Predictive factors for exacerbation and re-exacerbation in chronic obstructive pulmonary disease: an extension of the Cox model to analyze data from the Swiss COPD cohort

Chronic obstructive pulmonary disease (COPD) is a respiratory disease, characterized by irreversible airflow limitation and one of the most deadly, prevalent, and costly chronic diseases [1]. COPD is known to be a progressive disease affecting more than 5% of the entire population [2, 3]. COPD is the underlying cause for significant morbidity, it ranks 10^th on a worldwide ranking assessing disease burden by disability-adjusted life years (DALYs) with 27.7 DALYs [4]. According to the WHO health statistics of 2008, COPD was the fourth leading cause of mortality in 2004 and is projected to be the third leading cause of death in 2030 [5]. Like other chronic diseases, COPD causes a substantial human and economic burden to society [6]. The growing worldwide burden is considered to be mainly due to cigarette smoking, environmental and occupational factors and the aging population [7, 8].

In this context, the Swiss COPD cohort was established in 2006 to collect spirometric and other relevant data of COPD patients treated in a primary care setting and to facilitate research on the diagnosis, treatment and clinical course of COPD [9‐11].

Acute exacerbations of COPD (AECOPD) are key events in COPD. Not only do exacerbations increase the economic burden for society [12], but they are also associated with a faster decline in lung function [13, 14], lower quality of life [15] and increased morbidity [16] and mortality [17]. Although AECOPD are an emerging field of research and several possible associated risk factors have been reported, they are still not clearly defined. So far, the greatest risk factor seems to be a previous history of exacerbations [18]. More recently, Make et al. introduced an easily applicable score to predict short-term risk of COPD exacerbations (SCOPEX) which includes the following factors: sex, number of COPD maintenance medications, number of exacerbations in the previous year, FEV₁/FVC ratio and reliever use [19]. Almagro et al. described the CODEX index consisting of comorbidity assessment with Charlson index, airflow obstruction, dyspnea and previous severe exacerbations to predict survival and readmission after hospitalization for AECOPD [20]. With regards to re-exacerbation in patients with AECOPD, a recent study found age, lung function impairment, frequency of AECOPD during the previous year and some parameters of current AECOPD (such as pleural effusion, use of accessory respiratory muscles, medication and hospitalization length) to have a strong predictive capacity [21]. Another study showed an association between prolonged symptomatic duration of AECOPD and poorer health status with the risk of developing a new event [22]. In the primary care setting, however, only sparse data about potential risk factors for exacerbations and re-exacerbations are currently available [23].

The aims of this study were to analyze data of the entire patient population of the Swiss COPD cohort in a descriptive way and secondly, to evaluate known risk factors and their predictive association with exacerbation and re-exacerbation within a multi-state model framework previously reported by Therneau and Grambsch [24, 25].

With this multicenter, prospective, primary care cohort study, we were able to characterize a primary care COPD population and we were able to assess risk factors associated with exacerbation and re-exacerbation. In particular, lung function parameters (lower FEV₁/FVC and lower FEV₁) and symptoms such as pronounced dyspnea (in particular mMRC grade 4) or sputum production showed a significant association with exacerbation in a univariate analysis, whereas of these factors only pronounced dyspnea was significantly associated with re-exacerbation. Furthermore, prescription of short-acting bronchodilators, inhaled or systemic corticosteroids was significantly associated with exacerbation. We considered short-acting bronchodilator and corticosteroid prescription in this context most likely as surrogate markers of disease or symptom severity.

Using a multivariate Cox-regression model, formerly described in patients with Crohn’s disease, we were able to generate best subset models consisting of only two factors [24, 25]. Taking FEV₁-values and sputum into account, seemed to be most relevant in this primary care setting, when assessing the transition from having no exacerbation to having an exacerbation. These findings underline the importance of regular symptom and spirometric assessment in primary care even in so-called “stable disease”.

Finally, re-exacerbation was significantly associated with pronounced dyspnea and patients having had a cerebrovascular insult or being less physically active. These results could partly support a benefit from pulmonary and physical rehabilitation. On the other hand, treatment with long-acting anticholinergics seemed to play a significant protective role, which seems reasonable. The best subset model for re-exacerbation included only previous hospitalization for any reason and coronary heart disease. Whilst coronary heart disease increased risk of re-exacerbation significantly, hospitalization at last visit seemed to reduce risk for re-exacerbation in the best subset model. An explanation for these findings could be that patients with comorbidities are more likely to experience frequent exacerbations [31] and that these patients might possibly benefit from in-patient treatment to stabilize their condition. However, it is still counterintuitive to some extent that overall hospitalization is on the other hand strongly associated with exacerbation in the univariate analysis.

Baseline characteristics of our cohort were similar in comparison with Norwegian, Swedish, Canadian and UK primary care cohorts [32‐35]. However, with regards to GOLD severity grades, our patient population seemed to have more severe disease compared to the cohorts described by Wurst and colleagues (UK) or Sundh and colleagues (Sweden) [32, 34]. In accordance with the findings of Green et al. our analysis confirms the high prevalence of comorbidities, in contrast to their findings we found even higher rates of cardiac comorbidities [33].

The risk factors associated with exacerbation and re-exacerbation are largely in accordance with the literature [18, 36, 37], however the association of prescription of short-acting bronchodilators, inhaled or systemic corticosteroids was perhaps surprising, as some large trials have shown significant decrease in exacerbation risk with the use of inhaled steroids [38, 39]. However, a recent study of Magnussen et al. showed a similar risk of moderate or severe exacerbations for patients discontinuing inhaled glucocorticoids compared to patients who continued inhaled glucocorticoid treatment [40]. In addition, similar findings have been described in the Bergen COPD Cohort Study, a study which was designed to assess the ability of COPD characteristics and systemic inflammatory markers to predict the risk for acute COPD exacerbation frequency and duration [41]. Taking this into account, we suppose, as mentioned above, the prescription of these drugs to be surrogate markers for disease or symptom severity.

Concerning the prediction of exacerbation or hospital readmissions, some studies showed the value of other factors such as short acting bronchodilator use [42] or four meter gait speed, which we did not assess for in our cohort [43]. Furthermore, various new predictive scores such as the CODEX Index, the SCOPEX and the re-AE INDEX were established, which could be useful also in a primary care setting [19‐21]. Unfortunately we were not able to test the SCOPEX, which seems to be easily applicable in primary care, as we have not recorded daily reliever use in our study population so far. Some recent research underlined the value of clinical symptoms and questioned the sensitivity of airflow limitation to diagnose smoking induced disease [44, 45]. Even though our best subset model for exacerbation highlights the importance of FEV₁, which furthermore is in accordance with recently analyzed large data sources [46], we do agree that clinical symptoms do not only determine the degree of suffering of the patient but are a valuable and easy tool to evaluate the course of disease in primary care. The number of patients included in our cohort who did not fulfill a spirometric COPD diagnosis highlights the existence of patients with important clinical burden not fulfilling formal diagnostic criteria.

Our study confirmed well-established risk factors for AECOPD and confirmed the importance of spirometry in primary care, not only for the diagnosis of COPD in accordance with current guidelines but also as an important tool in order to improve treatment and reduce the risk for future exacerbations. Therefore, spirometry together with clinical assessment and medical history taking should build the basis for evaluating COPD patients in primary care. However, there is an ongoing debate on the sensitivity of spirometry as a diagnostic tool and our data revealed a substantial number of primary care patients suffering from respiratory symptoms whilst not fulfilling diagnostic spirometric criteria for COPD. Treatment for this patient collective remains challenging to physicians in their daily life and treatment guidelines probably do not reflect these circumstances adequately yet. Even if it is fairly difficult to perform trials in a primary care setting, we believe that further research is needed and more specifically elaborated treatment guidelines taking the circumstances of primary care into account.