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Clinical significance of lower-lobe interstitial lung disease on high-resolution computed tomography in patients with idiopathic pleuroparenchymal fibroelastosis
Respiratory Medicine 154 (2019) 122–126
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Clinical significance of lower-lobe interstitial lung disease on highresolution computed tomography in patients with idiopathic pleuroparenchymal fibroelastosis
T
Masato Konoa,*, Yuiko Fujitaa, Kenichiro Takedaa, Koichi Miyashitaa, Akari Tsutsumia, Takeshi Kobayashia, Yoshihiro Mikia, Dai Hashimotoa, Noriyuki Enomotob, Yutaro Nakamurab, Takafumi Sudab, Hidenori Nakamuraa a b
Seirei Hamamatsu General Hospital, Department of Pulmonary Medicine, Japan Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Pleuroparenchymal fibroelastosis Interstitial lung disease Usual interstitial pneumonia High-resolution computed tomography Prognostic factor
Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare form of idiopathic interstitial pneumonias (IIP) and may have other patterns of interstitial lung disease (ILD) in the lower lobe, such as usual interstitial pneumonia (UIP). However, the clinical significance of lower-lobe ILD in patients with IPPFE is unclear. Methods: A retrospective review of 40 consecutive patients with clinically diagnosed IPPFE in our institution from 2005 to 2016 was conducted. The presence of lower-lobe ILD on high-resolution computed tomography (HRCT) was assessed and classified into UIP or non-UIP pattern according to a modification of diagnostic criteria for idiopathic pulmonary fibrosis. Clinical characteristics and prognostic factors were evaluated. Results: Among the 40 patients with IPPFE, 21 (53%) had lower-lobe ILD, including 13 with UIP pattern and 8 with non-UIP pattern. Patients with IPPFE who had lower-lobe ILD had significantly older age, higher frequency of fine crackles, higher serum KL-6 level, lower residual volume (RV), and lower total lung capacity (TLC) than those without lower-lobe ILD. In addition, those with lower-lobe ILD, especially UIP pattern, had a significantly poorer survival than those without lower-lobe ILD (log-rank test; p = 0.014, p < 0.001, respectively). Multivariate Cox proportional hazards regression analysis revealed that low %forced vital capacity (%FVC) at baseline and coexistence of UIP pattern were significantly associated with poor prognosis in patients with IPPFE. Conclusions: The coexistence of lower-lobe ILD on HRCT, especially the UIP pattern, may predict poor survival in patients with IPPFE.
1. Introduction Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare form of idiopathic interstitial pneumonia (IIP) characterized by predominantly upper lobe pleural and subpleural lung parenchymal fibrosis [1]. Amitani et al. first reported this unique condition as idiopathic pulmonary upper lobe fibrosis (IPUF) in Japanese literature [2].
In 2004, Frankel et al. described five cases and named this condition as pleuroparenchymal fibroelastosis (PPFE) [3]. Although a consensus statement on IPPFE diagnosis is lacking, radiological and/or pathological findings are used in the diagnosis of IPPFE [4,5], and a recent report has been proposed the clinical diagnostic criteria [6]. IPPFE may have accompanied other patterns of interstitial lung disease (ILD) in the lower lobes [7,8]; previous cohort studies
Abbreviations: APDT/TDT, the ratio of anteroposterior diameter to transverse diameter of the thoracic cage; BMI, body mass index; CI, confidence interval; CT, computed tomography; DLco, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GAP, gender-age-physiology; HRCT, high-resolution computed tomography; IIPs, idiopathic interstitial pneumonias; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; IPPFE, idiopathic pleuroparenchymal fibroelastosis; IPUF, idiopathic pulmonary upper lobe fibrosis; ISA, immune suppressive agents; LTOT, long-term oxygen therapy; MDD, multidisciplinary discussion; mo, months; NPPV, noninvasive positive pressure ventilation; NSIP, non-specific interstitial pneumonia; PPFE, pleuroparenchymal fibroelastosis; PSL, prednisolone; PULF, pulmonary upper lobe fibrosis; RV, residual volume; SD, standard deviation; SLB, surgical lung biopsy; SP-D, surfactant protein-D; TLC, total lung capacity; UIP, usual interstitial pneumonia * Corresponding author. 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka, 430-8558, Japan. E-mail address: [email protected] (M. Kono). https://doi.org/10.1016/j.rmed.2019.06.018 Received 10 April 2019; Received in revised form 21 May 2019; Accepted 18 June 2019 Available online 20 June 2019 0954-6111/ © 2019 Elsevier Ltd. All rights reserved.
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interpreted by radiologists in our institution at the time of diagnosis. Regarding the pattern of lower-lobe ILD, two trained pulmonologists independently reviewed all HRCT without clinical data and confirmed it in consensus. The ratio of the anteroposterior diameter to transverse diameter of the thoracic cage (APTD/TDT) at the level of the sixth thoracic vertebra was measured according to a previous report [18].
demonstrated that more than half of patients with IPPFE have lowerlobe ILD [4–15], especially of the usual interstitial pneumonia (UIP) pattern [4–8,11–15]. A study indicated that patients with PPFE with histologic UIP pattern had poor prognosis and tendency of worse prognosis than that of patients with idiopathic pulmonary fibrosis (IPF) [16]. Several reports described lower-lobe ILD in patients with IPPFE and evaluated its association with prognosis [6,13–16]; however, the clinical significance of lower-lobe ILD in patients with IPPFE is still unclear. The present study aimed to determine the clinical implications of lower-lobe ILD on HRCT in patients with IPPFE.
2.4. Statistical methods Chi-square test or Mann-Whitney U test were used to compare between two groups. The Kaplan-Meier method was used to estimate cumulative survival, and log-rank test was performed. Cox proportional hazards analysis was used to identify significant variables that could predict survival status. Statistical analyses were performed using JMP® 13 software (SAS Institute Inc., Cary, NC, USA). A p-value of 0.05 was considered significant.
2. Patients and methods 2.1. Patients and diagnostic criteria for IPPFE A retrospective review of 52 consecutive patients who were diagnosed with PPFE or IPUF in our institutions from 2005 to 2016 was conducted. Clinical diagnostic criteria of IPPFE [6] in this study were as follows; 1) a radiologic PPFE pattern on chest CT defined as bilateral subpleural dense consolidation with or without pleural thickening in the upper lobes and less marked or no involvement of the lower lobes; 2) radiologic confirmation of disease progression defined as an increase in the upper-lobe consolidation with or without pleural thickening and/ or a decrease in the upper-lobe volume on serial radiologic assessment; 3) exclusion of other lung diseases with identifiable etiologies (connective tissue disease-related ILD, chronic hypersensitivity pneumonitis, pulmonary sarcoidosis, pneumoconiosis, and active pulmonary infection); based on these criteria, 12 patients were excluded, of which, six had secondary PPFE with collagen tissue disease, one had chronic hypersensitivity pneumonia, three had no confirmation of disease progression radiologically, and two had inadequate clinical information. Finally, 40 patients with confirmed IPPFE were enrolled in the study. Histological criteria of PPFE [4] were applied in patients from whom lung specimens were obtained. The study protocol was approved by the ethics committee of Seirei Hamamatsu General Hospital (approval number: 2685). Requirement of patient approval or informed consent was waived because the study was designed as a retrospective review.
3. Results 3.1. Patient characteristics The clinical diagnostic criteria of IPPFE were fulfilled in all patients, and PPFE was confirmed histologically in four patients (10%) through autopsy (n = 3) and/or surgical lung biopsy (SLB; n = 2). The baseline characteristics of 40 patients with IPPFE are shown in Table 1. The mean age was 67.6 years, and male sex (65%) and non-smokers (60%) were predominant. Emaciation with low BMI (17.1 ± 2.9 kg/m2) and flattered chest were present in the majority of patients. Cough and/or dyspnea occurred in approximately 40% of patients, and high values of serum surfactant protein-D (SP-D) and PaCO2 were achieved in most patients. In the entire study population, 21 patients (52.5%) had coexistence of lower-lobe ILD on HRCT, of which 13 (32.5%) had UIP pattern, including typical UIP pattern (n = 6) and probable UIP pattern (n = 7), and 8 (20.0%) had non-UIP pattern, including non-specific interstitial Table 1 Clinical characteristics of patients with IPPFE with or without lower-lobe ILD on HRCT. All subjects (n = 40)
2.2. Data collection Clinical data including age, sex, smoking status, body mass index (BMI), symptoms, physiological findings, treatment for ILD, and outcome were obtained from the patients’ medical records; the results of laboratory and pulmonary function tests at the time of diagnosis were recorded. In pulmonary function tests, the percentages of predicted values for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1)/FVC, residual volume (RV), total lung capacity (TLC), RV/TLC and the diffusing capacity of carbon monoxide (DLco) were calculated according to the formulae of the Japanese Respiratory Society.
Age, years 67.6 ± 11.9 Male sex, n (%) 26 (65.0) Non-smoker, n 24 (60.0) (%) BMI, kg/m2 17.1 ± 2.9 Symptoms and physical findings Cough, n (%) 15 (37.5) Dyspnea, n (%) 15 (37.5) Fine crackles, n 9 (22.5) (%) Desaturation on 11 (27.5) effort, n (%) Laboratory findings KL-6, U/mL 518 ± 287 SP-D, ng/mL 195 ± 97 PaO2, Torr 80.7 ± 10.3 PaCO2, Torr 46.5 ± 6.8 HRCT findings APDT/TDT, % 54.4 ± 5.1
2.3. High-resolution computed tomography (HRCT) HRCT examination of the lungs was performed on sections of < 1.5mm thickness to evaluate radiographic abnormalities. Presence of lower-lobe ILD was assessed on all HRCT images included in the review. The lower-lobe ILD pattern was classified as UIP or non-UIP according to a modification of the Fleischner Society Idiopathic Pulmonary Fibrosis (IPF) Diagnostic Criteria [17]: lower-lobe UIP pattern on HRCT was defined as either typical UIP CT pattern (honeycombing with or without peripheral traction bronchiectasis or bronchiolectasis) or probable UIP CT pattern (subpleural reticular pattern with peripheral traction bronchiectasis or bronchiolectasis) [17]. Furthermore, lowerlobe non-UIP pattern was based on the American Thoracic Society/ European Respiratory Society classification of IIPs [1]. All HRCT were
IPPFE with lower-lobe ILDa (n = 21)
IPPFE without lower-lobe ILD (n = 19)
p-value
74.3 ± 9.3 15 (71.4) 12 (57.1)
60.2 ± 9.9 11 (57.9) 12 (63.2)
0.002 0.38 0.69
16.6 ± 2.6
17.6 ± 3.2
0.35
7 (33.3) 10 (47.6) 8 (38.1)
8 (42.1) 5 (26.3) 1 (5.2)
0.56 0.16 0.008
8 (38.1)
3 (15.7)
0.10
626 ± 337 217 ± 104 79.6 ± 10.4 46.2 ± 7.4
405 ± 168 173 ± 86 82.7 ± 10.2 47.0 ± 6.0
0.009 0.19 0.62 0.63
54.7 ± 5.3
54.1 ± 5.1
0.78
Data are shown as mean ± SD. IPPFE; idiopathic pleuroparenchymal fibroelastosis, ILD; interstitial lung disease, HRCT; high-resolution computed tomography, BMI; body mass index, SPD; surfactant protein D, APDT/TDT; the ratio of anteroposterior diameter to transverse diameter of the thoracic cage. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8. 123
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Table 2 Pulmonary function test findings in patients with IPPFE with or without lowerlobe ILD on HRCT.
FVC, L FVC, % FEV1, L FEV1/FVC, % RV, L RV, % TLC, L TLC, % RV/TLC, % DLco, mL/ min/ mmHg DLco, %
All subjects (n = 40)
IPPFE with lower-lobe ILDa (n = 21)
IPPFE without lower-lobe ILD (n = 19)
p-value
2.04 ± 0.94 65.6 ± 22.1 1.88 ± 0.86 92.4 ± 9.6 1.90 ± 0.54 117.2 ± 32.1 4.39 ± 1.34 85.0 ± 18.6 45.1 ± 8.9 15.4 ± 5.8
1.76 59.5 1.64 93.1 1.62 99.2 3.65 72.3 45.8 12.8
0.72 18.6 0.71 11.6 0.48 27.4 0.91 13.7 10.8 4.4
2.33 ± 1.07 71.1 ± 24.1 2.13 ± 0.95 91.7 ± 7.23 2.10 ± 0.50 130.7 ± 27.8 4.88 ± 1.39 93.5 ± 16.7 44.5 ± 7.6 17.2 ± 5.7
0.08 0.10 0.10 0.14 0.03 0.03 0.04 0.007 0.77 0.08
99.1 ± 25.1
97.6 ± 27.3
100.0 ± 24.7
0.81
± ± ± ± ± ± ± ± ± ±
Table 3 Treatment and outcome of patients with IPPFE with or without lower-lobe ILD on HRCT.
Observation periods, mo Treatment, n (%) PSL + ISAb Pirfenidone LTOT NPPV Complication Pneumothorax, n (%) Outcome All-cause deathc, n (%)
Data are shown as mean ± SD. IPPFE; idiopathic pleuroparenchymal fibroelastosis, ILD; interstitial lung disease, FVC; forced vital capacity, FEV1; forced expiratory volume in 1 s, RV; residual volume, TLC; total lung capacity, DLco; diffusing capacity for carbon monoxide. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8.
All subjects (n = 40)
IPPFE with lower-lobe ILDa (n = 21)
IPPFE without lower-lobe ILD (n = 19)
p-value
33.9 ± 31.1
31.4 ± 28.4
36.7 ± 34.3
0.54
2 (5.0) 4 (10.0) 10 (25.0) 2 (5.0)
2 3 7 1
(9.5) (14.3) (33.3) (4.7)
0 1 (5.3) 3 (15.7) 1 (5.2)
0.10 0.33 0.20 0.88
19 (47.5)
11 (52.3)
8 (42.1)
0.51
13 (32.5)
11 (52.4)
2 (10.5)
0.003
Data are shown as mean ± SD. IPPFE; idiopathic pleuroparenchymal fibroelastosis, ILD; interstitial lung disease, PSL; prednisolone, ISA: immune suppressive agents, LTOT; long-term oxygen therapy, mo; months, NPPV; non-invasive positive pressure ventilation. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8. b Cyclophosphamide; n = 1, cyclosporine A; n = 1. c Respiratory failure; n = 11, aspiration pneumonia; n = 2.
pneumonia (NSIP) pattern (n = 2), PPFE pattern (n = 2), and unclassifiable (n = 4). In the two patients with PPFE pattern in the lower lobe on HRCT, there was bilateral subpleural dense consolidation, predominantly in the upper lobe, and similar findings in the lower lobes. As shown in Table 1, patients with IPPFE with lower-lobe ILD had significantly older age, higher rate of fine crackles on chest auscultation, higher KL-6 level, and higher frequency of dyspnea and desaturation on effort than those without lower-lobe ILD. 3.2. Pulmonary function test findings Pulmonary function test findings in patients with IPPFE are shown in Table 2. Restrictive ventilatory impairment with decreased FVC and an increased ratio of RV to TLC were observed the majority of patients, whereas a trend of reduced FVC and significant decrease of both RV and TLC was observed in patients with IPPFE with lower-lobe ILD compared with those without lower-lobe ILD.
Fig. 1A. Survival curves for patients with IPPFE with or without lower-lobe ILD. Patients with IPPFE with lower-lobe ILD had significantly poor survival than those without lower-lobe ILD (log-rank test; P = 0.014).
3.3. Treatment and outcome Treatments for ILD and outcomes are shown in Table 3. During the observation period after the diagnosis of IPPFE was achieved (33.9 ± 31.1 months), long-term oxygen therapy (LTOT) was administered in 10 patients (25.0%) and non-invasive positive pressure ventilation (NPPV) was performed at home in two patients (5.0%). Complication of pneumothorax occurred in approximately half of the patients (47.5%), and mortality, in 13 patients (32.5%) due to chronic respiratory failure (n = 11) and aspiration pneumonia (n = 2). Despite no significant differences in the treatment of ILD between the two groups, the IPPFE with lower-lobe ILD group had a higher mortality rate than the IPPFE without lower-lobe ILD group (52.4% vs 10.5%, respectively).
among the three groups (log rank test; p = 0.002) (Fig. 1B); in IPPFE patients with UIP pattern, survival was significantly poorer as compared to the value attained in those without lower-lobe ILD (log-rank test; p < 0.001), and trend of worse prognosis than those with lowerlobe non-UIP pattern was observed (log-rank test; p = 0.05). 3.5. Prognostic factors Finally, prognostic factors were examined in the entire cohort (Table 4). In univariate Cox proportional hazards analysis, older age, desaturation on effort, low %FVC, and RV/TLC at baseline, and coexistence of lower-lobe ILD and UIP pattern on HRCT were related to poor prognosis. Moreover, in multivariate Cox proportional hazards analysis, low %FVC and coexistence of lower-lobe UIP pattern on HRCT were significantly associated with a poor prognosis.
3.4. Survival A comparison of survival curves for patients with IPPFE with or without lower-lobe ILD is shown in Fig. 1. Survival was significantly worse in patients with IPPFE with lower-lobe ILD compared with those without lower-lobe ILD (log-rank test; p = 0.014) (Fig. 1A). Especially, the mortality rate was the highest in IPPFE patients with UIP pattern
4. Discussion This retrospective study included a relatively large cohort of 124
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clinical diagnosis of IPPFE should be discussed; nevertheless, our patients had distinctive clinical characteristics as in those of the previous reports of IPPFE [2–16,18–22] regardless of the presence of lower-lobe ILD, and in some cases (10%), histological diagnosis of definitive IPPFE was made. Amitani et al. originally described IPUF as pure upper lobe-localized fibrosis, which is conceptually similar to IPPFE, and reported its slow progression with a prognosis of 10–20 years of survival after diagnosis [2]; however, recent studies have revealed that 50–100% of patients with IPPFE have coexisting ILD in other lobes, based on radiologically and/or histological findings [4–15], and worse prognosis [15,16,21]. Several studies reported that some patients with IPPFE developed lower-lobe ILD with disease progression [7,9,14], and/or rapid rate of progression [9]. Whereas disease progression and prognosis of IPPFE is highly variable, the differences in prognoses among previous studies may be associated with the frequency of a coexistence of lower-lobe ILD in patients with IPPFE. Regarding pattern of coexisting ILD in the lower lobe in patients with IPPFE, reports indicated UIP as the most common pattern radiologically and/or histologically [4–8,11–15], as well as other ILD patterns, such as NSIP [4,6,11,15], PPFE [4,6], organizing pneumonia [6] and unclassifiable pattern [4,6,11,14]. In the present study, UIP pattern on HRCT was most common and occurred in 61.9% of patients with lower-lobe ILD. Ishii et al. performed multicenter study including 52 patients with PPFE, and reported that UIP lesion in the lower lobes on CT images was more frequently observed in non-survivors than in survivors, suggesting that the presence of UIP pattern could play an important role in the prognosis of these patients [14]. Recently, Kato et al. reported that UIP pattern defined as definite UIP pattern on HRCT, in the lower lung lobes was an independent variable for poor prognosis in 36 patients clinically diagnosed with IPPFE [16], which supports the results of our study of worse prognosis in patients with IPPFE with UIP pattern on HRCT than in those without UIP pattern. Some studies reported that the coexistence of UIP pattern was not associated with prognosis in patients with IPPFE [6,13], but the differences of study cohorts, such as the severity of disease and frequency of coexistence of lower-lobe ILD may be contributing factors for these findings. Oda et al. reported that PPFE with histological UIP pattern was a distinct disease entity compared to IPF, and patients’ clinical characteristics included low BMI, hypercapnia, high RV/TLC, and high complication rates of pneumothorax, in addition to a trend of shorter
Fig. 1B. Survival curves for patients with IPPFE among three groups according to lower-lobe ILD. Patients with IPPFE with lower-lobe UIP pattern had significantly poor survival than those without lower-lobe ILD (log-rank test; p < 0.001) and worse prognosis than those with lower-lobe non-UIP pattern (log-rank test; p = 0.05). There is no statistical significance in terms of survival between patients with IPPFE with lower-lobe non-UIP pattern and those without lower-lobe ILD (logrank test; p = 0.44).
patients with IPPFE despite the rarity of the disease and evaluated the clinical features of 40 patients clinically diagnosed with IPPFE. In the study population, coexistence of lower-lobe ILD, especially UIP pattern on HRCT, was present in approximately half of the patients, and judged as an independent poor prognostic factor in these patients, which suggest the importance evaluating the lower-lobe ILD on HRCT in patients with IPPFE. Definitive diagnosis of IPPFE requires histological examination; however, the procedure was not performed in a substantial number of IPPFE cases due to unfavorable risk-effectiveness profile [8,19] considering several reasons such as severe pulmonary-function impairment due to advanced disease, risks related to the surgical procedure, including those of iatrogenic pneumothorax, and absence of effective treatment for IPPFE. In addition, clinical and radiological characteristics of patients with IPPFE are well known. Therefore, clinical diagnostic criteria for IPPFE based on modification of the radiological criteria of Reddy et al. [4], were proposed recently [6]. Validity of the
Table 4 Prognostic factors in patients with IPPFE by Cox proportional hazards analysis. Univariate analysis Hazard ratio
Age, years Male sex BMI, kg/m2 Desaturation KL-6, U/mL PaO2, Torr PaCO2, Torr FVC, % RV/TLC, % DLco, % Coexistence with lower-lobe ILDa on HRCT Coexistence with lower-lobe UIP pattern on HRCT APDT/TDT, % Pneumothorax
1.095 2.501 0.911 3.198 1.001 0.989 1.098 0.955 1.174 0.963 5.372 6.380 0.946 1.967
Multivariate analysis 95% CI
p-value
Lower
Upper
1.030 0.643 0.729 1.056 0.999 0.929 0.993 0.923 1.045 0.894 1.437 2.056 0.854 0.551
1.176 16.409 1.107 9.987 1.002 1.053 1.225 0.984 1.356 1.011 34.772 23.741 1.047 9.164
0.003 0.20 0.36 0.04 0.17 0.72 0.06 0.003 0.005 0.14 0.01 0.001 0.28 0.30
Hazard ratio
95% CI
p-value
Lower
Upper
1.057
0.989
1.139
0.10
0.931
0.882
0.972
< 0.001
6.306
1.508
32.693
0.01
IPPFE; idiopathic pleuroparenchymal fibroelastosis, BMI; body mass index, FVC; forced vital capacity, DLco: diffusion capacity for carbon monoxide, ILD; interstitial lung disease, HRCT; high-resolution computed tomography, UIP; usual interstitial pneumonia, APDT/TDT; the ratio of the anteroposterior diameter of the thoracic cage to the transverse diameter of the thoracic cage, CI; confidence interval. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8. 125
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survival time [16], which is in agreement with the results of our study. Our study defined lower-lobe UIP pattern as definite or probable UIP pattern on HRCT; most cases with these findings had UIP pattern histologically on SLB in the previous reports [17,23,24]. In contrast, patients with IPF may have features of PPFE at the lung apices. The guideline on IPF mentioned that these cases should be regarded as IPF after multidisciplinary discussion (MDD) [25]. Sugino et al. reported that cases of atypical IPF characterized by the coexistence of PPFE-like lesions or multiple cysts radiologically showed poor survival compared with those with typical IPF [26]. These data suggest that the existence of both PPFE and UIP pattern on radiologic and/or histologic assessment may be related to poor prognosis. The prognostic factors in patients with IPPFE have not been fully investigated. Previous reports demonstrated that low %FVC, high gender-age-physiology (GAP) index [22], presence of granuloma in histological findings [13], high level of serum KL-6 [14], and lowerlobe UIP pattern on HRCT [15] were associated with poor prognosis in patients with PPFE; in agreement, our study also revealed that low % FVC and coexistence of UIP pattern on HRCT were independent predictors of worse survival in these patients. Our study has several limitations. Retrospective study was conducted at a single center and small number of patients were included due to rarity of the disease. With regard to diagnosis of IPPFE, the clinical diagnostic criteria in this study have not been validated and only few patients were definitively diagnosed histologically; in addition, diagnosis of lower-lobe ILD was based on radiological classification without histological confirmation. In conclusion, the coexistence of lower-lobe ILD on HRCT, especially UIP pattern, could predict worse survival and should be routinely assessed in patients with clinically diagnosed IPPFE. Future study including a large cohort is needed to confirm the current findings.
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[22] M. Shioya, M. Otsuka, G. Yamada, Y. Umeda, K. Ikeda, H. Nishikiori, et al., Poorer prognosis of idiopathic pleuroparenchymal fibroelastosis compared with idiopathic pulmonary fibrosis in advanced stage, Can. Respir. J. 2018 (2018) 6043053. [23] G. Raghu, D. Lynch, J.D. Godwin, R. Webb, T.V. Colby, K.O. Leslie, et al., Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomized, controlled trial, Lancet Respir. Med. 2 (2014) 277–284. [24] J.H. Chung, A. Chawla, A.L. Peljto, C.D. Cool, S.D. Groshong, J.L. Talbert, et al., CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis, Chest 147 (2015) 450–459. [25] G. Raghu, M. Remy-Jardin, J.L. Myers, L. Richeldi, C.J. Ryerson, D.J. Lederer, et al., Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline, Am. J. Respir. Crit. Care Med. 198 (2018) e44–e68. [26] K. Sugino, H. Shimizu, Y. Nakamura, T. Isshiki, K. Matsumoto, S. Homma, Clinicoradiological features and efficacy of anti-fibrotic agents in atypical idiopathic pulmonary fibrosis, J. Thorac. Dis. 10 (2018) 899–908.
Financial disclosure The authors have nothing to disclose. Conflicts of interest The authors declare no conflict of interest related to this work. Funding source None. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] W.D. Travis, U. Costabel, D.M. Hansell, T.E. King Jr., D.A. Lynch, A.G. Nicholson, et al., An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 188 (2013) 733–748. [2] R. Amitani, A. Niimi, F. Kuse, Idiopathic pulmonary upper lobe fibrosis (IPUF),
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Clinical significance of lower-lobe interstitial lung disease on highresolution computed tomography in patients with idiopathic pleuroparenchymal fibroelastosis
T
Masato Konoa,*, Yuiko Fujitaa, Kenichiro Takedaa, Koichi Miyashitaa, Akari Tsutsumia, Takeshi Kobayashia, Yoshihiro Mikia, Dai Hashimotoa, Noriyuki Enomotob, Yutaro Nakamurab, Takafumi Sudab, Hidenori Nakamuraa a b
Seirei Hamamatsu General Hospital, Department of Pulmonary Medicine, Japan Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Pleuroparenchymal fibroelastosis Interstitial lung disease Usual interstitial pneumonia High-resolution computed tomography Prognostic factor
Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare form of idiopathic interstitial pneumonias (IIP) and may have other patterns of interstitial lung disease (ILD) in the lower lobe, such as usual interstitial pneumonia (UIP). However, the clinical significance of lower-lobe ILD in patients with IPPFE is unclear. Methods: A retrospective review of 40 consecutive patients with clinically diagnosed IPPFE in our institution from 2005 to 2016 was conducted. The presence of lower-lobe ILD on high-resolution computed tomography (HRCT) was assessed and classified into UIP or non-UIP pattern according to a modification of diagnostic criteria for idiopathic pulmonary fibrosis. Clinical characteristics and prognostic factors were evaluated. Results: Among the 40 patients with IPPFE, 21 (53%) had lower-lobe ILD, including 13 with UIP pattern and 8 with non-UIP pattern. Patients with IPPFE who had lower-lobe ILD had significantly older age, higher frequency of fine crackles, higher serum KL-6 level, lower residual volume (RV), and lower total lung capacity (TLC) than those without lower-lobe ILD. In addition, those with lower-lobe ILD, especially UIP pattern, had a significantly poorer survival than those without lower-lobe ILD (log-rank test; p = 0.014, p < 0.001, respectively). Multivariate Cox proportional hazards regression analysis revealed that low %forced vital capacity (%FVC) at baseline and coexistence of UIP pattern were significantly associated with poor prognosis in patients with IPPFE. Conclusions: The coexistence of lower-lobe ILD on HRCT, especially the UIP pattern, may predict poor survival in patients with IPPFE.
1. Introduction Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare form of idiopathic interstitial pneumonia (IIP) characterized by predominantly upper lobe pleural and subpleural lung parenchymal fibrosis [1]. Amitani et al. first reported this unique condition as idiopathic pulmonary upper lobe fibrosis (IPUF) in Japanese literature [2].
In 2004, Frankel et al. described five cases and named this condition as pleuroparenchymal fibroelastosis (PPFE) [3]. Although a consensus statement on IPPFE diagnosis is lacking, radiological and/or pathological findings are used in the diagnosis of IPPFE [4,5], and a recent report has been proposed the clinical diagnostic criteria [6]. IPPFE may have accompanied other patterns of interstitial lung disease (ILD) in the lower lobes [7,8]; previous cohort studies
Abbreviations: APDT/TDT, the ratio of anteroposterior diameter to transverse diameter of the thoracic cage; BMI, body mass index; CI, confidence interval; CT, computed tomography; DLco, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GAP, gender-age-physiology; HRCT, high-resolution computed tomography; IIPs, idiopathic interstitial pneumonias; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; IPPFE, idiopathic pleuroparenchymal fibroelastosis; IPUF, idiopathic pulmonary upper lobe fibrosis; ISA, immune suppressive agents; LTOT, long-term oxygen therapy; MDD, multidisciplinary discussion; mo, months; NPPV, noninvasive positive pressure ventilation; NSIP, non-specific interstitial pneumonia; PPFE, pleuroparenchymal fibroelastosis; PSL, prednisolone; PULF, pulmonary upper lobe fibrosis; RV, residual volume; SD, standard deviation; SLB, surgical lung biopsy; SP-D, surfactant protein-D; TLC, total lung capacity; UIP, usual interstitial pneumonia * Corresponding author. 2-12-12 Sumiyoshi, Hamamatsu, Shizuoka, 430-8558, Japan. E-mail address: [email protected] (M. Kono). https://doi.org/10.1016/j.rmed.2019.06.018 Received 10 April 2019; Received in revised form 21 May 2019; Accepted 18 June 2019 Available online 20 June 2019 0954-6111/ © 2019 Elsevier Ltd. All rights reserved.
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interpreted by radiologists in our institution at the time of diagnosis. Regarding the pattern of lower-lobe ILD, two trained pulmonologists independently reviewed all HRCT without clinical data and confirmed it in consensus. The ratio of the anteroposterior diameter to transverse diameter of the thoracic cage (APTD/TDT) at the level of the sixth thoracic vertebra was measured according to a previous report [18].
demonstrated that more than half of patients with IPPFE have lowerlobe ILD [4–15], especially of the usual interstitial pneumonia (UIP) pattern [4–8,11–15]. A study indicated that patients with PPFE with histologic UIP pattern had poor prognosis and tendency of worse prognosis than that of patients with idiopathic pulmonary fibrosis (IPF) [16]. Several reports described lower-lobe ILD in patients with IPPFE and evaluated its association with prognosis [6,13–16]; however, the clinical significance of lower-lobe ILD in patients with IPPFE is still unclear. The present study aimed to determine the clinical implications of lower-lobe ILD on HRCT in patients with IPPFE.
2.4. Statistical methods Chi-square test or Mann-Whitney U test were used to compare between two groups. The Kaplan-Meier method was used to estimate cumulative survival, and log-rank test was performed. Cox proportional hazards analysis was used to identify significant variables that could predict survival status. Statistical analyses were performed using JMP® 13 software (SAS Institute Inc., Cary, NC, USA). A p-value of 0.05 was considered significant.
2. Patients and methods 2.1. Patients and diagnostic criteria for IPPFE A retrospective review of 52 consecutive patients who were diagnosed with PPFE or IPUF in our institutions from 2005 to 2016 was conducted. Clinical diagnostic criteria of IPPFE [6] in this study were as follows; 1) a radiologic PPFE pattern on chest CT defined as bilateral subpleural dense consolidation with or without pleural thickening in the upper lobes and less marked or no involvement of the lower lobes; 2) radiologic confirmation of disease progression defined as an increase in the upper-lobe consolidation with or without pleural thickening and/ or a decrease in the upper-lobe volume on serial radiologic assessment; 3) exclusion of other lung diseases with identifiable etiologies (connective tissue disease-related ILD, chronic hypersensitivity pneumonitis, pulmonary sarcoidosis, pneumoconiosis, and active pulmonary infection); based on these criteria, 12 patients were excluded, of which, six had secondary PPFE with collagen tissue disease, one had chronic hypersensitivity pneumonia, three had no confirmation of disease progression radiologically, and two had inadequate clinical information. Finally, 40 patients with confirmed IPPFE were enrolled in the study. Histological criteria of PPFE [4] were applied in patients from whom lung specimens were obtained. The study protocol was approved by the ethics committee of Seirei Hamamatsu General Hospital (approval number: 2685). Requirement of patient approval or informed consent was waived because the study was designed as a retrospective review.
3. Results 3.1. Patient characteristics The clinical diagnostic criteria of IPPFE were fulfilled in all patients, and PPFE was confirmed histologically in four patients (10%) through autopsy (n = 3) and/or surgical lung biopsy (SLB; n = 2). The baseline characteristics of 40 patients with IPPFE are shown in Table 1. The mean age was 67.6 years, and male sex (65%) and non-smokers (60%) were predominant. Emaciation with low BMI (17.1 ± 2.9 kg/m2) and flattered chest were present in the majority of patients. Cough and/or dyspnea occurred in approximately 40% of patients, and high values of serum surfactant protein-D (SP-D) and PaCO2 were achieved in most patients. In the entire study population, 21 patients (52.5%) had coexistence of lower-lobe ILD on HRCT, of which 13 (32.5%) had UIP pattern, including typical UIP pattern (n = 6) and probable UIP pattern (n = 7), and 8 (20.0%) had non-UIP pattern, including non-specific interstitial Table 1 Clinical characteristics of patients with IPPFE with or without lower-lobe ILD on HRCT. All subjects (n = 40)
2.2. Data collection Clinical data including age, sex, smoking status, body mass index (BMI), symptoms, physiological findings, treatment for ILD, and outcome were obtained from the patients’ medical records; the results of laboratory and pulmonary function tests at the time of diagnosis were recorded. In pulmonary function tests, the percentages of predicted values for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1)/FVC, residual volume (RV), total lung capacity (TLC), RV/TLC and the diffusing capacity of carbon monoxide (DLco) were calculated according to the formulae of the Japanese Respiratory Society.
Age, years 67.6 ± 11.9 Male sex, n (%) 26 (65.0) Non-smoker, n 24 (60.0) (%) BMI, kg/m2 17.1 ± 2.9 Symptoms and physical findings Cough, n (%) 15 (37.5) Dyspnea, n (%) 15 (37.5) Fine crackles, n 9 (22.5) (%) Desaturation on 11 (27.5) effort, n (%) Laboratory findings KL-6, U/mL 518 ± 287 SP-D, ng/mL 195 ± 97 PaO2, Torr 80.7 ± 10.3 PaCO2, Torr 46.5 ± 6.8 HRCT findings APDT/TDT, % 54.4 ± 5.1
2.3. High-resolution computed tomography (HRCT) HRCT examination of the lungs was performed on sections of < 1.5mm thickness to evaluate radiographic abnormalities. Presence of lower-lobe ILD was assessed on all HRCT images included in the review. The lower-lobe ILD pattern was classified as UIP or non-UIP according to a modification of the Fleischner Society Idiopathic Pulmonary Fibrosis (IPF) Diagnostic Criteria [17]: lower-lobe UIP pattern on HRCT was defined as either typical UIP CT pattern (honeycombing with or without peripheral traction bronchiectasis or bronchiolectasis) or probable UIP CT pattern (subpleural reticular pattern with peripheral traction bronchiectasis or bronchiolectasis) [17]. Furthermore, lowerlobe non-UIP pattern was based on the American Thoracic Society/ European Respiratory Society classification of IIPs [1]. All HRCT were
IPPFE with lower-lobe ILDa (n = 21)
IPPFE without lower-lobe ILD (n = 19)
p-value
74.3 ± 9.3 15 (71.4) 12 (57.1)
60.2 ± 9.9 11 (57.9) 12 (63.2)
0.002 0.38 0.69
16.6 ± 2.6
17.6 ± 3.2
0.35
7 (33.3) 10 (47.6) 8 (38.1)
8 (42.1) 5 (26.3) 1 (5.2)
0.56 0.16 0.008
8 (38.1)
3 (15.7)
0.10
626 ± 337 217 ± 104 79.6 ± 10.4 46.2 ± 7.4
405 ± 168 173 ± 86 82.7 ± 10.2 47.0 ± 6.0
0.009 0.19 0.62 0.63
54.7 ± 5.3
54.1 ± 5.1
0.78
Data are shown as mean ± SD. IPPFE; idiopathic pleuroparenchymal fibroelastosis, ILD; interstitial lung disease, HRCT; high-resolution computed tomography, BMI; body mass index, SPD; surfactant protein D, APDT/TDT; the ratio of anteroposterior diameter to transverse diameter of the thoracic cage. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8. 123
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Table 2 Pulmonary function test findings in patients with IPPFE with or without lowerlobe ILD on HRCT.
FVC, L FVC, % FEV1, L FEV1/FVC, % RV, L RV, % TLC, L TLC, % RV/TLC, % DLco, mL/ min/ mmHg DLco, %
All subjects (n = 40)
IPPFE with lower-lobe ILDa (n = 21)
IPPFE without lower-lobe ILD (n = 19)
p-value
2.04 ± 0.94 65.6 ± 22.1 1.88 ± 0.86 92.4 ± 9.6 1.90 ± 0.54 117.2 ± 32.1 4.39 ± 1.34 85.0 ± 18.6 45.1 ± 8.9 15.4 ± 5.8
1.76 59.5 1.64 93.1 1.62 99.2 3.65 72.3 45.8 12.8
0.72 18.6 0.71 11.6 0.48 27.4 0.91 13.7 10.8 4.4
2.33 ± 1.07 71.1 ± 24.1 2.13 ± 0.95 91.7 ± 7.23 2.10 ± 0.50 130.7 ± 27.8 4.88 ± 1.39 93.5 ± 16.7 44.5 ± 7.6 17.2 ± 5.7
0.08 0.10 0.10 0.14 0.03 0.03 0.04 0.007 0.77 0.08
99.1 ± 25.1
97.6 ± 27.3
100.0 ± 24.7
0.81
± ± ± ± ± ± ± ± ± ±
Table 3 Treatment and outcome of patients with IPPFE with or without lower-lobe ILD on HRCT.
Observation periods, mo Treatment, n (%) PSL + ISAb Pirfenidone LTOT NPPV Complication Pneumothorax, n (%) Outcome All-cause deathc, n (%)
Data are shown as mean ± SD. IPPFE; idiopathic pleuroparenchymal fibroelastosis, ILD; interstitial lung disease, FVC; forced vital capacity, FEV1; forced expiratory volume in 1 s, RV; residual volume, TLC; total lung capacity, DLco; diffusing capacity for carbon monoxide. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8.
All subjects (n = 40)
IPPFE with lower-lobe ILDa (n = 21)
IPPFE without lower-lobe ILD (n = 19)
p-value
33.9 ± 31.1
31.4 ± 28.4
36.7 ± 34.3
0.54
2 (5.0) 4 (10.0) 10 (25.0) 2 (5.0)
2 3 7 1
(9.5) (14.3) (33.3) (4.7)
0 1 (5.3) 3 (15.7) 1 (5.2)
0.10 0.33 0.20 0.88
19 (47.5)
11 (52.3)
8 (42.1)
0.51
13 (32.5)
11 (52.4)
2 (10.5)
0.003
Data are shown as mean ± SD. IPPFE; idiopathic pleuroparenchymal fibroelastosis, ILD; interstitial lung disease, PSL; prednisolone, ISA: immune suppressive agents, LTOT; long-term oxygen therapy, mo; months, NPPV; non-invasive positive pressure ventilation. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8. b Cyclophosphamide; n = 1, cyclosporine A; n = 1. c Respiratory failure; n = 11, aspiration pneumonia; n = 2.
pneumonia (NSIP) pattern (n = 2), PPFE pattern (n = 2), and unclassifiable (n = 4). In the two patients with PPFE pattern in the lower lobe on HRCT, there was bilateral subpleural dense consolidation, predominantly in the upper lobe, and similar findings in the lower lobes. As shown in Table 1, patients with IPPFE with lower-lobe ILD had significantly older age, higher rate of fine crackles on chest auscultation, higher KL-6 level, and higher frequency of dyspnea and desaturation on effort than those without lower-lobe ILD. 3.2. Pulmonary function test findings Pulmonary function test findings in patients with IPPFE are shown in Table 2. Restrictive ventilatory impairment with decreased FVC and an increased ratio of RV to TLC were observed the majority of patients, whereas a trend of reduced FVC and significant decrease of both RV and TLC was observed in patients with IPPFE with lower-lobe ILD compared with those without lower-lobe ILD.
Fig. 1A. Survival curves for patients with IPPFE with or without lower-lobe ILD. Patients with IPPFE with lower-lobe ILD had significantly poor survival than those without lower-lobe ILD (log-rank test; P = 0.014).
3.3. Treatment and outcome Treatments for ILD and outcomes are shown in Table 3. During the observation period after the diagnosis of IPPFE was achieved (33.9 ± 31.1 months), long-term oxygen therapy (LTOT) was administered in 10 patients (25.0%) and non-invasive positive pressure ventilation (NPPV) was performed at home in two patients (5.0%). Complication of pneumothorax occurred in approximately half of the patients (47.5%), and mortality, in 13 patients (32.5%) due to chronic respiratory failure (n = 11) and aspiration pneumonia (n = 2). Despite no significant differences in the treatment of ILD between the two groups, the IPPFE with lower-lobe ILD group had a higher mortality rate than the IPPFE without lower-lobe ILD group (52.4% vs 10.5%, respectively).
among the three groups (log rank test; p = 0.002) (Fig. 1B); in IPPFE patients with UIP pattern, survival was significantly poorer as compared to the value attained in those without lower-lobe ILD (log-rank test; p < 0.001), and trend of worse prognosis than those with lowerlobe non-UIP pattern was observed (log-rank test; p = 0.05). 3.5. Prognostic factors Finally, prognostic factors were examined in the entire cohort (Table 4). In univariate Cox proportional hazards analysis, older age, desaturation on effort, low %FVC, and RV/TLC at baseline, and coexistence of lower-lobe ILD and UIP pattern on HRCT were related to poor prognosis. Moreover, in multivariate Cox proportional hazards analysis, low %FVC and coexistence of lower-lobe UIP pattern on HRCT were significantly associated with a poor prognosis.
3.4. Survival A comparison of survival curves for patients with IPPFE with or without lower-lobe ILD is shown in Fig. 1. Survival was significantly worse in patients with IPPFE with lower-lobe ILD compared with those without lower-lobe ILD (log-rank test; p = 0.014) (Fig. 1A). Especially, the mortality rate was the highest in IPPFE patients with UIP pattern
4. Discussion This retrospective study included a relatively large cohort of 124
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clinical diagnosis of IPPFE should be discussed; nevertheless, our patients had distinctive clinical characteristics as in those of the previous reports of IPPFE [2–16,18–22] regardless of the presence of lower-lobe ILD, and in some cases (10%), histological diagnosis of definitive IPPFE was made. Amitani et al. originally described IPUF as pure upper lobe-localized fibrosis, which is conceptually similar to IPPFE, and reported its slow progression with a prognosis of 10–20 years of survival after diagnosis [2]; however, recent studies have revealed that 50–100% of patients with IPPFE have coexisting ILD in other lobes, based on radiologically and/or histological findings [4–15], and worse prognosis [15,16,21]. Several studies reported that some patients with IPPFE developed lower-lobe ILD with disease progression [7,9,14], and/or rapid rate of progression [9]. Whereas disease progression and prognosis of IPPFE is highly variable, the differences in prognoses among previous studies may be associated with the frequency of a coexistence of lower-lobe ILD in patients with IPPFE. Regarding pattern of coexisting ILD in the lower lobe in patients with IPPFE, reports indicated UIP as the most common pattern radiologically and/or histologically [4–8,11–15], as well as other ILD patterns, such as NSIP [4,6,11,15], PPFE [4,6], organizing pneumonia [6] and unclassifiable pattern [4,6,11,14]. In the present study, UIP pattern on HRCT was most common and occurred in 61.9% of patients with lower-lobe ILD. Ishii et al. performed multicenter study including 52 patients with PPFE, and reported that UIP lesion in the lower lobes on CT images was more frequently observed in non-survivors than in survivors, suggesting that the presence of UIP pattern could play an important role in the prognosis of these patients [14]. Recently, Kato et al. reported that UIP pattern defined as definite UIP pattern on HRCT, in the lower lung lobes was an independent variable for poor prognosis in 36 patients clinically diagnosed with IPPFE [16], which supports the results of our study of worse prognosis in patients with IPPFE with UIP pattern on HRCT than in those without UIP pattern. Some studies reported that the coexistence of UIP pattern was not associated with prognosis in patients with IPPFE [6,13], but the differences of study cohorts, such as the severity of disease and frequency of coexistence of lower-lobe ILD may be contributing factors for these findings. Oda et al. reported that PPFE with histological UIP pattern was a distinct disease entity compared to IPF, and patients’ clinical characteristics included low BMI, hypercapnia, high RV/TLC, and high complication rates of pneumothorax, in addition to a trend of shorter
Fig. 1B. Survival curves for patients with IPPFE among three groups according to lower-lobe ILD. Patients with IPPFE with lower-lobe UIP pattern had significantly poor survival than those without lower-lobe ILD (log-rank test; p < 0.001) and worse prognosis than those with lower-lobe non-UIP pattern (log-rank test; p = 0.05). There is no statistical significance in terms of survival between patients with IPPFE with lower-lobe non-UIP pattern and those without lower-lobe ILD (logrank test; p = 0.44).
patients with IPPFE despite the rarity of the disease and evaluated the clinical features of 40 patients clinically diagnosed with IPPFE. In the study population, coexistence of lower-lobe ILD, especially UIP pattern on HRCT, was present in approximately half of the patients, and judged as an independent poor prognostic factor in these patients, which suggest the importance evaluating the lower-lobe ILD on HRCT in patients with IPPFE. Definitive diagnosis of IPPFE requires histological examination; however, the procedure was not performed in a substantial number of IPPFE cases due to unfavorable risk-effectiveness profile [8,19] considering several reasons such as severe pulmonary-function impairment due to advanced disease, risks related to the surgical procedure, including those of iatrogenic pneumothorax, and absence of effective treatment for IPPFE. In addition, clinical and radiological characteristics of patients with IPPFE are well known. Therefore, clinical diagnostic criteria for IPPFE based on modification of the radiological criteria of Reddy et al. [4], were proposed recently [6]. Validity of the
Table 4 Prognostic factors in patients with IPPFE by Cox proportional hazards analysis. Univariate analysis Hazard ratio
Age, years Male sex BMI, kg/m2 Desaturation KL-6, U/mL PaO2, Torr PaCO2, Torr FVC, % RV/TLC, % DLco, % Coexistence with lower-lobe ILDa on HRCT Coexistence with lower-lobe UIP pattern on HRCT APDT/TDT, % Pneumothorax
1.095 2.501 0.911 3.198 1.001 0.989 1.098 0.955 1.174 0.963 5.372 6.380 0.946 1.967
Multivariate analysis 95% CI
p-value
Lower
Upper
1.030 0.643 0.729 1.056 0.999 0.929 0.993 0.923 1.045 0.894 1.437 2.056 0.854 0.551
1.176 16.409 1.107 9.987 1.002 1.053 1.225 0.984 1.356 1.011 34.772 23.741 1.047 9.164
0.003 0.20 0.36 0.04 0.17 0.72 0.06 0.003 0.005 0.14 0.01 0.001 0.28 0.30
Hazard ratio
95% CI
p-value
Lower
Upper
1.057
0.989
1.139
0.10
0.931
0.882
0.972
< 0.001
6.306
1.508
32.693
0.01
IPPFE; idiopathic pleuroparenchymal fibroelastosis, BMI; body mass index, FVC; forced vital capacity, DLco: diffusion capacity for carbon monoxide, ILD; interstitial lung disease, HRCT; high-resolution computed tomography, UIP; usual interstitial pneumonia, APDT/TDT; the ratio of the anteroposterior diameter of the thoracic cage to the transverse diameter of the thoracic cage, CI; confidence interval. a Usual interstitial pneumonia (UIP) pattern; n = 13, Non-UIP pattern; n = 8. 125
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survival time [16], which is in agreement with the results of our study. Our study defined lower-lobe UIP pattern as definite or probable UIP pattern on HRCT; most cases with these findings had UIP pattern histologically on SLB in the previous reports [17,23,24]. In contrast, patients with IPF may have features of PPFE at the lung apices. The guideline on IPF mentioned that these cases should be regarded as IPF after multidisciplinary discussion (MDD) [25]. Sugino et al. reported that cases of atypical IPF characterized by the coexistence of PPFE-like lesions or multiple cysts radiologically showed poor survival compared with those with typical IPF [26]. These data suggest that the existence of both PPFE and UIP pattern on radiologic and/or histologic assessment may be related to poor prognosis. The prognostic factors in patients with IPPFE have not been fully investigated. Previous reports demonstrated that low %FVC, high gender-age-physiology (GAP) index [22], presence of granuloma in histological findings [13], high level of serum KL-6 [14], and lowerlobe UIP pattern on HRCT [15] were associated with poor prognosis in patients with PPFE; in agreement, our study also revealed that low % FVC and coexistence of UIP pattern on HRCT were independent predictors of worse survival in these patients. Our study has several limitations. Retrospective study was conducted at a single center and small number of patients were included due to rarity of the disease. With regard to diagnosis of IPPFE, the clinical diagnostic criteria in this study have not been validated and only few patients were definitively diagnosed histologically; in addition, diagnosis of lower-lobe ILD was based on radiological classification without histological confirmation. In conclusion, the coexistence of lower-lobe ILD on HRCT, especially UIP pattern, could predict worse survival and should be routinely assessed in patients with clinically diagnosed IPPFE. Future study including a large cohort is needed to confirm the current findings.
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Financial disclosure The authors have nothing to disclose. Conflicts of interest The authors declare no conflict of interest related to this work. Funding source None. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] W.D. Travis, U. Costabel, D.M. Hansell, T.E. King Jr., D.A. Lynch, A.G. Nicholson, et al., An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 188 (2013) 733–748. [2] R. Amitani, A. Niimi, F. Kuse, Idiopathic pulmonary upper lobe fibrosis (IPUF),
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