Chronic obstructive pulmonary disease (COPD) is a highly prevalent respiratory pathology that entails considerable healthcare costs.1 Although it has well-defined diagnostic criteria, the individual clinical characteristics differ from one patient to another.2 National3 and international4 practice guidelines exist for the management of this disease. Of these, the Spanish COPD guideline (GesEPOC)3 was the first to propose individualized patient management using a phenotype classification.

Phenotypes are defined as those characteristics of the disease that, individually or in combination with others, allow studying the differences between patients with COPD concerning different parameters with clinical significance.5 The 2017 version of GesEPOC classified patients in the following way3: if a patient had an postbronchodilator FEV1 of ≥50% predicted, and dyspnoea of grade 0–1 according to the mMRC scale with or without an exacerbation in the last year (without admission), they were considered low risk; patients who did not meet any of these criteria were high risk. The latter were classified into four different phenotypes: non-exacerbator, exacerbator with emphysema, exacerbator with chronic bronchitis, and asthma–COPD overlap (ACO). A patient was considered a non-exacerbator if in the previous year they had presented one or no episodes of moderate exacerbation. They were classified as an exacerbator with emphysema if they had experienced at least two exacerbations classified as moderate or severe per year, requiring at least treatment with systemic corticosteroids and/or antibiotics together with the clinical, radiological or functional diagnosis of emphysema. However, if it had been characterized by the presence of cough accompanied by expectoration maintained for a minimum of three months a year in two consecutive years, they were classified as an exacerbator with chronic bronchitis. If the patient presented diagnostic criteria for asthma and/or asthmatic characteristics such as an increase in FEV1 >400mL and 15% and/or peripheral blood eosinophilia >300cells/μL, they were considered to have an asthma–COPD overlap.

In its last update in 2021, GesEPOC redefined the classification by phenotypes.6 The concept of low-risk or high-risk patients has been maintained, with three phenotypes established for the latter: non-exacerbator, non-eosinophilic exacerbator and eosinophilic exacerbator. A patient is considered a non-exacerbator if they have presented at most one exacerbation in the previous year without requiring hospital care. A patient is classified as a non-eosinophilic exacerbator if they have had two or more outpatient exacerbations in the previous year, or one or more serious exacerbations that required hospital care, together with <300eosinophils/mm3 in peripheral blood. A patient belongs to the eosinophilic exacerbator phenotype if, in addition to meeting the criteria for the exacerbator phenotype, they have a count of >300eosinophils/mm3 in the stable phase.

Due to the update in the phenotype classification, the present study aimed to analyse the differences in the survival of patients with different COPD phenotypes based on the current 2021 classification, identify risk factors independently associated with mortality and compare the prognostic capacity of the current classification compared to the previous 2017 version.

A total of 273 patients were included, of whom 243 (89%) were male. The mean age was 68 years (SD 10.62), the mean weight was 75.03kg (SD 16.89), the mean height was 1.63m (SD 0.08), and the mean body mass index (BMI) was 28.05kg/m2 (SD 5.49). Regarding lung function, the mean FEV1 in absolute value was 1211.39mL (SD 416.55), and the mean FEV1 in relative value was 48.64% (SD 12.59). Regarding comorbidities, the median Charlson comorbidity index score was 2 (IQR 1–4). At the time of inclusion in the study, 92 patients (34%) were current smokers. The median prospective follow-up was 68.16 months (IQR 40.69–72.12). During this time, 93 patients (34.1%) died.

The distribution of patients by GesEPOC 2017 phenotypes was as follows: 71 (26.0%) had a positive bronchodilator response, 135 (49.5%) were non-exacerbators, 27 (9.9%) were exacerbators with emphysema and 40 (14.7%) were exacerbators with chronic bronchitis. According to GesEPOC 2021, 190 patients (69.6%) were non-exacerbators, 69 patients (25.3%) were non-eosinophilic exacerbators and 14 patients (5.1%) were eosinophilic exacerbators.

Tables 1 and 2 show the comparison of the general characteristics of the patients according to the phenotypes defined by GesEPOC 2017 and GesEPOC 2021, respectively. Classifying the patients according to GesEPOC 2017, the mean age was higher in the non-exacerbator and exacerbator phenotypes with chronic bronchitis (p<0.001), and patients with positive PBD presented less active smoking (p=0.009) and a higher lung function measured in FEV1 in absolute value (p<0.001). Based on GesEPOC 2021, non-exacerbator patients had better lung function (p=0.012).

Figs. 1 and 2 illustrate the survival of COPD patients according to the phenotypes defined by GesEPOC 2017 and GesEPOC 2021, respectively. There are some significant differences between the survival curves, and the exacerbator patients with chronic bronchitis and the non-eosinophilic exacerbator patients had lower survival in their respective classifications (p<0.001 and p=0.034, respectively).

Fig. 1.

Survival according to 2017 GesEPOC phenotypes.

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Fig. 2.

Survival according to 2021 GesEPOC phenotypes.

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Fig. 3 represents the comparison of the area under the ROC curve of both versions of GesEPOC. A greater area under the curve was observed for GesEPOC 2017 compared to GesEPOC 2021 (0.632 vs 0.566, p=0.018).

Fig. 3.

ROC curve comparison of both versions of GesEPOC.

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Table 3 shows the risk factors independently associated with mortality. These were advanced age (hazard ratio [HR] 1.06; 95% confidence interval [CI] 95% 1.02–1.08; p<0.001), non-eosinophilic exacerbator phenotype (HR 1.74; 95% CI 1.10–2.73; p=0.017) and a high score on the Charlson index (HR 1.33; 95% CI 1.18–1.49; p<0.001). In contrast, elevated FEV1 measured in absolute value was identified as a protective factor (HR 0.89; 95% CI 0.83–0.96; p=0.002).

The main conclusion of this study was the lower survival of non-eosinophilic exacerbator patients compared to non-exacerbator patients. Additionally, the new classification by phenotypes of the 2021 GesEPOC predicts the survival of patients with COPD worse compared to the 2017 GesEPOC.

This difference in survival between non-eosinophilic and non-exacerbator patients could be related to the severity and frequency of exacerbations, whose predictive role in mortality has been described in previous studies.6–8

In our study, the non-eosinophilic exacerbator phenotype was a risk factor independently associated with mortality. The absence of eosinophilia could contribute to the lower survival of non-eosinophilic exacerbator patients. This is because eosinophilia in peripheral blood reflects a Th2-dependent inflammation, characteristic of patients with bronchial asthma and in response to inhaled corticosteroids, which by itself could confer a better prognosis to patients who present it.9–12

Decreased FEV1 has been described on numerous occasions as a poor prognostic factor in COPD since the discoveries of Burrows et al.13 In addition, studies by Cabrera López et al.14 and Golpe et al.15 confirm the prognostic capacity of this lung function parameter and its correct inclusion in the risk stratification of COPD patients according to the classification of GesEPOC. Our finding that a high FEV1 is a protective factor for mortality in COPD patients is consistent with the previously mentioned studies.

In our study, advanced age was a risk factor independently associated with mortality. Advanced age in patients with COPD is a well-known poor prognostic factor since these patients present defective cell repair, as well as a disorder in some of the molecules involved in protection against ageing, so it can develop an additive effect.16–18

On the other hand, our study showed that, as the presence of comorbidities, measured by the Charlson index, increased, the prognosis of these patients worsened. This finding is consistent with those of the GesEPOC Working Group,19 Diaz Moreno et al.20 and Vázquez et al.21 On the other hand, Almagro et al.22 and Aramburu et al.23 reported comorbidity as a risk factor independently associated with mortality. This is because many of the comorbidities present in these patients share the same routes or processes of accelerated ageing, as well as risk factors, such as smoking. However, studies such as SUMMIT24 show that it has not been possible to demonstrate that COPD is a clue in the pathogenesis of different comorbidities.

Active smoking at the time of inclusion in the study could not be demonstrated as an independent risk factor for mortality in our study, which could be explained by the high percentage of patients who had quit smoking. In this sense, the literature shows inconclusive results.25

There are few published data on the mortality of COPD patients according to the GesEPOC 2021 classification. Recently, Golpe et al.26 published a study with a similar methodology, applying this classification to a previously existing cohort of COPD patients, concluding that low-risk patients had less mortality, but without finding significant differences between the 3 phenotypes. This difference with the results of our study could be justified because we have not considered the distinction between low-risk and high-risk patients, understanding that the concept of low-risk patients is to simplify the management of patients with mild COPD in primary care.

Lastly, we found a loss of mortality predictive power of the 2021 GesEPOC classification compared to the 2017 GesEPOC, which could be justified by the mere fact of presenting one fewer category in the phenotype classification. It is true that the objective of the classification into phenotypes is to facilitate the individualized management of patients with COPD and not so much to predict the evolution of the patients, but rather the expected evolution could condition the management of the patients. In this study, only the capacity to predict mortality was analyzed, but it would also be interesting to analyze other aspects of the disease in future studies, such as the probability of having exacerbations.

The present study has some limitations. First, it did not consider patients with mild COPD. This is because differences in mortality are less likely to be found in milder patients regardless of their phenotype. In any case, when extrapolating the results of this study to the general population, it must be considered that this sample is not representative of patients with mild COPD.

Second, we used a modified version of the GesEPOC 2017 to compare with the GesEPOC 2021 clasification, because we consider that the ACO phenotype proposed by this guideline has high specificity but low sensitivity when considering a very positive response in the bronchodilator test. We proposed a different phenotype to improve this sensitivity, with a positive response in the bronchodilator test. In this modified version, we also did not consider eosinophil levels or classification into high-risk and low-risk patients. The results obtained in this study could be different if we consider the original definition of the GesEPOC 2017.

Third, the classification into different phenotypes was based on the initial characteristics of the patients at the time of inclusion in the study. This may be a limitation due to the evolution of the disease, with it being possible for patients to develop characteristics different from those of the initial phenotype in which they were classified. This study intended to classify the patients from the initial moment, and from these data, to predict the evolution of the patient over the subsequent years.

Finally, there are some other minor limitaciones: (1) Our cohort was predominantly male, due to the characteristics of the disease itself. This fact could make this sample not representative of the female population. (2) The sample size is small, and there are few patients in some phenotypes. This could affect the statistical power in certain comparisons. (3) Dyspnea is a variable strongly associated with mortality, but it was not included among the study variables. This fact was due to that the comparison of dyspnea was not an objective of the study. When interpreting the mortality data, it must be taken into account that the severity of dyspnea was not considered.

In conclusion, patients with non-eosinophilic exacerbator COPD had lower survival compared to non-exacerbator patients according to the GesEPOC 2021 classification. Advanced age, non-eosinophilic exacerbator phenotype and greater presence of comorbidities measured by the Charlson index were identified as risk factors independently associated with mortality. The GesEPOC 2021 classification had less ability to predict mortality compared to the previous version from 2017. When applying the new GesEPOC 2021 phenotype definition, it is important to take these data into account to offer more individualized management to COPD patients.

The authors confirm that written consent has been obtained from all patients.

Menarini supported this study with an unconditional scholarship.

The authors declare that they have no conflict of interest directly or indirectly related to the contents of this manuscript.

Conceptualization: Zichen Ji, Julio Hernández-Vázquez and Javier de Miguel-Díez

Methodology: Zichen Ji, Julio Hernández-Vázquez and Javier de Miguel-Díez

Software: José María Bellón-Cano

Validation: Irene Milagros Domínguez-Zabaleta, Marta Esteban-Yagüe and Paula García-Valentín

Formal analysis: José María Bellón-Cano

Investigation: Ismael Ali-García, Carmen Matesanz-Ruiz and María Jesús Buendía-García

Resources: Julio Hernández-Vázquez and Javier de Miguel-Díez

Data curation: José María Bellón-Cano and Irene Milagros Domínguez-Zabaleta

Writing – original draft preparation: Marta Esteban-Yagüe and Paula García-Valentín

Writing – review and editing: Julio Hernández-Vázquez and Javier de Miguel-Díez

Visualization: José María Bellón-Cano

Supervision: Julio Hernández-Vázquez and Javier de Miguel-Díez

Project administration: Javier de Miguel-Díez

Funding acquisition: Julio Hernández-Vázquez