An Epidemiological Overview of Chronic Obstructive Pulmonary Disease: What Can Real-Life Data Tell Us about Disease Management?

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a common condition, associated with increasing age and smoking exposure. COPD is a leading cause of morbidity, mortality and health care expenditure worldwide; yet, only 10–15% of all cases are identified medically. Alpha-1-antitrypsin deficiency (AATD) is responsible for about 1% of COPD cases but is also largely under-recognised, leading to diagnostic delay and missed treatment opportunities in patients who remain undetected. New evidence has recently highlighted the extent of overlap between COPD and bronchiectasis and the implications of comorbidity on clinical course and mortality. COPD with comorbid bronchiectasis deserves to be given research priority. This article overviews the epidemiology of COPD and examines the implications of overlap between COPD and AATD and between COPD and bronchiectasis.

KEYWORDS:

• Alpha-1-antitrypsin deficiency
• bronchiectasis
• chronic obstructive pulmonary disease
• epidemiology
• real life

Current challenges in COPD

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous condition responsible for considerable morbidity, mortality and health care expenditure worldwide (1). The estimated prevalence of COPD is about 1% in the general population and rises sharply in persons aged ≥40 years (2).

Irrespective of world region and independent of prevalence within a world region, COPD is substantially underdiagnosed; only about 10–15% of all cases are identified (Figure 1) (3). A contributing factor to underdiagnosis is the failure of physicians and patients to recognise the significance of symptoms. This was recently confirmed in a primary practice study from the United Kingdom in which data were analysed for 39,000 patients with a COPD diagnosis to determine whether opportunities for earlier diagnosis had been missed (4). During the 20 years leading up to a diagnosis, and particularly the last five years, the annual per-patient frequency of consultations for lower respiratory symptoms, lower respiratory prescriptions (antibiotics and oral corticosteroids) and chest radiographs increased (Figure 2), but these diagnostic opportunities went unrecognised.

Figure 1. Reported prevalence of chronic obstructive pulmonary disease and relative underdiagnosis in selected population studies from various world regions. Reproduced from (3) with permission.

Figure 2. Mean frequency of consults per patient per year. For lower respiratory symptoms (A), for lower respiratory prescriptions (B), chest radiography (C) and outpatient consultations (D). Reproduced from (4) with permission.

Misdiagnosis of COPD is also relatively common, with many patients being labelled as having ‘smoker's cough’, asthma or a lower respiratory tract infection (3). In a one-of-its-kind study, spirometry results for more than 500,000 adults were analysed to determine whether the prevalence of airflow obstruction on spirometry matched with the prevalence of self-reported physician-diagnosed chronic bronchitis or emphysema (5). The patients came from ten diverse regions of China and, for study purposes, were stratified by gender and location (rural or urban). Across the regions, the age-adjusted prevalence of airflow obstruction on spirometry ranged from <2% to approximately 18% for both men and women. Consistent with global patterns, only 13.8% of the men and 9.3% of the women with spirometry data had previously been diagnosed with COPD. Further, the occurrence of overdiagnosis was high: 67.7% of men and 73.7% of women who had been diagnosed at some point with chronic bronchitis, emphysema or COPD were found to have normal lung function.

Over the past few years, newly introduced concepts such as clinical phenotype and endotype have become increasingly relevant in COPD management. Clinical phenotypes can be defined as a ‘single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes’ (symptoms, exacerbations, response to therapy, rate of disease progression, and death) (6). Endotypes are patient subtypes defined by a distinct pathophysiological mechanism, with or without a biomarker-directed personalised medicine approach (6). Some proposed endotypes in COPD include (Figure 3):

•	COPD with persistent systemic inflammation (eosinophilic or Th2 high COPD);
•	COPD with persistent pathogenic bacterial colonisation;
•	COPD with alpha-1-antitrypsin deficiency (AATD).

Figure 3. A representation of potential endotypes in chronic obstructive pulmonary disease (COPD), indicating the pathognomonic role of infection, inflammation and alpha-1-antitrypsin deficiency. Reproduced from (6) with permission.

Figure 4. Hyperinflated, hyperlucent lungs fields and scattered bronchiectasis evident on chest X-ray in a patient with α1-antitrypsin deficiency-related chronic obstructive pulmonary disease.

The purpose^{Figure 3, Figure 4} of grouping patients in such a manner is to identify subsets most likely to benefit from targeted treatment, as a first step in the shift towards personalised management of COPD.

In selecting pharmacological therapy for patients with COPD, physicians are advised to consider the expected benefits, as determined by individual presentation and underlying disease mechanisms, and the potential risks, which depend on individual risk factors and comorbidities (6). Based on lung function (spirometry), current symptoms and risk of future exacerbations, as of November 2016, COPD patients are classified into one of four groups (A, B, C or D) according to Global initiative for chronic Obstructive Lung Disease (GOLD) criteria (7). Triple therapy, consisting of a long-acting β2-agonist bronchodilator, with a long-acting muscarinic antagonist and an inhaled corticosteroid is reserved for patients in Group D, which is defined by: forced expiratory volume in 1 second (FEV₁) < 50% predicted and/or a history of two or more exacerbations per year or one or more hospitalisations for a COPD exacerbation and a modified Medical Research Council grade ≥2 or a COPD assessment test score ≥10 or a clinical COPD questionnaire >1 (7). However, there is evidence that prescribing practices in primary care are not compliant with these recommendations. A historical analysis of prescribing pathways using data for COPD patients from the Optimum Patient Care Research Database (387 primary care practices across the United Kingdom) identified considerable overuse of triple therapy, particularly in low-risk patients (8); irrespective of their GOLD classification at the time of diagnosis, all patients had progressed to triple therapy within 8–10 years of their initial diagnosis. The authors identified the ‘need for dissemination and implementation of COPD guidelines to physicians’ to ensure that patients receive recommended therapy.

As the proposed COPD endotypes suggest, some patients exhibit clinical characteristics outside the usual symptom profile. To explore this concept further, a case is presented of a patient with AATD-related COPD (Table 1). Recent evidence investigating the impact of comorbid bronchiectasis on patients with COPD is also examined.

Table 1. Case study: COPD with AATD.

History	52-year-old female
	Smoker (currently 1 pack/day); total exposure: 35 pack-years
	Chronic intermittent cough
	Several episodes of pneumonia in past few years treated with outpatient antibiotics
Family history	Father died from complications of pulmonary disease attributed to heavy tobacco use
	Sibling twin died in infancy from liver failure of unknown aetiology
Presentation	Progressive fatigue and easy bruising of skin
	Increased shortness of breath on physical exertion; salbutamol inhaler prn for intermittent respiratory symptoms
Investigations:	Physical examination: scattered ecchymosis along extremities; diffuse wheezing and crackles throughout lung fields, firm liver edge 5 cm below the costal margin; palpable spleen
	Spirometry: severe airflow limitation; FEV1 44% predicted
	Chest X-ray and high-resolution computed tomography: hyperinflated, hyperlucent lung fields; scattered bronchiectasis (Figure 4)
	Liver ultrasound: diffusely coarsened echo texture suggestive of fibrosis and 2 cm focal hypoechoic lesion in right hepatic lobe
	Laboratory assessment: mild elevation in liver transaminases (ALT  =  67 IU/L, AST  =  52 IU/L); decreased albumin (2.9 g/dL), elevated prothrombin time (INR 1.8)
	Genotyping: PiZZ; α1-antitrypsin serum level 31 mg/dL
Diagnosis	COPD with AATD

The most remarkable aspect of this case is the diagnostic delay. The patient's family history, and her signs and symptoms (ecchymosis, wheezing and crackles, firm liver edge, palpable spleen) should have alerted clinicians to the possibility of AATD. Pulmonary function tests, imaging and AATD screening were indicated in this patient many years (decades) before her presentation to specialist care at the age of 52 years.

Similar to COPD, AATD is largely under-recognised. Failure to diagnose or diagnostic delays mean that opportunities are missed for lifestyle changes and/or treatments that can limit the progression of lung damage (9). Moreover, AATD is a substantial burden to health care systems. For example, in Germany, AATD was found to be responsible for significantly more hospitalisations than COPD, emphysema or asthma (10). COPD currently ranks 38th on the World Health Organisation's list for global prevalence of diseases and injuries, with an estimated 175 million cases worldwide (2). As AATD accounts for about 1% of COPD cases, this figure equates to approximately 1.75 million AATD cases worldwide. Earlier diagnosis of AATD therefore has the potential to positively influence the lives of many individuals.

The goal of personalised management in AATD-related COPD remains a distant prospect as the evidence pool for respiratory medicines in this setting is limited to a single randomised controlled trial (RCT) published nearly a decade ago. In this double-blind crossover study, significant improvements in dyspnoea and exercise tolerance were observed when patients with AATD-related COPD (PiZZ genotype) were treated with bronchodilators + extra-fine inhaled corticosteroids versus bronchodilator alone (11). The study serves as a call for action in an overlooked area of research. Well-conducted RCTs are required in AATD and AATD-related COPD. At present, management recommendations are based on expert opinion extrapolated for the entire COPD population.

COPD and bronchiectasis

The frequency of overlap between COPD and bronchiectasis is increasingly recognised. A systematic review and meta-analysis of observational studies (n  =  6) involving 881 patients with COPD reported a mean prevalence of 54% for comorbid bronchiectasis, ranging from 25.6% to 69% across studies (12). Comorbid bronchiectasis occurred most frequently in male patients with a longer smoking history. Patients with COPD + bronchiectasis had greater daily sputum production, more frequent exacerbations, poorer lung function, higher levels of inflammatory biomarkers, more chronic colonisation by potentially pathogenic micro-organisms and a higher rate of Pseudomonas aeruginosa isolation than those without bronchiectasis. The findings are supported and extended by another systematic review and meta-analysis that examined 14 observational studies involving 1572 COPD patients comorbid with bronchiectasis (13). Compared to COPD without bronchiectasis, comorbidity with bronchiectasis significantly increased the risk of exacerbations (odds ratio [OR] 1.97, 95% CI 1.29–3.00), isolation of a potentially pathogenic micro-organism (OR 4.11, 95% CI 2.16–7.82), severe airway obstruction (OR 1.31, 95% CI 1.09–1.58) and mortality (OR 1.96, 95% CI 1.04–3.70). The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC), a landmark European Respiratory Society initiative, has identified 55 key research priorities in bronchiectasis (14). Ideally, future iterations of this consensus statement will extend to COPD with comorbid bronchiectasis.

High^{Table 1} rates of underdiagnosis in chronic airway diseases are expected to persist for many years, and there are no simple solutions. Widespread availability of spirometry is not the answer as the equipment needs to be used not just ‘available’. Over the longer term, resolving the problem of COPD underdiagnosis will require trained personnel to administer and interpret spirometry, greater public awareness about standards of diagnosis and care, and collaborative efforts by pharmacists and other health professionals to identify individuals and refer them to a general practitioner (GP) or respiratory specialist (15). In the 1990s, a National Asthma Programme was undertaken in Finland to reduce the burden of asthma to individuals and society (16). The programme has evolved to become a population-wide chronic bronchitis and COPD plan involving physicians, nurses, pharmacists, technicians, scientists and politicians. Emulating this model and implementing a similar multidisciplinary approach in other countries might be expected to reduce the burden of disease and improve quality of care for patients with COPD, AATD and Bronchiectasis.

Conclusions

The uses of spirometry differ according to the level of care. At the GP level there are many conflicts of time and priority. Quality spirometry should be used to screen in or out any chronic airflow limitation and to begin the diagnostic process. Algorithms should be kept simple. At the pulmonologist level, spirometry can assist in differential diagnosis and in the management of the most severe and comorbid patients. At the epidemiology and Public Health level, we must agree on universal criteria to apply to populations and compare within studies and between other chronic conditions associated with high population burden. The same applies for AATD screening and identification of bronchiectasis.

COPD, non-cystic fibrosis bronchiectasis and AATD are (and will continue to be) major health issues, and all are largely underdiagnosed. Regrettably, respiratory management of AATD remains largely non-evidence based.

Declaration of interest

J. B. S. has received pharmaceutical company grants from GlaxoSmithKline in 2011 and Chiesi in 2012 via CIMERA his former home institution and in 2014–2016 from Linde via Hospital Universitario de La Princesa.

J. B. S. has participated in speaking activities, advisory committees and consultancies during the period 2011–2016 sponsored by: Almirall, AstraZeneca, Boehringer-Ingelheim, Chiesi, ERS, Gebro Pharma, Grifols, GlaxoSmithKline, Linde, Lipopharma, Mundipharma, Novartis, Pfizer, RiRL, Rovi, Separ and Takeda.

Editorial assistance was provided by Content Ed Net (Madrid, Spain) with funding from Grifols SA (Barcelona Spain).