This study aimed to elucidate the relation between the baseline amount of fibrosis quantified by an automated CT technique and the subsequent course of patients with CPFE. Our results show progression in patients with baseline fibrosis < 5% was not as prominent as in the other CPFE groups and the ≥ 10% fibrosis group had the poorest overall survival as well as the highest incidence of acute exacerbation. Baseline amount of fibrosis was an independent and strong predictor of prognosis. In contrast, in terms of progression-free survival, 5 to < 10% fibrosis group showed a similar Kaplan-Meier curve compared to the ≥ 10% fibrosis group. The incidence of composite progression (especially decline in PFTs), change per year in total lung volume, and progression of fibrosis on chest CT was highest in the 5 to < 10% fibrosis group.
In the Cox regression analysis, we considered the following factors: age, sex, and amount of cigarette smoking, which were previously reported to be associated with emphysema, interstitial lung abnormality, and disease progression by a sub-analysis of the Framingham Heart Study [11, 22]. The CCI [12] was also included in the regression analysis. Finally, lung-specific variables were entered into the models such as lung cancer and IPF, both of which have been identified to be independent poor prognostic factors [23], and CTD-ILD, another common cause of CPFE [24, 25]. Our results revealed that age and male sex were associated with an increased amount of fibrosis. Moreover, patients with CPFE had a high prevalence of lung cancer (23.2%), CTD (20.6%), and IPF (14.9%). It appears that our modelling was appropriate when considering the results of patient characteristics in the current study. Given our Cox regression analysis, we concluded that the extent of fibrosis was an independent and strong prognostic factor for patients with CPFE.
Our subgroup analysis comparing patients with CTD and those without showed that the majority of CTD was rheumatoid arthritis and many others with CPFE had autoantibodies related to rheumatoid arthritis, reinforcing the potential role of cigarette smoking in both diseases [26, 27].
Most previous studies have investigated CPFE within the IPF population rather than investigate the broader CPFE population including those with other fibrotic ILDs, or analysed only patients above a certain threshold of fibrosis extent [5, 28]. To the best of our knowledge, our study included the largest cohort of patients with CPFE with the full spectrum of fibrosis extent encountered in the real-world setting, adding evidence regarding the independent prognostic value of fibrosis quantification.
Although Wiggins et al. [4] first reported combined cryptogenic fibrosing alveolitis and emphysema in eight cigarette smokers in the 1980s, with a unique presentation of severe breathlessness and low gas transfer without apparent airflow obstruction; CPFE remained poorly recognised until the 2000s [5]. In 2010, many studies conducted on CPFE in IPF recognised a poor prognosis due to the high prevalence of pulmonary hypertension and lung cancer [2, 5, 29]; the current study also showed that IPF is associated with poor outcome. Alsumrain et al. reported a similar proportion of IPF to that in our study in their CPFE cohort [10], and the remaining patients were either unclassifiable or diagnosed with secondary ILD using clinico-radiological characteristics. This suggests that careful assessment is needed to identify patients who may benefit from lung biopsy to diagnose UIP patterns or another potentially progressive ILD. We might consider such an intensive approach especially for patients with 5 to < 10% fibrosis who apparently showed radiological and functional progression, yet had less mortality and acute exacerbation than the > 5% fibrosis group. Conversely, patients with CPFE with < 5% showed stable disease behaviour for up to 10 years. We might say that the patients with < 5% do not require monitoring as closely as that required for patients with > 5% fibrosis.
This study has several limitations. First, its single-centre, retrospective design may limit external validity. However, an advantage of our hospital was that over 80% of board-certified pulmonary physicians were within a 50 km radius, making it possible to follow-up patients with multiple assessments over long periods, similar to that in a population-based study. Second, the inclusion criteria are debatable. We included any proportion of emphysema and fibrosis. According to the American Thoracic Society/European Respiratory Society 2013 statement of idiopathic interstitial pneumonias (IIP) [28], CPFE was classified as a smoking-related IIP. Thus, there is no global consensus on the definition of CPFE. Third, the definition of progression is a matter of debate. Cottinet al. published a pooled analysis reporting that FVC measurements might be inappropriate for monitoring disease progression in patients with IPF and emphysema extent greater than or equal to 15% [30]. Certainly, our results for CPFE showed discrepancy in survival and progression in patients > 10% fibrosis. However, FVC remains the standard for evaluating disease progression. Further study is necessary to improve the prognostic predictability of CPFE. Finally, CT scans were obtained for clinical reasons and not at regular intervals as part of a prospective study; thus, there may have been more intensive follow-up in participants with more rapid disease progression.