Study population
In this retrospective study, patients with IPF at two centers in Japan (Tsuboi Hospital and Toho University Omori Medical Center) were enrolled from April 2006 to March 2019. IPF was diagnosed based on 2011 international IPF guidelines [1]. The diagnosis of emphysema was based on upper lobe predominant and scattered distribution of low attenuation areas on chest HRCT, either no wall or with wall of less than 1 mm in thickness [14]. Combined pulmonary fibrosis and emphysema (CPFE) was defined as concomitant IPF and ≥ 10% emphysema on chest HRCT by criteria proposed by Ryerson, et al. [15]. Based on these findings, we excluded patients with CPFE in this study. The diagnosis of all patients was evaluated by a multidisciplinary team based on patients’ clinical, radiological and/or pathological findings. In total, 431 patients with suspected IPF were enrolled. Patients with absence of pulmonary function test findings at baseline and at a follow-up of 6 months (n = 45), unavailable chest high-resolution computed tomography (HRCT) results (n = 17), lung cancer (n = 33), and untraceable survival (n = 21) were excluded. A total of 315 patients were included. The number of patients with JRS stage I, II, III, and IV was 179, 28, 71, and 71, respectively (Fig. 1).
The modified diagnostic criteria for acute exacerbation (AE) of IPF proposed by Collard et al. [16] was as follows: (1) previous/concurrent IPF diagnosis; (2) unexplained worsening or development of dyspnea within 30 days; (3) chest HRCT with new bilateral ground-glass opacities and/or consolidation superimposed on a reticular or honeycomb background; (4) exclusion of alternative causes of acute lung injury such as pneumonia, left-sided heart failure, and pulmonary embolism.
Clinical and laboratory data was obtained from medical records, including IPF disease severity, efficacy of antifibrotic treatment, changes in pulmonary function (every 6 months), and prognosis. In Japan, classification of IPF disease severity in IPF is as follows: stage I (PaO2 ≥ 80 Torr at rest), stage II (80 > PaO2 ≥ 70 Torr at rest), stage III (70 > PaO2 ≥ 60 Torr at rest), and stage IV (PaO2 < 60 Torr at rest). If patients with stage II or III have oxygen desaturation (the lowest SpO2 is < 90%) during the 6MWT, they are classified as stage III or IV, respectively [11]. The GAP score and stage were calculated according to a method described by Ley et al. [12].
In this study, pirfenidone and nintedanib have been used since 2008, and 2015, respectively. In addition, patients who were diagnosed as IPF from 2006 to 2008, were treated as non-treated group. To evaluate the response to treatment, we defined disease progression as a relative decline of ≥ 5% and stable disease as a relative decline of < 5% in percentage predicted FVC (%FVC) over a period of 6 months.
All methods were carried out in accordance with relevant guidelines and regulations.
The study was approved by the Institutional Review Board of Tsuboi Hospital (no. Zizan 1-3). The Ethical Committees of Tsuboi Hospital waived the need for informed consent because of the retrospective clinical review.
Chest computed tomography (CT) scan
Helical CT scanners (Aquilion 16, Toshiba, Tokyo, Japan and Aquilion Prime, Canon, Tokyo, Japan) were used. Thin-section CT images were obtained during full inspiration, and the scanning protocol consisted of reconstruction of a 1- to 2-mm slice thickness with a high spatial frequency algorithm. Thin-section chest CT images were photographed at window settings appropriate for the lung parenchyma (window level, − 600 to − 450 HU; width, 1600–1900 HU) in all patients.
Pulmonary function test
Spirometry and measurements of diffusing capacity of the lungs for carbon monoxide (DLco) were performed using a pulmonary function test (PFT) system (Chestac-33, CHEST Co. Ltd., Tokyo, Japan). The diffusion capacity was measured using the single breath technique. These PFTs were performed by two technicians according to the method described in the American Thoracic Society criteria [17].
6MWT
The 6MWT was performed according to the ATS recommendations [17], and continuous monitoring of heart rate and oxygen arterial saturation with pulse oximetry, and walking distance were recorded. During 6MWT, patients were instructed to walk as fast as possible and were allowed to slow down or to stop if necessary. The oxygen desaturation on the 6MWT was defined as indicating < 90% on oxygen saturation with pulse oximetry during 6MWT.
Statistical analysis
Data is presented as the number of patients with percentage or mean with standard deviation, as appropriate. The comparisons between the two groups were evaluated using Pearson’s Chi-squared test or Fisher’s exact test for categorical variables and the Student’s t-test for parametric continuous variables. Survival curves and the cumulative incidence of disease progression were estimated using the Kaplan–Meier method, and differences in the curves were calculated using the log-rank test. A two-sided p value of < 0.05 was considered statistically significant. Statistical analyses were performed using JMP statistical software (version 10.0.0, SAS Institute, Cary, NC, USA).