Relationship of flow-volume curve pattern on pulmonary function test with clinical and radiological features in idiopathic pulmonary fibrosis

All patients with IPF—diagnosed in accordance with the 2011 IPF guidelines [13]—who visited the outpatient clinic of our hospital between April 2012 and March 2015 were enrolled in this study. Patients with secondary interstitial pneumonitis (such as collagen vascular disease, pneumonia caused by occupational or environmental exposure, chronic hypersensitivity pneumonitis, and drug-induced pneumonia), combined pulmonary fibrosis and emphysema (CPFE), and pleuroparenchymal fibroelastosis (PPFE) were excluded. Patients who had not undergone a PFT and high-resolution computed tomography (HRCT) within three months from the first visit were excluded. Patients whose PFT was presence of cough in the FV curve were also excluded. Mortality and survival data up to December 31, 2017, were collected. The study protocol conformed to the Declaration of Helsinki and was approved by the ethics committee of Kanagawa Cardiovascular and Respiratory Center (approval number KCRC-17-0027). The need for informed consent was waived because of the retrospective study design.

To evaluate what FV curve meant in IPF, the classification of FV curve was performed using the following steps: 1; dividing convex or non-convex with visual inspection, 2; dividing concave or non-concave with the ratio of the maximal expiratory flows at 50 and 25% of the FVC (MEF₅₀/MEF₂₅), 3; mixing these two shapes of flow to create four groups. First, the patients’ FV curves were independently reviewed by two thoracic physicians (R.O. and K.I.) who were blinded to the clinical and radiological data and all other PFT data, except the FV curve. The two physicians visually evaluated the FV curves and classified the pattern as convex or non-convex, as previously described [14, 15] (Fig. 1). In cases of conflict between the two reviewers, a third thoracic physician (T.K.) made the decision. Second, toevaluate the presence of peripheral airway obstruction, MEF₅₀/MEF₂₅ was calculated. The FV curve patterns were again divided into two categories based on the MEF₅₀/MEF₂₅ ratio, with MEF₅₀/MEF₂₅ ≥ 4 defined as the concave pattern and MEF₅₀/MEF₂₅ < 4 defined as the non-concave pattern (Fig. 1). Third, we divided into four groups based on the presence or absence of the convex pattern and the concave pattern. The patient groups with the convex/concave pattern, non-convex/concave pattern, convex/non-concave pattern, and non-convex/non-concave pattern were defined as A group, B group, C group, and D group, respectively (Fig. 1). Composite physiologic index (CPI) and gender, age, and physiology stage (GAP stage) were determined as previously described [16, 17]. The PFTs had been performed in accordance with the Japanese Respiratory Society guidelines [18].

Chest HRCT images were acquired using the Toshiba Aquillion ONE (Toshiba Medical Systems Corp., Otawara, Tochigi, Japan). These images were reconstructed with 0.5–1.0 mm slice thickness and 10-mm intervals. A computer-aided method for quantitative CT analysis of honeycombing area was used to automatically measure honeycombing areas on whole HRCT images, as previously described [19]. In brief, low-attenuation areas enclosed by thick walls were extracted as honeycombing areas, and the sum of honeycombing areas in all slices was calculated as the HA. This HA included traction bronchiectasis. Next, the low attenuation area (LAA) was measured, as previously described [20, 21]. This LAA included not only the emphysematous area, but also the honeycombing area and traction bronchiectasis in IPF. We calculated the pure emphysematous area as the subtracted LAA (sLAA), which was obtained by subtracting the HA from the LAA (Fig. 2). The HA and sLAA as a percentage of the lung area were also calculated (%HA and %sLAA, respectively). To evaluate the distribution of these CT findings, we divided the lung area into four areas. First, the location of the tracheal bifurcation was used to divide the lung into the upper and lower areas. Second, the 15-pixel area on the pleural side was defined as the peripheral lung area, and the other areas constituted the central lung area (Fig. 3). A public domain computer program, ImageJ (Version 1.46. National Institutes of Health, Bethesda, MD, USA) was used for the quantitative CT analysis.

The interobserver agreement regarding the classification of the FV curve pattern was evaluated using the kappa statistic. The clinical and radiological variables were compared using the Mann–Whitney U test, Kruskal Wallis test, and the chi-square test. Predictors of time to death were determined using the Cox proportional hazards analysis. Survival analysis was also performed in accordance with the method of Kaplan–Meier, with the endpoint being death. Differences in mortality were assessed using the log-rank test. All statistical analyses were performed using JMP version 9.0.2 (SAS Institute, Cary, NC). For all tests, p values < 0.05 were considered statistically significant.

Of the 191 consecutive patients with IPF who visited the outpatient clinic of our hospital between April 2012 and March 2015, 30 patients were excluded because of the absence of HRCT images or PFT results obtained within three months from the first visit. Another 31 patients were excluded because of the presence of cough in the FV curve. Thus, 130 patients with IPF were finally enrolled in this study. The demographic, clinical, and physiologic characteristics of these 130 patients are summarized in Table 1. The median age of the study group was 71 (65–76) years. Most of the patients (104 patients; 80.0%) were men and were either current smokers or had a history of smoking (102 patients; 78.5%). The median %predicted FVC, forced expiratory volume in 1 s (FEV₁), and DL_CO were 76.2, 76.3, and 70.1%, respectively. The median CPI was 31.3 (18.2–45.4). Seventy-one (57.3%) patients were classified as GAP stage I, 50 (40.3%) as stage II, and 3 (2.4%) as stage III. The median follow-up period was 3.0 (1.4–3.8) years.

Of the 130 patients, 93 (71.5%) patients had a convex pattern of the FV curve. The agreement between the two physicians was excellent for the convex pattern (kappa = 0.86). There were significant differences between patients with convex and non-convex patterns in gender, body mass index (BMI), and smoking history (in pack-years), but not in FVC, DL_CO, or CPI (Table 2).

The concave pattern was observed in 72 (55.4%) patients. Significant differences were noted between the concave and non-concave patterns in age, BMI, FVC, and CPI, but not in FEV₁ or DL_CO (Table 3).

The numbers of patients in A group, B group, C group, and D group were 47, 25, 46, and 12, respectively (Table 4). There were significant differences between these groups in BMI and FVC (p < 0.001, and p = 0.018, respectively), but not in FEV₁, DL_CO, or CPI.

The median (interquartile range) %HA and %sLAA were 3.0% (1.3–5.1%) and 6.0% (3.5–9.2%), respectively. There were no significant differences between the convex and non-convex patterns in terms of the %HA and %sLAA (Table 5). In contrast, significant differences were found between the concave and non-concave patterns only in the %HA (p = 0.009, Table 6). Among the four groups, significant differences were observed only in the %HA (p = 0.046, Table 7).

Among the CT findings, only the %HA of the upper/peripheral lung area was significantly different among the four groups (p = 0.005, Table 7); no intergroup differences were observed in the %sLAA of any lung area.

The Kaplan-Meier survival curve demonstrated a significant difference between the concave and non-concave patterns, but not between the convex and non-convex patterns (Fig. S1A, S1B). Among the four groups, patients in C group had the worst survival rates (Fig. S1C). The survival curve also showed a significant difference in mortality between C group and non-C group (log-rank test; p = 0.010, Fig. 4). In the Cox hazard regression analysis adjusted for age, gender, BMI, and smoking history in terms of pack-years, the C group was a significant predictor of mortality for IPF (hazard ratio, 2.19; 95% confidence interval [CI]: 1.07–4.49; p = 0.032, Table 8).