COPD – do the right thing

COPD is a heterogeneous disease characterised by persistent respiratory symptoms and airflow limitation [1]. It provides a significant burden for patients and society due to the natural progression of COPD, reduced daily/physical activities, exacerbations and impact on work and social isolation, which often leads to psychological conditions such as anxiety and depression [1, 15, 16]. Together, these factors decrease health-related quality of life (HRQL) and increase mortality, compared with the general population [1], and are further confounded by a number of comorbidities that are frequently associated with COPD, including cardiovascular, metabolic and other chronic conditions (see the ‘Common comorbidities’ section for additional details [17, 18]).

Symptoms of COPD may include chronic and progressive dyspnoea, chronic cough, sputum production, chest tightness or fatigue [1, 19‐21]. In many patients, chronic cough with or without sputum production may be intermittent and may precede the development of airflow limitation by many years [1, 22]. Indeed, the occurrence of a productive cough in young smokers constitutes a substantial risk of developing COPD in later life [23]. Conversely, dyspnoea and decline in health status are weakly correlated with airflow limitation [19, 21]. As a result of this variation, symptoms may not be obvious until forced expiratory volume in 1 s (FEV₁) has declined to approximately 50–60% of predicted, therefore COPD typically remains undiagnosed until it has reached at least moderate severity [24]. COPD should therefore be considered in any patient with a history of exposure to risk factors. Patients with COPD may also be more prone to ‘winter colds’ or ‘acute bronchitis’, and primary care practitioners should consider the possibility of COPD in middle-aged or older smokers with recurrent respiratory tract infections [1, 25, 26].

According to the classical Fletcher–Peto model [51], FEV₁ decreases gradually over a lifetime. In susceptible individuals exposed to smoke or other noxious gases who develop COPD, the decline progresses more rapidly. However, the rate of lung function decline in COPD is highly variable, being negatively affected by smoking and exacerbations, but also remains relatively stable for long periods in many patients [52]. Increased incidence of COPD has been associated with indoor and outdoor air pollution [53] (particularly the burning of biomass/solid fuels in developing countries and rural areas [54, 55]), occupational exposure to dust and gases [56, 57] and lower socioeconomic status and poverty [1, 58]; other risk factors include genetic predisposition, abnormal lung development and accelerated ageing [1].

One major driver of the disease process in COPD is ongoing chronic inflammation of the small airways, known as bronchiolitis [59]. Neutrophilic granulocytes, CD8⁺ lymphocytes and macrophages were initially identified as being among the most important in the pathogenesis of COPD [60], but we now know that other immune cells, such as eosinophils, are also involved [61]. Recruitment and activation of immune cells and release of inflammatory mediators lead to mucous hypersecretion, luminal obstruction/mucous plugging and tissue destruction [37, 41]. Inflammation is also coupled with a dysfunctional repair/remodelling process that destroys the alveolar walls and thickens the walls of the airways [37, 42]. Pulmonary vascular remodelling may also result in pulmonary hypertension and right-sided heart failure (cor pulmonale) [62]. Bronchiectasis may also add to the symptom burden [63].

COPD is also characterised by periodic acute worsening of symptoms beyond normal day-to-day variation, known as acute exacerbations; symptoms can last several weeks, and severe exacerbations result in hospitalisation and increased risk of death (Table 1) [1, 64].

Exacerbations are characterised by an initial increase in airway inflammation, resulting in airway oedema, mucus production and bronchoconstriction (Fig. 2) [68]. An acute exacerbation is a serious event triggering a catastrophic cascade that is potentially overwhelming and life-threatening, akin to a ‘stroke of the lungs’ [69]. There is also emerging evidence showing that a proportion of patients with mild COPD may be susceptible to exacerbations [70]; however, at present, due to their mild disease, these patients might not be identified for intervention [71]. It is vital to improve early detection and diagnosis of patients with mild COPD in primary care. Smoking cessation and/or recognising harmful work exposures early may halt disease progression, and simple measures may be taken to reduce the risk of exacerbations, such as influenza and pneumococcal vaccinations.

COPD exacerbations are associated with a more rapid decline in FEV₁ [71‐74], poorer HRQL [71, 75‐77], hospitalisations [1, 72], increased risk of cardiovascular disease (CVD) [78‐81], risk of further exacerbations [82] and increased mortality [1, 39, 82‐87]. Moreover, the risk of severe exacerbation or death has been found to increase with each subsequent exacerbation [82]. Even a single exacerbation can drastically decrease HRQL (St George’s Respiratory Questionnaire total score) [75, 88], with HRQL remaining worse 6 months later in some patients, versus no exacerbations [89]. In addition, damage from exacerbations has been found to go beyond the lungs due to the associated systemic inflammation during the exacerbation [68] and may increase the risk of thromboembolism, stroke, myocardial infarction and cardiovascular mortality, particularly following a severe exacerbation [78, 90‐92]. While in around 30% of exacerbation cases, no clear cause is found [93], exacerbations are known to be triggered by multiple factors, including infections and exposure to particulate matter [1, 94]. In patients with moderate/severe COPD, bacterial pathogens account for 40–50%, viral pathogens for 30–40% and atypical bacteria for 5–10% of exacerbations [94]; following an exacerbation, bacterial colonisation has been found to rise to 70%, with Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis being the most common species found [95]. While many patients take some action (e.g. rest, cut down on smoking, increase medication etc.), over 40% of patients do not contact healthcare providers during an exacerbation [96]. Under-treatment is also common in patients hospitalised because of severe COPD exacerbations [97]. Across four different studies, between 40 and 68% of exacerbations were under-recognised, under-reported and thus under-treated; moreover, this proportion was largely unchanged over 12 years (Fig. 3) [76, 98‐100]. This suggests that patients with COPD require education on exacerbation symptoms and when to seek professional healthcare [101].

Several factors may predict risk of future exacerbations (Table 2) and should be considered when initiating treatment and at follow-up/annual review.

Elevated blood eosinophils are associated with higher COPD-related hospital readmission rates and all-cause readmission [108] (see the ‘Pharmacological treatment of COPD’ section).

COPD should be considered in any patient with clinical symptoms and risk factors for the disease (predominantly smoking). Diagnosis is confirmed by a post-bronchodilator FEV₁/forced vital capacity (FVC) ratio < 0.70 [1] or below the lower limit of normal. Of note, the FEV₁/FVC ratio has a natural decline with age, and the fixed ratio may lead to an underestimation of COPD in younger patients and an overestimation in elderly patients [109‐111].

Spirometry is important not only for the diagnosis of COPD, but also to classify the severity of airflow limitation (based on FEV₁% predicted) [1]. In addition, baseline and post-baseline FEV₁ measurements can be compared with future spirometric assessments to identify patients who demonstrate a rapid decline in lung function (rapid decliners), and may be used when considering alternative diagnoses, such as when symptoms appear disproportionate to the degree of airflow obstruction [1]. It is important to ensure that healthcare professionals first carry out spirometry [112] and that those who carry out spirometry are appropriately trained [113], as incorrect interpretation or performance of the procedure readily leads to misdiagnosis of COPD [114].

Reversibility with a fast-acting bronchodilator has historically been used to distinguish asthma from COPD; however, it is now accepted that significant reversibility (FEV₁ ≥ 12% and ≥ 200 mL change from baseline) or FVC ≥10% is at least as common in patients with COPD, despite having no features of asthma [115‐118], and can vary in the same patient between assessments for both asthma and COPD [119, 120]. A significantly improved FEV₁ with normalisation of the FEV₁/FVC ratio post-bronchodilator or post 4–12 weeks of inhaled corticosteroids (ICS) means that COPD, but not asthma, can be excluded.

Once confirmed as COPD, phenotyping is important to ensure optimal pharmacological and non-pharmacological treatment [1]. Typically, patients with COPD and low eosinophil counts have a poor response to ICS while patients with higher levels of eosinophils or asthma–COPD overlap have a better response to ICS [1]. Another phenotype of importance, with regard to medication, is the frequent exacerbator, defined as patients with ≥2 exacerbations per year [121]. Other phenotypes described are chronic bronchitis, emphysematous and rare exacerbator; emerging COPD phenotypes included pulmonary cachexia phenotype, overlap COPD and bronchiectasis, upper lobe-predominant emphysema phenotype, rapid decliner, comorbidities or systemic phenotype, α-₁ antitrypsin deficiency and no-smoking COPD [122].

COPD is often overlooked in the initial consultation between physician and patient. Some patients with COPD appear to be asymptomatic, adapt to symptoms and adjust their daily activities to reduce their occurrence [29]; thus, it is vital that patients are asked the correct questions during the consultation with their physician so that as much information can be obtained as possible. It is only by understanding the impact of COPD on multi-morbidities or other health issues that a patient can be optimally prioritised in primary healthcare [123]. Furthermore, in order to maximise the window of opportunity to impact disease progression (e.g. via smoking cessation), it is necessary to be proactive and diagnose early during the mild disease stage [124].

Whereas the Global Initiative for Chronic Obstructive Lung Disease (GOLD) once focussed primarily on airflow limitation as a measure of COPD severity (GOLD stages 1–4 – mild-to-very-severe COPD) to characterise patients, the ABCD assessment tool adds patient symptoms (based on the COPD assessment test [CAT] and/or modified Medical Research Council dyspnoea scale [mMRC]) and exacerbation history in the previous 12 months to the assessment (Fig. 4) [1]. Patients in Group A have a low risk of future exacerbations with low symptom burden; patients in Group B have a low risk of future exacerbations but significant symptom burden; patients in Group C have a high risk of future exacerbations and low disease burden; patients in Group D have a high risk of future exacerbations and significant disease burden.

In addition to the ABCD assessment, the 6-min walking test is a simple but very useful tool for assessing impaired exercise tolerance [125]; in patients who have experienced a severe exacerbation, lower physical activity levels are associated with increased all-cause mortality [126].

Diagnosing COPD can sometimes be challenging and, particularly as it is a lifelong diagnosis, it is of utmost importance that the clinician gives full consideration to alternative diagnoses and is aware of the many pitfalls and potential impact of misdiagnosis of COPD. Clinical history, patient characteristics and exposure are important considerations, in addition to spirometry, to differentiate not only between obstructive lung diseases (asthma, bronchiectasis and COPD) but also restrictive lung disease and heart failure, as these may both be misinterpreted as COPD or may co-exist with COPD (Table 3) [1, 127, 128].

Other useful diagnostic tools include blood tests for haemoglobin, erythrocyte sedimentation rate, eosinophil count and N-terminal pro B-type natriuretic peptide (NT-proBNP). Electrocardiograms, chest X-rays and echocardiography in patients with increased NT-proBNP may detect the presence of significant comorbidities, such as CVD, heart failure, lung cancer, pleural disease and changes associated with COPD [1, 129‐131].

Computed tomography (CT) or high-resolution CT can be helpful for quantifying emphysema and for the differential diagnosis of bronchiectasis, suspected lung cancer or interstitial lung disease [1, 130]. Pulmonary lung function can further be evaluated by measuring the lung volumes in a plethysmograph and by measuring the diffusion capacity of the lungs for carbon monoxide (DLCO). DLCO may be helpful to differentiate between asthma (usually normal or increased DLCO) and mild COPD (impaired DLCO due to emphysema) but is not a routine examination [1, 132, 133].

COPD often co-exists with other diseases that may have a significant impact on prognosis [17, 18, 137, 138]. Indeed, it has been suggested that almost all patients have ≥1 comorbidity, with half having ≥4 [139, 140]. Some comorbidities arise independently of COPD, whereas others are causally related, either with shared risk factors (e.g. age, smoking, systemic inflammation) or by one disease increasing the risk severity of the other [18, 141]. Common comorbidities include bronchiectasis, CVD, chronic kidney disease, dyslipidaemia, diabetes, hypertension, lung cancer, mental disorders, osteoporosis, obstructive sleep apnoea syndrome and skeletal muscle dysfunction [17, 18, 137]. Ellingsen et al. found that the strongest predictor of death in patients with COPD was comorbid heart failure, which was associated with a nearly doubled mortality risk [142]. Stroke and myocardial infarction were also associated with an approximately 50% increased risk of death. An observational retrospective registry study of > 21,000 patients with diagnosed COPD found that the frequency of comorbidities increased during 8 years of observation (Table 4) [8].

Due to the significant impact of comorbidities on prognosis and the rising incidence with time and disease progression [8, 141, 143], it is vital that comorbidities are assessed at diagnosis and at every follow-up review (Table 4). In addition, since the psychological impact of COPD (e.g. anxiety and depression) is known to be substantial [144, 145] and is associated with higher mortality [146], it is important that psychological health is assessed at diagnosis.

COPD treatment goals include smoking cessation (or the termination of other exposure), symptom relief (improved physical capacity and reduced dyspnoea) and reduced risk of exacerbations and mortality [1]. The treatment approach for COPD should be based on clinical, functional and/or biological features that can be observed at the individual level, i.e. treat the treatable traits. Management options include pharmacological and non-pharmacological treatments carried out by a multidisciplinary team comprising a physician, specialist nurse and physiotherapist, as well as a counsellor/psychologist, occupational therapist and nutritionist in some cases [1, 147].

COPD is a complex, progressive disease, therefore routine, individualised monitoring/assessment at follow-up is essential. International and national guidelines suggest annual follow-up visits for stable, non-exacerbating patients at least once per year and a follow-up visit 1–4 weeks after an acute exacerbation for a thorough, overall medical assessment that includes spirometric measurements, documentation of symptom burden and optimisation of COPD medication [1, 186]. Ideally, patients with very severe COPD should be reviewed at least twice a year and multimorbid patients should see their physician at least once a year [186, 187]. The key issue for all members of the multidisciplinary team responsible for monitoring/follow-up is to plan for the next visit based on the patient’s individual needs.

Recent GOLD guidelines have included a pharmacological follow-up algorithm that can be applied to any patient who is already taking maintenance treatment(s) irrespective of the GOLD group allocated at treatment initiation (Fig. 5) [1]. At follow-up/annual review, the first priority is to identify whether the initial treatment was successful in helping the patients meet their treatment goals, whether disease progression has occurred and what the predominant symptom is (dyspnoea, exacerbations or both). If dyspnoea dominates, treatment should be stepped up to dual bronchodilator therapy or triple therapy depending on the patients’ current pharmacological maintenance treatment (Fig. 5a). If exacerbations dominate (or both dyspnoea and exacerbations), the alternative algorithm should be followed (Fig. 5b). In addition, patient handling of the inhaler and inhalation technique must be reviewed both annually and before stepping up medication [184, 185, 188]. Recommendations for the annual review are shown in Table 5.