvi] Jones P, Lamarca R, Chuecos F et al. Characterisation and Impact of Report and Unreported Exacerbations: Results from ATTAIN. Eur Respir J. 2014;44(5):1156-1165.
[lxvii] Pavord I, Jones P, Burgel P et al. Exacerbations of COPD. Int J Chron Obstruct Pulmon Dis. 2016; 11 (Spec Iss): 21 – 30.
[lxviii] Trappenburg J, Schaap D, Monninkhof E et al. How do COPD patients respond to exacerbations?. BMC Pulm Med. 2011; 11(43).
[lxix] García-Sanz MT, Cánive-Gómez JC, Senín-Rial L et al. One-year and long-term mortality in patients hospitalized for chronic obstructive pulmonary disease. J Thorac Dis. 2017; 9:636–645.
[lxx] Ho T, Tsai Y, Ruan S et al. In-hospital and One-Year Mortality and Their Predictors in Patients Hospitalised for First-Ever Chronic Obstructive Pulmonary Disease Exacerbations : A Nationwide Population-Based Study. PLoS ONE. 2014;9(12):e114866.
[lxxi] Watz H, Tetzlaff K, Magnussen H et al. Spirometric changes during exacerbations of COPD: post hoc analysis of the WISDOM trial. Respiratory Research. 2018; 19:251.
[lxxii] Donaldson GC, Hurst JR, Smith CJ et al. Increased risk of myocardian infarction and stroke following exacerbation of COPD. Chest. 2010; 137(5):1091 – 1097.
[lxxiii] Bourbeau J, Ford G, Zackton H et al. Impact on patients’ health status following early identification of COPD exacerbation. Eur Respir J. 2007; 30:907-913.
[lxxiv] Tal-Singer R and Crapo J. COPD at the time of COVID-19: a COPD Foundation perspective. Chronic Obstr Pulm Dis. 2020; 7(2): 73-75.9
[lxxv] Alqahtani J, Oyelade T, Aldhahir A ret al. Prevalence, Severity and Motality associate with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and Meta-Analysis. PLoS ONE. 2020.; 15(5): e0233147.
[lxxvi] Leung J, Niikura M, Wei C et al. COVID-19 and COPD. Eur Respir J. 2020. 56:2002108.
[lxxvii]Taskforce for Lung Health. Patients needing urgent care for lung conditions saw referrals drop by as much as 70% during lockdown. 2020. Available at: https://www.blf.org.uk/taskforce/get-in-touch/media/patients-needing-urgent-care-for-lung-conditions. [Accessed: January 2021]