Previous studies suggested that patients with CPFE form a subgroup of IPF or have a different disease,14 as they present with different clinical, radiological and functional alterations than patients with IPF.22 Isolating this group of patients can facilitate diagnosis and enable early treatment. Evaluating CPFE in a study series is difficult because many patients with various types of interstitial diseases are included, such as patients with connective tissue diseases, particularly rheumatoid arthritis23 and non-specific fibrotic interstitial pneumonia.24 The inclusion of several standards makes it difficult to assess prognosis. We included only patients with a well-established UIP pattern and identified important differences from a functional perspective and in blood biomarker profiles. In the blood samples, patients with CPFE had higher levels of periostin while patients with IPF had higher levels of mucin–16. Functionally, CV/VC (%) and CC/TLC (%) were higher in patients with CPFE than in those with IPF, suggesting increased air trapping associated with emphysema.
The smoking history was common in the three groups, while the smoking load was significantly higher in the COPD group compared to the other groups and higher in the CPFE group than in the IPF group. Patients with CPFE are typically smokers or former smokers with a history of smoking over 40 packets per year.25 This suggests a minimum smoking load leading to progression of the combined disease. However, CPFE has been reported in patients with no smoking history, suggesting that there is a genetic predisposition for the development of the syndrome.24
As in previous studies, differentiating between IPF and CPFE by spirometry was difficult.2,26 Patients with CPFE showed flow measurements close to those with IPF and volume measurements close to those in patients with COPD. No spirometric variable could differentiate CPFE from the IPF, which agrees the results of previous studies.22 This may delay diagnosis, as spirometry is the most easily accessible pulmonary function test.27
Although some studies reported lower values of DLco in patients with CPFE compared to in IPF,24 including in our study and a study by Jacob et al28, similar values were observed in both groups (IPF and CPFE). Interestingly, Kco was lower in the CPFE group. The coexistence of emphysema and fibrosis leads to normal or subnormal volumes and pulmonary fluxes, while DLco was substantially reduced.24,28
SBWN2 is an important tool for evaluating the homogeneity of alveolar ventilation and for the early detection of small airway changes in patients with COPD.5 The main parameters obtained by SBWN2 are SIII and CV, which are directly correlated with FEV1 and FVC in patients with COPD.5 SIII is characterized by changes in the N2 concentration expired between 25% and 75% of the VC and ΔN2 750–1250mL. Both parameters reflect the distribution of ventilation, ie, whether there is homogeneity in ventilation. CV is the portion of the VC that begins after the start of airway closure (phase IV) and affects the RV. In ordinary individuals, this value is <20% of VC; higher values are observed in both obstructive and restrictive patients. The CC is the CV associated with RV. 4
No studies comparing SBWN2 have been conducted in patients with IPF and CPFE. Silva et al. conducted SBWN2 in patients with systemic sclerosis and pulmonary involvement and compared them with a healthy population. They found that SIII was the most sensitive pulmonary function alteration in these patients, even when other pulmonary function tests were normal.29
The SBWN2 test showed heterogeneity in pulmonary ventilation in all three conditions (IPF, CPFE and COPD), without large differences between groups, which did not aid in the functional differentiation between IPF and CPFE. Additionally, our data suggested that patients with CPFE experienced significant air trapping, even when the lung volumes were within normal limits. Patients included in our study had evident fibrosis in CT scanning. Thus, SBWN2 may be a sensitive test for evaluating the progression of fibrosis in patients with initial fibrosing disease.
Periostin levels were significantly higher in the serum of the CPFE group than in the other two groups. Periostin is involved in processes that lead to pulmonary fibrosis formation and pulmonary remodeling, as well as in eosinophil recruitment and mucus production.6 Periostin has been evaluated in the context of pulmonary fibrosis and asthma, but a recently published study revealed no significant difference between the levels of periostin in asthma compared to in COPD.30Several studies suggested that periostin is a biomarker in patients with IPF,6,7 but no studies have evaluated periostin behaviour in CPFE. Caswell-Smith et al. reported reference values for periostin in adults without asthma and no COPD at 50 ng/mL.30 In our study, only the CPFE group showed values higher than the reference. As this biomarker may be increased in both fibrosis and COPD, it is possible that the association of the two changes contributed to the outstanding increase in patients with CPFE.
Mucin–16 (MUC16 or CA–125) is a tumor biomarker widely evaluated in medical practice and is mainly related to gynecological tumors, such as those in the ovaries.12,13 However, some authors observed increased levels (>35 U/mL) in patients with interstitial lung diseases, particularly IPF, even suggesting a worse prognosis with increased mortality and increased risk of lung cancer.12,13 We found that patients with IPF had higher levels of mucin–16 than patients with CPFE. This may be related to the fibrosis degree. One hypothesis to explain this results is that the presence of emphysema reduces lung density, as mucin–16 is present on the pulmonary epithelial surface.
PDGF-BB and TGF-β1 have been proposed as biomarkers for differentiating between IPF and CPFE. These molecules participate in collagen formation and complement system regulation9–11 and may help in this differentiation; however, the data revealed no significant difference in PDGF-BB and TGF-β1 among the three groups.
Because of the cross-sectional design of the study, the prognostic role of these functional and biochemical markers could not be assessed. Another limitation of this study was that the study was conducted in a single center and included only patients with an evident UIP pattern, and it was not possible to evaluate whether the observed changes also occurred in patients with incipient lesions. In addition, the lack of a control group with healthy patients may be a limiting factor. However, this study provides insight useful for future studies that include patients with IPF and CPFE.