Phenotypes of COPD patients with a smoking history in Central and Eastern Europe: the POPE Study

Discussion

The POPE study is an investigator-initiated, real-life, multinational study to assess the prevalence of predefined clinical phenotypes in a large sample of patients with COPD in CEE. We observed significant differences in the distribution of phenotypes between countries and significant differences in lung function, symptom scores, comorbidities and treatment patterns between patient categories of interest.

COPD has long been categorised using the FEV₁-based GOLD classification [11]; however, it is now widely recognised as a complex heterogeneous syndrome with pulmonary and extrapulmonary features [12]. Marked heterogeneity exists within each GOLD stage in terms of symptoms, exacerbations, quality of life and exercise capacity [13]. Phenotypes are defined by “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes like symptoms, exacerbations, response to therapy, rate of disease progression and/or death” [3, 14].

Although prevalence data on phenotypes are rather scarce, various countries, such as the Czech Republic, England, Poland, Russia, Spain and Sweden have adopted the concept of COPD phenotyping in their respective guidelines according to a recent European survey [15]. Indeed, several of the national guidelines prefer tailored treatment recommendations on the basis of such patient phenotypes. Although this approach introduces complexity into the treatment algorithm and departs from the “one size fits all” treatment based on the level of FEV₁ alone, it is likely to improve the clinical outcomes of most patients with COPD [12].

The phenotypic classification used in the present report was based on the Czech COPD guidelines and was consistent with the Spanish recommendation for patient phenotyping in COPD [9, 10]. Using the cohort definitions put forward in the latter report, a recent longitudinal study of 831 COPD patients in Spain demonstrated stability of these phenotypes over the course of 1 year, and, similar to our findings, distinct differences in lung function and symptom load according to the predefined phenotypes [16]. We observed that the majority of patients were classified as nonexacerbators. As these patients may present with exacerbations in the future, the term “low exacerbation risk” or infrequent exacerbators may have been more appropriate. However, the term “nonexacerbator” was used in the Spanish and Czech guidelines and thus been retained for the current study [4]. Indeed, using this definition we observed a prevalence of 63% non-AE patients, which was similar to a 61% prevalence rate in Spain [17], although there were substantial differences in prevalence between participating countries in the current report. Consistent with previous studies, these patients had on average better lung function and lower symptom and comorbidity scores compared with exacerbators [13, 18, 19]. A mean CAT score of 15.8 in these patients, who are characterised with stable disease and a maximum of one acute exacerbation in the past 12 months, raises questions as to the clinical usefulness of the current threshold of 10 points, discriminating patients with low symptom load, as opposed to those with high symptom load. In fact, a recent meta-analysis of studies using the CAT did not support the recommended cut-off of 10 points for the purpose of assessing patient symptoms [20].

Within the group of exacerbators, patients with chronic bronchitis had a greater extent of dyspnoea, higher total frequency of exacerbations and a greater prevalence of cardiovascular and other comorbidities, such as depression, insomnia and anaemia, compared with the non-chronic bronchitis and ACOS phenotypes. It is therefore not surprising that frequent exacerbators with chronic bronchitis present with higher healthcare costs and are at an increased risk of death compared with other COPD phenotypes [21, 22]. However, identifying these patients has therapeutic implications, as exacerbators with chronic bronchitis may be particularly responsive to specific anti-inflammatory treatments, such as phosphodiesterase-4 inhibitors [23].

Recently, the characterisation of ACOS as a separate phenotype has similarly attracted much interest due a consensus statement by the Global Initiative for Asthma (GINA) and GOLD on the diagnosis, assessment and treatment of this condition [24]. The prevalence of ACOS in the POPE study was 7% and ranged between 5% and 10% between the countries. In agreement with previous reports, ACOS patients were younger, more frequently female and had milder airflow obstruction [17]. Prevalence rates for ACOS in other recent reports vary between 3% and 27% [17, 25, 26]. This wide range between reports may be partially due to differences in the definition of or diagnostic criteria for ACOS [27], concentrations of fine particulate matter in the respective region of interest [28] and/or genetic variants associated with this syndrome [29]. According to a recent global expert consensus the key features of ACOS should include persistent airflow obstruction, a history of cigarette smoking and a physician diagnosis of asthma before the age of 40 years [30]. Indeed, the majority of patients within this cohort received the diagnosis of ACOS on the basis of a previous asthma history before the age of 40 years, which has also been used as a diagnostic criterion in large epidemiological studies, such as COPDGene [31]. A recent study demonstrated that this simple criterion is equally useful to diagnose ACOS compared with a more in-depth diagnostic algorithm including sputum eosinophilia, large bronchodilator reversibility, atopy and/or elevated IgE levels [27]. In addition, the simple medical history of asthma in patients with COPD is an independent predictor of response to inhaled corticosteroids with respect to survival benefits [32]. Despite these proven benefits of ICS in patients with concomitant bronchial asthma, our data also suggest potential ICS undertreatment in patients with ACOS: only 81.1% of such subjects were receiving ICS. In contrast, a substantial proportion of GOLD group B patients received ICS treatment in the absence of ACOS, which is not in line with current GOLD strategy, GINA guidelines and several national recommendations [1, 9, 15, 24]. Similarly, in a recent analysis of prescribing patterns in the primary-care setting in the United Kingdom, most COPD patients received ICS treatment irrespective of severity of airflow limitation, asthma diagnosis and exacerbation history [33]. While we cannot rule out that the lack of exacerbations is a result of ICS treatment in some cases, our data appear to confirm other studies which have similarly demonstrated poor adherence to GOLD treatment recommendations [34, 35]. The limited adherence to guidelines may be due to multiple factors, including, but not restricted to, lack of familiarity with treatment recommendations [36], disbeliefs regarding efficacy of treatments [37] and/or difficulties in distinguishing between asthma and COPD [38].

We have to acknowledge a number of limitations in the present report. First, the cross-sectional design of the POPE study did not allow us to prospectively validate clinical outcomes of the phenotypes. However, using an almost identical phenotypic classification to that used in our study, Cosio et al. [16] recently reported statistically significant differences in 1-year mortality between patients with ACOS and those with AE-CB. Second, the assessment of comorbidities was based on physician diagnosis rather than on a systematic diagnostic work-up [39]. Thus, the current report may have potentially underestimated the burden of comorbidities in COPD in the CEE region. Third, as this was a real-life study across multiple countries we need to acknowledge that some of the data presented may be subject to regional or local recruitment bias and test performance. Indeed, we observed significant differences in the distribution of phenotypes depending on whether patients were recruited at hospital-based pulmonary outpatient clinics or pulmonologists’ offices. At the same time, significant heterogeneity was observed in the distribution of phenotypes between the participating countries, which may reflect differences in access to healthcare, treatment patterns and/or reimbursement of therapy, and also other factors whose identification and analyses were beyond the scope of the present study. Nevertheless, it is remarkable that the global distribution of phenotypes observed in CEE is quite consistent to that reported for other countries [16, 17].

In conclusion, the POPE study provides data on clinical COPD phenotypes in a large population of COPD patients from CEE countries in a real-life setting. Prospective studies are necessary to investigate the evolution of phenotypes and their impact on selecting treatments and subsequent outcomes among COPD patients.