Exploring the impact of number and type of comorbidities on the risk of severe COPD exacerbations in Korean Population: a Nationwide Cohort Study

Chronic obstructive pulmonary disease (COPD) is a major global health concern. Medical comorbidities are prevalent among COPD patients [1] and have a notable impact on the clinical outcomes of COPD [2‐4]. Previous studies have investigated the individual impact of comorbidities on COPD outcomes [5]. However, most patients with COPD have multiple comorbidities, some of which share risk factors, such as aging, smoking, or systemic inflammation, with COPD, while others have no evident pathophysiological relationship with COPD [3, 6]. Therefore, it has been challenging for researchers to consider the impact of multiple comorbidities when assessing the possible outcomes of patients with COPD.

A few disease-specific instruments are available to assess the burden of multiple comorbidities on the clinical outcomes of COPD. For example, the COPD-specific comorbidity test (COTE) was recently developed and validated to predict mortality [4]. Another tool, the COMorbidities in COPD (COMCOLD) index, is available to assess the effect of multiple comorbidities on the quality of life in COPD patients [7]. Putcha et al. reported that a simple count of comorbidities could predict exacerbation risk [8]. In our recent study, we also observed that the number of comorbidities might be an independent risk factor for COPD mortality [9].

Using a nationwide population-based cohort, the current study aimed to investigate the comorbidities associated with exacerbation, to determine whether the number of comorbidities could be an independent risk factor for exacerbation, and to identify other predictors associated with exacerbation in a Korean COPD population. The study focused on severe COPD exacerbations, which were defined as hospitalisations or emergency room visits due to worsening respiratory symptoms [1].

We aimed to examine the comorbidities and other risk factors associated with severe exacerbation of COPD. We also checked the effect of the comorbidity number on severe COPD exacerbation among physician-diagnosed COPD patients. We observed that comorbidities such as asthma, lung cancer, and heart failure or low BMI and old age were associated with an increased risk of severe exacerbation in COPD patients. Our study also implicated that the number of comorbidities could be an independent risk factor of severe exacerbation of COPD.

Most of the study participants had comorbidities, and patients with a history of severe exacerbations had more comorbidities than patients without exacerbations (Tables 1 and 2). Though the difference was small, these findings are in agreement with previous studies [4, 14‐16]. Further segmentation of the comorbidity numbers made it clear that the differences between the two groups (exacerbation and no exacerbation) occur owing to participants without any comorbidity and those with more than five comorbid diseases in both cohorts.

The multivariable logistic analysis revealed that only asthma, lung cancer, and heart failure were common comorbidities significantly associated with severe exacerbations of COPD in both cohorts (Figs. 2 and 3). Asthma has been reported to be a comorbidity that adversely affects the clinical outcome of COPD, including exacerbations [16, 17]. There are several similarities between asthma and COPD. Both are chronic airway inflammatory diseases even though inflammatory phenotypes are different, and both are characterized by mucous production and bronchoconstriction, though the reversibility of bronchoconstriction is different. Additionally, both can cause intermittent exacerbations of airway inflammation. Therefore, when combined, airway inflammation may perpetuate leading to a more severe airflow limitation [19]. It is not surprising that patients with both asthma and COPD may frequently experience severe exacerbations.

Among cardiovascular comorbidities, only heart failure was significantly associated with severe exacerbations in both cohorts. Heart failure has previously been shown to be an independent risk factor for adverse outcomes in patients with COPD [16, 20]. Heart failure often imposes diagnostic challenges since it can mimic an acute exacerbation of COPD. Since COPD and heart failure often precipitate each other’s exacerbations, it is not surprising that heart failure was found to be associated with severe COPD exacerbation in this study [20]. However, other cardiovascular comorbidities showed no significant association with exacerbation, which was unexpected given that cardiovascular comorbidity is a well-established factor associated with adverse clinical outcomes in patients with COPD [14, 21, 22]. Lung cancer was also an independent predictor of exacerbation, which is consistent with the results of previous studies [16, 23, 24]. Of note, it has been reported that COPD exacerbation tends to be more severe in the setting of lung cancer, and the presence of COPD is associated with worse outcomes in patients with lung cancer [25, 26].

Overall, the findings of our study support those of previous studies that have shown an association between key comorbidities and severe exacerbation of COPD. However, given that this study only examined comorbidities previously reported to be risk factors for poor clinical outcomes in COPD, the effect of comorbidities on severe exacerbation of COPD appears to be less evident in the current study. Notably, one previous study on the effect of chronic comorbidities on COPD exacerbations in the Korean population also found that of the 13 common chronic comorbidities evaluated in that study, only asthma was an independent risk factor for COPD exacerbation [17]. Taken together, these findings indicate that severe exacerbations of COPD might be less or differently affected by the presence of chronic comorbidities in the Korean population. However, a comparative study is required to confirm the ethnic differences in this area.

The impact of factors other than comorbidities was also assessed (Figs. 2 and 3). In this study, both cohorts showed that male sex was significantly associated with severe COPD exacerbation, unlike some previous studies [27]. Older age is also a widely accepted risk factor for COPD exacerbations [28], and this was confirmed in this study. In addition, low BMI contributed to exacerbations, and a high TC level protected against exacerbations in our study participants, suggesting a relationship with nutritional deficits. Indeed, previous studies have shown that low BMI is a risk factor for all-cause mortality in patients with COPD, and it is a well-established predictor of COPD exacerbation [28, 29]. As seen in previous study [28], the current study provided evidence that smoking cessation reduces exacerbations, emphasizing the importance of smoking cessation in the COPD population. Notably, the use of ICS and LAMA was associated with exacerbations, and the use of LABA was associated with fewer exacerbations in both cohorts. However, given the lack of a detailed history of the patients’ condition and other critical information, including pulmonary function data, it is difficult to interpret this finding.

Assessment of the impact of multimorbidity showed a significant association between the number of comorbidities or comorbid groups and severe exacerbations in both cohorts (Table 3). This indicates that the number of comorbidities or comorbid groups could be another independent contributor to severe exacerbations of COPD. Given that the majority of individual comorbidities were not seen to be independent predictors of exacerbation in this study, this finding is quite intriguing. These observations suggest that, first, some, but not all, comorbidities can have a direct impact on the development of severe exacerbations; second, comorbidities that were not independent risk factors for exacerbation may still contribute to the development of severe COPD exacerbations, possibly by increasing the total burden of comorbidities.

As discussed above, it is quite challenging to identify ways in which physicians can consider the impact of multiple comorbidities when assessing exacerbation risk. Recently, Putcha et al. reported a simple score using 14 comorbidities, in which a one-point increase in the comorbidity count was associated with a 21% higher exacerbation risk [8]. Although this comorbidity score was calculated without including some of the common comorbidities of COPD, such as lung cancer or asthma, this study suggested that a simple count of comorbidities could assess exacerbation risk. Our recently published study using the same NHIS-NCS v2.0 cohort also suggested that the number of comorbidities might be an independent risk factor for COPD mortality, especially all-cause mortality [9]. We believe that our study, as well as the study by Putcha et al., provide evidence supporting the use of number of comorbidities as a reasonable tool to assess the burden of multiple comorbidities given the lack of a proven evaluation tool.

Overall, our study suggested that some comorbidities associated with COPD could directly affect severe exacerbation of the disease. In contrast, though some comorbidities did not have any direct effect, they might indirectly influence COPD exacerbation, probably by increasing the total comorbidity burden, as the number of comorbidities was an independent risk factor for severe exacerbation. Therefore, the findings of our study are in line with those of previous studies that reported that comorbidities are important risk factors for COPD exacerbation.

The present study had some limitations. To diagnose COPD, pre- and post-bronchodilator spirometry data are needed. This is important to differentiate between asthma and COPD, and to assess the severity of COPD. Unfortunately, these data were not available for further analyses. It has been shown that one of the important predictors of frequent exacerbations is an exacerbation history in COPD [30], but we did not analyse the impact of the number of exacerbations in each patient separately as the aim of our study was to compare the effects of comorbidities between groups with and without exacerbations. We followed only newly diagnosed patients by physicians and addressed drug compliance by checking medication use. We believe that these measures minimised any potential bias. Furthermore, the current study examined only physician-diagnosed comorbidities, whereas most previous comorbidity studies used self-reported data, which may limit their internal validity [4, 31, 32]. This is a population-based study, and our study findings only apply to this set of population. Results should be further evaluated by performing external validation on diverse COPD populations.

Of the 15 comorbidities reported to be associated with adverse outcomes of COPD, only 3, i.e., asthma, lung cancer, and heart failure, were found to be associated with an increased risk of severe exacerbation in this population of Korean patients with COPD. In addition, low BMI and old age were related to severe exacerbation in COPD patients. This study also observed that the number of comorbidities could be an independent risk factor for severe exacerbations. Further research is required to translate the current knowledge into standard patient-centred COPD care.