Introduction
Idiopathic pulmonary fibrosis (IPF) is a disorder characterized by chronic progressive pulmonary fibrosis of unknown etiology [
1], but shows variable course, including acute exacerbation (AE). AE of IPF could be provoked by viral infection, aspiration, and mechanical stress such as that from thoracic surgery. After thoracic surgery, IPF patients may experience more frequent postoperative complications than non-IPF patients [
2‐
6]. AE occurs in 3–25% of IPF patients after thoracic surgery and is the most lethal postoperative complication, with a mortality rate between 7 and 23% [
2,
7‐
9]. Therefore, it is important to identify the population at risk for postoperative AE among IPF patients before surgery. Previous studies reported several risk factors for postoperative AE, including low lung function, poor performance status, high composite physiologic index (CPI), and high lactate dehydrogenase (LDH) levels, in IPF patients [
5,
7,
10‐
12]. However, in another study involving 56 IPF patients, no association between clinical parameters (lung function, levels of surfactant protein-D [SP-D] and Krebs von den Lungen-6 [KL-6], and operation type and time) and postoperative AE was observed [
6]. Due to these conflicting results, predictors for postoperative AE in IPF are not well defined.
18F-fluorodeoxyglucose positron emission tomography with computed tomography (
18F-FDG PET/CT) can assess the metabolic activity of lung tissue by detecting increased FDG uptake [
13]. Fibrotic lung parenchyma shows an increased uptake of FDG due to increased numbers of erythrocytes and inflammatory cells with glucose transporter-1 expression resulting from neovascularization [
14]. Previous studies reported that the standardized uptake value (SUV), a semi-quantitative index for FDG uptake in PET/CT, was associated with lung function, levels of C-reactive protein [CRP], LDH, SP-D, and KL-6, and clinical outcomes (decline in lung function, transplant-free survival, and death) in IPF patients [
15‐
18]. These results suggest that
18F-FDG PET/CT could provide additional information on disease activity and prognosis in IPF patients before thoracic surgery. Therefore, we aimed to investigate the usefulness of
18F-FDG PET/CT in predicting postoperative complications, including AE, in IPF patients.
Discussion
In this study, increased SUV was associated with postoperative AE in IPF patients. Among SUV parameters, the SUVR and SUVRTF were independent predictors for postoperative AE in IPF patients, and the SUVRTF was the best parameter for predicting postoperative AE in IPF patients.
Although lung function of the subjects was relatively preserved in our study, 43.8% of subjects experienced postoperative complications including AE (12.5%), which were similar to those of previous studies [
6,
32,
33]. Saito et al. reported that 10.7% and 40.7% of IPF patients (n = 28, mean vital capacity: 87.1%) with stage IA non-small cell lung cancer (NSCLC) developed postoperative AE and complications, respectively [
32]. Watanabe et al., in IPF patients with lung cancer (n = 56, vital capacity: 103.8%, DLco: 61.4%), also reported that 7.1% experienced postoperative AE [
6]. Moreover, Otsuka et al., in IPF patients with lung cancer (n = 9), reported that 44.4% experienced AE after thoracic surgery although lung function of the subjects was not impaired (mean vital capacity: 89% predicted, DLco: 73% predicted) [
33]. These results suggest that occurrence of AE is not uncommon after thoracic surgery even in IPF patients with relatively preserved lung function.
Patient demographics and baseline lung function were not associated with postoperative AE in IPF patients in our study. Our findings are consistent with those of previous studies [
6,
34]. Watanabe et al. reported that clinical parameters (vital capacity, DLco, white blood cell count, CRP, LDH, SP-D. KL-6, operation time and type, and histopathologic cancer type) were not different between IPF patients suffering from lung cancer with (n = 4) and without (n = 52) postoperative AE after lung resection [
6]. However, other studies showed different results [
5,
7,
10‐
12,
35]. Sato et al. reported that in 1763 patients with interstitial lung disease (ILD, including 1235 IPF) who underwent thoracic surgery for lung cancer, the male gender, history of previous acute exacerbation, preoperative steroid use, serum KL-6 levels, low vital capacity, usual interstitial pneumonia pattern on chest CT scan, and type of surgery were independent predicting factors for postoperative AE [
35]. Kumar et al., in 22 IPF patients with NSCLC, also showed that postoperative acute respiratory distress syndrome (ARDS) was associated with low baseline DLco and high CPI [
7]. In addition, Kusibe et al. reported that baseline FVC in 33 IPF patients with lung cancer was lower in patients who developed acute lung injury or ARDS (n = 9) after lung resection (74.0 vs. 103.7% predicted, P < 0.001) compared to those without acute lung injury or ARDS [
5]. These inconsistent results suggest that clinical variables might be insufficient to predict the occurrence of postoperative AE in IPF patients.
In our study, SUV parameters such as SUVR, SUV
meanTF, and SUVR
TF were only significant predictors for postoperative AE in IPF patients. No study has demonstrated the role of PET/CT in predicting postoperative complications in IPF patients. However, some studies suggested that FDG uptake was associated with severity and prognosis in IPF patients [
15‐
18]. Lee et al. reported significant correlation between SUV and baseline lung function (FVC: r = -0.6,
P = 0.024; DLco: r = -0.7,
P = 0.001) in 8 IPF patients [
15]. Low baseline lung function was reported to be associated with postoperative AE in IPF patients [
5,
7,
10]. Nobashi et al. reported that SUV parameters (SUV
max, SUV
mean, SUV
meanTF) in 90 patients with ILD (including 24 IPF) were correlated with baseline CRP and LDH, which are risk factors for postoperative AE in ILD patients [
10]. These findings support the role of SUV parameters in predicting postoperative AE in IPF. Justet et al. also reported that in 27 IPF patients, lung volume adjusted SUV metrics, were significantly associated with disease progression including AE, using the multivariate Cox analysis adjusted by age, FVC, and DLco [
18]. Therefore, these results suggest that patients with high SUV levels in the fibrotic area need measures to prevent acute exacerbation such as preoperative antifibrotic treatment, and careful observation after surgery.
In our study, SUVR
TF, which was corrected for both individual variation and air component of lung tissue, was an independent predictor and was the best predictor of postoperative AE among SUV parameters. Although SUV parameters such as SUV
max and SUV
mean are useful in assessing disease activity, they can be affected by multiple factors such as individual variations [
27] and distribution of air component without SUV activity [
29]. Other studies also suggested that adjusted SUV parameters have higher correlation with disease severity [
17] and prognosis [
18] compared to the SUV
max and SUV
mean, similar to our results.
This study has some limitations. First, this was a retrospective observational study in a single center. However, the baseline characteristics of patients were similar to those in previous reports [
6,
32,
33]. Secondly, PET/CT images were acquired from various PET/CT scanners. Thus, our analysis was also conducted using adjusted SUV parameters, such as the SUVR, which adjusts each individual’s
18F-FDG uptake [
28]. Third, most subjects had malignant lung nodules. This may have affected SUV measurement in the fibrotic area. However, we attempted to minimize these effects by excluding patients with clinical findings that could affect the results (e.g. lung mass, and multiple lung nodules) and measured SUV of fibrosis area except a nodule. Lastly, some known risk factors for AE, such as treatment (home oxygen, antifibrotic agents, or steroids) before thoracic surgery or the time of surgery, were not addressed in this study, and this might affect the results. However, we could not include home oxygen and antifibrotic use in our analysis, because all patients did not use them due to the relatively preserved lung function or limited access (in South Korea, pirfenidone was covered by insurance after 2016, and most patients in this study underwent surgery before 2016). Also, most of the patients except for one did not use steroids before surgery (only one patient used steroids for a short time before surgery), and data on operation time were not available.
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