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Original Research Diffuse Lung Disease
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Distinct Characteristics of Pleuroparenchymal Fibroelastosis With Usual Interstitial Pneumonia Compared With Idiopathic Pulmonary Fibrosis Tsuneyuki Oda, MD; Takashi Ogura, MD; Hideya Kitamura, MD, PhD; Eri Hagiwara, MD, PhD; Tomohisa Baba, MD; Yasunori Enomoto, MD; Tae Iwasawa, MD, PhD; Koji Okudela, MD, PhD; Tamiko Takemura, MD, PhD; Fumikazu Sakai, MD, PhD; and Yoshinori Hasegawa, MD, PhD, FCCP
BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia and sometimes coexists with a histologic usual interstitial pneumonia (UIP) pattern. This study aimed to describe the distinct clinical features of PPFE with UIP pattern compared with idiopathic pulmonary fibrosis (IPF).
We conducted a retrospective review of the medical records of 110 consecutive patients with IPF with a histologic UIP pattern on surgical lung biopsy specimen. Patients meeting radiologic criteria for the diagnosis of PPFE based on high-resolution CT scan and with a histologic UIP pattern were included.
METHODS:
Nine of eleven patients meeting radiologic criteria for the diagnosis of PPFE were histologically confirmed as having PPFE with UIP pattern. The PPFE with UIP pattern group showed a significantly higher residual volume (1.8 L vs 1.3 L, P , .01), higher Paco2 (44.6 mm Hg vs 41.7 mm Hg, P 5 .04), and higher complication rate of pneumothorax and pneumomediastinum than the 99 patients with IPF/UIP. The ratio of anteroposterior to transthoracic diameter in patients with PPFE with UIP pattern was significantly lower than that in patients with IPF/UIP (P 5 .04). Survival time tended to be shorter in patients with PPFE with UIP pattern.
RESULTS:
The results support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP and may well be classified as PPFE. CHEST 2014; 146(5):1248-1255
CONCLUSIONS:
Manuscript received December 4, 2013; revision accepted May 26, 2014; originally published Online First June 19, 2014. ABBREVIATIONS: APDT 5 anteroposterior diameter of the thorax; ATS 5 American Thoracic Society; ERS 5 European Respiratory Society; HRCT 5 high-resolution CT; IPF 5 idiopathic pulmonary fibrosis; PPFE 5 pleuroparenchymal fibroelastosis; RV 5 residual volume; TDT 5 transthoracic diameter of the thorax; TLC 5 total lung capacity; UIP 5 usual interstitial pneumonia AFFILIATIONS: From the Department of Respiratory Medicine (Drs Oda, Ogura, Kitamura, Hagiwara, Baba, and Enomoto) and Department of Radiology (Dr Iwasawa), Kanagawa Cardiovascular and Respiratory Center, Yokohama; Department of Pathobiology (Dr Okudela), Yokohama City University Graduate School of Medicine, Yokohama; Department of Pathology (Dr Takemura), Japan Red Cross Medical Center, Tokyo; Department of Diagnostic Radiology (Dr Sakai), Inter-
1248 Original Research
national Medical Center of Saitama Medical University, Saitama; and Department of Respiratory Medicine (Drs Oda and Hasegawa), Nagoya University Graduate School of Medicine, Nagoya, Japan. FUNDING/SUPPORT: This study was supported in part by a grant-in-aid for interstitial lung diseases from the Japanese Ministry of Health, Labor and Welfare [Grant H23-Nanchi-Ippan-023]. CORRESPONDENCE TO: Takashi Ogura, MD, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomioka-higashi, Kanazawa-ku, Yokohama 236-0051, Japan; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2866
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Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia. In 2004, five cases were reported of a unique idiopathic pleuroparenchymal lung disease characterized by a chronic idiopathic interstitial pneumonia with upper lobe-predominant marked pleural and parenchymal involvement.1 The disease shares common features with idiopathic pulmonary upper lobe fibrosis proposed by Amitani et al.2 Since, several case reports of PPFE have been published,3-13 but no consensus has been reached regarding disease entity, characteristics, and diagnostic criteria. Lobar histologic variability is frequent in patients with idiopathic interstitial pneumonia, and multiple histologic and high-resolution CT (HRCT) image patterns may coexist in the same patient. Cases with coexisting usual interstitial pneumonia (UIP) pattern and fibrotic nonspecific interstitial pneumonia pattern named as discordant UIP appear to behave similarly to those of
Materials and Methods Study Population We retrospectively reviewed medical records of 291 consecutive patients with idiopathic interstitial pneumonia who underwent surgical lung biopsy between January 2001 and December 2011 at Kanagawa Cardiovascular and Respiratory Center. Included were 110 consecutive patients with IPF diagnosed according to the 2002 ATS/ERS statement,18 with histologic UIP pattern shown in the biopsy specimen from the lower lobe. This study was approved by an institutional review board of Kanagawa Cardiovascular and Respiratory Center (approval number 24-14). Radiologic Criteria for PPFE Two expert pulmonary radiologists (T. I. and F. S.) identified patients according to the following radiologic criteria for the diagnosis of PPFE as previously reported in the literature16 and without knowledge of their clinical background or histologic findings:
concordant UIP.14,15 One study on PPFE reported that HRCT imaging could show other interstitial lung disease patterns in other locations in some patients.16 Indeed, specimens from patients with PPFE occasionally show a UIP pattern in the lower lobe (ie, PPFE with UIP pattern). Because PPFE with UIP pattern is regarded as inconsistent with UIP on HRCT scan and as UIP by histopathologic analysis, it is considered possible idiopathic pulmonary fibrosis (IPF) in accordance with the 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/Latin American Thoracic Association official statement on IPF.17 However, whether this diagnosis is appropriate when PPFE coexists with UIP pattern is not clear. This retrospective study has two objectives: to define the clinical and radiologic features of PPFE with UIP pattern compared with IPF/UIP by identifying PPFE with UIP pattern from surgically proven IPF/UIP and to determine whether PPFE with UIP pattern is a disease entity distinct from IPF/UIP.
bacterial infection, and connective tissue disease-related lung disease on biopsy specimens were excluded. Histologic UIP pattern was diagnosed according to the 2002 ATS/ERS consensus classification of idiopathic interstitial pneumonias.18 Histologic criteria for the diagnosis of PPFE were previously described in the literature as follows16: • Definite PPFE: upper zone pleural fibrosis with subjacent intraalveolar fibrosis accompanied by alveolar septal elastosis. • Consistent with PPFE: intraalveolar fibrosis present but (1) not associated with pleural fibrosis, (2) not predominantly beneath the pleura, or (3) not observed in an upper lobe biopsy specimen. • Inconsistent with PPFE: lacking the requisite features just described. If the two pathologists disagreed, the final diagnosis was reached by consensus. In this study, only patients with definite or consistent with PPFE by histologic criteria were included.
• Definite PPFE: demonstrating pleural thickening with associated subpleural fibrosis concentrated in the upper lobes, with involvement of lower lobes being less marked or absent. • Consistent with PPFE: upper lobe pleural thickening with associated subpleural fibrosis present, but (1) distribution of these changes not concentrated in the upper lobes or (2) features of coexistent disease present elsewhere. • Inconsistent with PPFE: lacking the requisite features just described. In this study, only patients with definite or consistent with PPFE by radiologic criteria were included. If the two radiologists disagreed, the final diagnosis was reached by consensus. HRCT scan had been performed within 2 months before surgical lung biopsy.
Clinical and Radiologic Review The pulmonologists reviewed the medical records, pulmonary function data, and laboratory data, analyzing pulmonary function data obtained within 6 months before surgical lung biopsy. Radiologic features such as dense subpleural consolidation, honeycombing, and degree of flattened thoracic cage were also analyzed. The anteroposterior diameter of the thorax (APDT) was measured on HRCT scan as the longest distance of the anterior-posterior dimension of the thoracic cage at the level of the sixth thoracic vertebra.19 The transthoracic diameter of the thorax (TDT) was measured as the longest transverse diameter of the thoracic cage at the level of the sixth thoracic vertebra.19 The ratio of anteroposterior to transthoracic diameter was then derived. Survival analysis was performed from the time of initial consultation. Patients with clinical connective tissue disease, autoimmune disease, or hypersensitivity pneumonitis were excluded.
Histologic Criteria for PPFE Surgical biopsies of multiple lobes were performed in all patients. All available slides were reviewed independently by two expert pulmonary pathologists (K. O. and T. T.) who were not aware of the clinical and radiologic findings for the patients. Patients with a possibility of chronic hypersensitivity pneumonitis, pneumoconiosis, fungal or myco-
Statistical Analysis Data are presented as mean ⫾ SD unless otherwise stated. Fisher exact test or Mann-Whitney U test was used for between-group comparisons as appropriate. Survival time from initial consultation was analyzed by the Kaplan-Meier method and log-rank test, with the end points being death or last contact. P , .05 was considered significant.
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1250 Original Research
[
Dead Dead Dead Alive Outcome
Dead
42.7
Normal Restrictive
28.3 24.3
Restrictive Restrictive
31.5 29.6
Restrictive
Survival, mo
PFT
None
None None
None None
None None None
Sister Mother/aunt Family history
Autoantibody
PT
10 Never
PM PT/PM
Never Never
PT PT
33
PT or PM
Smoking history, pack-y
Male
Cough Cough
Female Male
Cough/DOE Cough Symptoms
Female Male
Cough
Sex
5
69 71
4 3
65 64
2 1
46
Characteristic
Chest HRCT images and histopathology of a typical case, patient 8, are shown in Figures 1 and 2. An HRCT image in the coronal plane showed bilateral dense subpleural consolidation. Upper lobe volume loss and hilar elevation were observed bilaterally. Less marked subpleural reticulation and ground glass opacities were observed in the lower lobes. Biopsy specimens from the upper lobe revealed subpleural fibroelastosis and abrupt transition from fibroelastosis to normal lung parenchyma, with no evidence of pleural fibrosis. A UIP pattern was seen in the lower lobe.
Age, y
Imaging and Histopathology of PPFE With UIP Pattern
] Clinical Characteristics in Nine Patients With PPFE With UIP Pattern
Biopsy specimens from multiple lobes were performed in the nine patients. The histology of all patients with PPFE with UIP pattern showed subpleural fibroelastosis and intraalveolar fibrosis in the upper lobes and UIP pattern in the lower lobes. Six had histologic UIP features along with PPFE in the upper lobes. Pleural fibrosis was present in two patients.
TABLE 1
The clinical features of the nine patients (five men) with PPFE with UIP pattern are described in Table 1. Median age was 64 years (range, 46-71 years) at the time of biopsy. Four patients died of respiratory failure between 24.3 and 42.7 months after the initial evaluation. Spontaneous pneumothorax or pneumomediastinum developed in six patients during the follow-up period. None of the patients had a significant history of anticancer drug therapy, radiotherapy, bone marrow transplantation, or connective tissue disorders.
Patient
Clinical Findings in the Nine Patients With PPFE With UIP Pattern
DOE 5 dyspnea on exertion; PFT 5 pulmonary function test; PM 5 pneumomediastinum; PPFE 5 pleuroparenchymal fibroelastosis; PT 5 pneumothorax; UIP 5 usual interstitial pneumonia.
Alive Alive Alive Alive
Normal
30.8 14.9
Restrictive Restrictive
24.7 47.8
Normal
None
Mother/sister None
None None
None None
None
None
Never Never
PT None
7 23
None
DOE
9
Female Female
Cough DOE
Male Male
Check up
65
8 7 6
53
Eleven of the 110 consecutive patients with IPF met radiologic criteria for PPFE. Of these, nine fulfilled the histologic criteria of PPFE. Two patients were excluded because their upper lobe biopsy specimens showed marked interstitial inflammatory cell infiltrates within the intraalveolar fibrosis, and we found it difficult to completely rule out other interstitial pneumonia, such as connective tissue disease-related UIP. Accordingly, the nine patients meeting both radiologic and histologic criteria for PPFE comprised the final study group. The remaining 99 patients were given a diagnosis of IPF/UIP after multidisciplinary discussion among radiologists, pathologists, and pulmonologists.
64
Patient Identification
60
Results
146#5 CHEST NOVEMBER 2014
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Figure 1 – High-resolution CT imaging of patient 8, a 65-y-old woman. A, Coronal image showing bilateral, apical, irregular pleural thickening. B, Subpleural thickening with fibrotic changes in the upper lobes. C, Less marked subpleural reticulation and ground glass opacities in the lower lobes.
Clinical, Laboratory, and Radiologic Findings of PPFE With UIP Pattern Compared With IPF/UIP
The clinical characteristics of the nine patients with PPFE with UIP pattern were compared with those of the 99 patients with IPF/UIP and are summarized in Table 2. Age, sex, and symptoms at initial consultation were not significantly different between the groups. Significant differences were observed in terms of BMI (P , .01) and complication rates of pneumothorax or pneumomediastinum (P 5 .01) between the groups. These complications all occurred during the follow-up period.
Radiologic findings in patients with PPFE with UIP pattern and those with IPF/UIP are shown in Table 3. The ratio of APDT to TDT was significantly lower in patients with PPFE with UIP pattern than in those with IPF/UIP (P 5 .04). The presence of honeycombing was not significantly different between the groups. Physiologic testing indicated that % predicted diffusing capacity of lung for carbon monoxide was not decreased in the PPFE group in contrast to a significant decrease observed in the IPF group (P , .01) (Table 4). Compared with the IPF group, the PPFE group showed
Figure 2 – Histopathologic findings in patient 8. A, A biopsy specimen from the upper lobe at low-power magnification shows subpleural fibroelastosis and abrupt transition from fibroelastosis to normal lung parenchyma (hematoxylin-eosin staining). B, A biopsy specimen from the upper lobe at high-power magnification shows an abundance of elastic fiber (elastic van Gieson staining); however, there was no evidence of pleural fibrosis. C and D, A biopsy specimen from the lower lobe at lowpower magnification (hematoxylineosin staining) (C) and high-power magnification (hematoxylin-eosin staining) (D) shows subpleural fibrosis and fibroblastic foci adjacent to established fibrosis.
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TABLE 2
] Clinical Characteristics in Patients With PPFE With UIP Pattern and Those With IPF/UIP
Characteristic
PPFE With UIP Pattern (n 5 9)
IPF/UIP (n 5 99)
64 (46-71)
67 (37-80)
.26
5
76
.22
5
23
Median age (range), y Male sex Smoking history
.049
Never Former and current, pack-y BMI, kg/m
2
P Value
4 (18 ⫾ 12)
76 (41 ⫾ 28)
18.6 ⫾ 1.8
25.1 ⫾ 3.6
, .01
Initial symptoms Cough
5
34
.28
DOE
2
18
.67
DOE and cough
1
22
.68
No symptoms
1
22
.68
Clubbing
0
22
.20
PT/PM
6
23
.01
Acute exacerbation
1
23
.68
Data are presented as counts or mean ⫾ SD unless otherwise indicated. IPF 5 idiopathic pulmonary fibrosis. See Table 1 legend for expansion of other abbreviations.
higher residual volume (RV) and ratio of RV to total lung capacity (TLC). The PPFE group also showed significantly higher Paco2 (P 5 .04). In contrast, alveolararterial oxygen tension differences were within the normal range in the PPFE group. The PPFE group had lower levels of serum biomarkers, such as Krebs von den Lungen-6, than the IPF group. BAL fluid yielded lower cell counts in the PPFE group. No significant difference was found between groups in cell fraction and the CD4/ CD8 ratio. Survival Analysis of PPFE With UIP Pattern and IPF/UIP
Survival analysis in patients with PPFE with UIP pattern compared with patients with IPF/UIP is shown in Figure 3. The median survival time was 31.5 and 82.1 months, respectively. Although the survival time tended to be TABLE 3
shorter in the PPFE group, the difference was not significant (P 5 .13).
Discussion To our knowledge, this study is the first to describe the clinical characteristics of PPFE with UIP pattern compared with IPF/UIP. We identified nine patients with PPFE with UIP pattern among 110 consecutive patients with surgically proven IPF/UIP diagnosed according to the 2002 ATS/ERS statement.18 We identified three characteristic features of PPFE with UIP pattern. Compared with patients with IPF/UIP, patients with PPFE with UIP pattern had (1) a higher complication rate of pneumothorax or pneumomediastinum and lower BMI; (2) a flattened chest (ie, lower APDT/TDT ratio); and (3) distinct features of pulmonary function in the form of restrictive pattern and alveolar hypoventilation, including
] Radiologic Findings of Patients With PPFE With UIP Pattern and Those of IPF/UIP
Characteristic
PPFE With UIP Pattern (n 5 9)
IPF/UIP (n 5 99)
P Value
Image ¿nding Dense subpleural consolidation
9
30
, .01
Honeycombing
2
25
.07
APDT, cm
13.2 ⫾ 1.4
14.7 ⫾ 1.2
, .01
TDT, cm
22.7 ⫾ 1.9
23.1 ⫾ 1.5
.49
APDT/TDT, %
58.4 ⫾ 6.8
63.8 ⫾ 5.6
.04
Thoracic dimensions
Data are presented as counts or mean ⫾ SD. APDT 5 anteroposterior diameter of the thorax; TDT 5 transverse diameter of the thorax. See Table 1 and 2 legends for expansion of other abbreviations.
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TABLE 4
] Pulmonary Function, Arterial Blood Gas Analysis, Laboratory Data, and BAL Fluid Findings in Patients With PPFE With UIP Pattern and Those With IPF/UIP
Parameter
PPFE With UIP Pattern (n 5 9)
IPF/UIP (n 5 99)
76.5 ⫾ 15.0
80.8 ⫾ 16.8
.36
P Value
Pulmonary function FVC, % predicted FEV1, % predicted
90.1 ⫾ 19.1
90.4 ⫾ 18.7
.79
FEV1/FVC ratio
87.1 ⫾ 7.8
82.3 ⫾ 6.8
.08
DLCO, mL/min/mm Hg
17.5 ⫾ 5.7
DLCO, % predicted
14.2 ⫾ 4.2
109 ⫾ 25.5
78.7 ⫾ 20.5
.12 , .01
DLCO/VA, mL/min/mm Hg/L
5.1 ⫾ 0.8
4.6 ⫾ 1.1
.16
DLCO/VA, % predicted
111 ⫾ 15.9
101 ⫾ 23.7
.16
92.4 ⫾ 18.1
79.5 ⫾ 15.4
1.8 ⫾ 0.5
1.3 ⫾ 0.4
, .01
42.6 ⫾ 8.7
33.1 ⫾ 7.6
, .01
pH
7.39 ⫾ 0.02
7.41 ⫾ 0.02
.12
PaO2, mm Hg
87.2 ⫾ 10.7
81.0 ⫾ 8.2
.15
PaCO2, mm Hg
44.6 ⫾ 4.1
41.7 ⫾ 3.5
.04
7.7 ⫾ 6.3
16.8 ⫾ 8.9
, .01
TLC, % predicted RV, L RV/TLC, %
.05
Blood gas test
P(A-a)O2, mm Hg Laboratory data LDH, International Units/L
238 ⫾ 32.2
KL-6, International Units/mL
600 ⫾ 340
SP-D, ng/mL
177 ⫾ 86.7
238 ⫾ 53.3
.64
1213 ⫾ 784
, .01
299 ⫾ 233
.09
BAL Àuid ¿ndings Cell count, 3 104/mL
10.5 ⫾ 3.5
24.8 ⫾ 18.7
, .01
Macrophages, %
70.3 ⫾ 20.2
77.4 ⫾ 18.0
.36
Neutrophils, %
5.0 ⫾ 4.1
3.8 ⫾ 6.4
.14
22.0 ⫾ 19.5
15.6 ⫾ 15.5
.31
Eosinophils, %
2.6 ⫾ 3.0
2.8 ⫾ 4.2
.95
CD4/CD8 ratio
2.7 ⫾ 1.8
2.4 ⫾ 2.3
.34
Lymphocytes, %
Data are presented as mean ⫾ SD. DLCO 5 diffusing capacity of lung for carbon monoxide; KL-6 5 Krebs von den Lungen-6; LDH 5 lactate dehydrogenase; P(A-a)O2 5 alveolar-arterial oxygen tension difference; RV 5 residual volume; SP-D 5 surfactant protein-D; TLC 5 total lung capacity; VA 5 alveolar volume. See Table 1 and 2 legends for expansion of other abbreviations.
an increased RV/TLC ratio and Paco2. The results define the clinical and radiologic characteristics of PPFE with UIP pattern and support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP. A higher complication rate of pneumothorax or pneumomediastinum in the PPFE group was consistent with the results of previously published reports.1,2,4,11,12,16 It is true that findings similar to PPFE could be observed as sequelae of ordinary spontaneous pneumothorax. However, all the patients experienced pneumothorax or pneumomediastinum after the initial visit, and it is unlikely that the pneumothorax caused PPFE. journal.publications.chestnet.org
Flattened chest is a characteristic finding in idiopathic pulmonary upper lobe fibrosis and PPFE in the literature.2,13 It is also reported that the thoracic cage becomes flattened in the progression of PPFE.19,20 The present study showed that the APDT/TDT ratio and APDT in the PPFE group were lower than those in the IPF group. In addition, despite the PPFE group having upper lobe volume loss, TLC was increased in the PPFE group compared with the IPF group. These results imply that upper lobe volume loss led to flattened chest and the compensatory hyperinflation of the middle and lower lobes in the PPFE group. Respiratory function in PPFE with UIP pattern was characterized by a restrictive pattern and alveolar hypoventilation, 1253
The histopathologic features of PPFE, such as intraalveolar fibrosis and elastosis, correspond to the presence of an apical cap.24,25 Patients with PPFE with UIP pattern showed dense subpleural consolidation with more diffuse distribution in biopsy specimens not from the apex but mainly from the posterior segment in which apical cap is not usually observed. In addition, we confirmed progressive upper lobe volume loss in some patients, which is inconsistent with the natural course of the apical cap.
Figure 3 – Kaplan-Meier distribution of survival time in patients with PPFE with UIP pattern vs those with IPF/UIP. IPF 5 idiopathic pulmonary fibrosis; PPFE 5 pleuroparenchymal fibroelastosis; UIP 5 usual interstitial pneumonia.
as indicated by the increased RV/TLC ratio and Paco2. Although both the IPF and the PPFE groups showed a restrictive pattern, some differences existed. In the IPF group both TLC and RV were decreased as expected. In the PPFE group, however, TLC was somewhat decreased, whereas RV was increased. Because this type of restrictive change is common in patients with neuromuscular disorders or pleural diseases, there is a strong possibility that lung movement is being restricted in patients with PPFE with UIP pattern. In this study, none of the patients had neuromuscular or neurologic complications. It is possible that pleural and subpleural thickening causes restricted lung movement in patients with PPFE with UIP pattern, resulting in alveolar hypoventilation. The survival time tended to be shorter in patients with PPFE with UIP pattern than in patients with IPF/UIP. In the four patients who died, the cause of death was chronic respiratory failure with recurrent pneumothorax or pneumomediastinum; the incidence of pneumothorax or pneumomediastinum was significantly higher in the PPFE group. Pneumothorax in patients with IPF/UIP is reportedly associated with rapid deterioration on HRCT imaging21 and poor prognosis.22 Moreover, the PPFE group had a lower BMI than the IPF group. Low BMI at IPF diagnosis has been associated with poor prognosis.23 The present observation of poorer survival outcome in the PPFE group can be explained in the same way.
1254 Original Research
In the present study, the clinical and radiologic features of PPFE with UIP pattern were similar to those previously reported for PPFE. In the 2011 ATS/ERS/ Japanese Respiratory Society/Latin American Thoracic Association statement,17 upper or mid-lung-predominant distribution is one of the seven features of inconsistent with UIP on HRCT imaging. PPFE with UIP pattern has been judged inconsistent with UIP on HRCT imaging and as UIP by histopathologic analysis and then considered possible IPF. A certain number of patients with this disease may have been given a diagnosis of IPF/UIP. In a recently published ATS/ERS statement on the classification of idiopathic interstitial pneumonias, PPFE was mentioned for the first time, to our knowledge, as a rare form of independent idiopathic interstitial pneumonia.26 The present results show that the characteristics of PPFE with UIP pattern more closely resemble those previously reported for PPFE than those for IPF/UIP and support the idea that this disease is distinct from IPF/UIP and classifiable as PPFE. This study has several limitations. It was a singlecenter retrospective study, and the number of patients with PPFE with UIP pattern was small. However, PPFE is a rare form of interstitial lung disease, and, thus, prospective studies will prove difficult. Moreover, the patients with IPF/UIP in this study had a longer survival time compared with previous reports.17 A possible reason is that the present study only included patients able to undergo surgical lung biopsy; therefore, the survival result for IPF/UIP may exclude the more severe cases. In conclusion, the results support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP. It may well be classified as PPFE rather than UIP.
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Acknowledgments Author contributions: T. Oda had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. T. Ogura contributed to the study concept and design, data analysis and interpretation, and final approval of the manuscript; H. K. and Y. H. contributed to the study concept and design and submission of the manuscript; E. H. contributed to the data collection, organization, and analysis and preparation, review, writing, and submission of the manuscript; and T. B., Y. E., T. I., K. O., T. T., and F. S. contributed to the data collection, organization, and analysis and preparation, review, and submission of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Others contributions: Editorial assistance was provided by Stephen L. Nishimura, PhD, Department of Pathology, University of California, San Francisco, California.
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6. Becker CD, Gil J, Padilla ML. Idiopathic pleuroparenchymal fibroelastosis: an unrecognized or misdiagnosed entity? Mod Pathol. 2008;21(6):784-787. 7. Nei T, Kawamoto M, Satoh E, et al. A case of suspected idiopathic pulmonary upper lobe fibrosis (Amitani disease) with acute exacerbation [in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2009;47(2):116-121. 8. Morimoto A, Mochizuki Y, Nakahara Y, Kawamura T, Sakaki S, Kobashi Y. Case of idiopathic pulmonary upper lobe fibrosis [in Japanese]. Nihon Kokyuki Gakkai Zasshi. 2010;48(12):944-949. 9. von der Thüsen JH, Hansell DM, Tominaga M, et al. Pleuroparenchymal fibroelastosis in patients with pulmonary disease secondary to bone marrow transplantation. Mod Pathol. 2011;24(12):1633-1639. 10. Piciucchi S, Tomassetti S, Casoni G, et al. High resolution CT and histological findings in idiopathic pleuroparenchymal fibroelastosis: features and differential diagnosis. Respir Res. 2011;12(1):111. 11. Watanabe K, Nagata N, Kitasato Y, et al. Rapid decrease in forced vital capacity in patients with idiopathic pulmonary upper lobe fibrosis. Respir Investig. 2012;50(3):88-97. 12. Kusagaya H, Nakamura Y, Kono M, et al. Idiopathic pleuroparenchymal fibroelastosis: consideration of a clinicopathological entity in a series of Japanese patients. BMC Pulm Med. 2012;12:72. 13. Iesato K, Ogasawara T, Masuda A, et al. Idiopathic pulmonary upper lobe fibrosis; clinical and pathological features [in Japanese]. Rinsho Hoshasen. 2005;50(1):13-25. 14. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164(9):1722-1727. 15. Monaghan H, Wells AU, Colby TV, du Bois RM, Hansell DM, Nicholson AG. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest. 2004;125(2):522-526. 16. Reddy TL, Tominaga M, Hansell DM, et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J. 2012;40(2):377-385.
17. Raghu G, Collard HR, Egan JJ, et al; ATS/ ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011; 183(6):788-824. 18. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 20001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002;165(2): 277-304. 19. Harada T, Yoshida Y, Kitasato Y, et al. The thoracic cage becomes flattened in the progression of pleuroparenchymal fibroelastosis. Eur Respir Rev. 2014;23(132):263-266. 20. Watanabe K. Pleuroparenchymal fibroelastosis: its clinical characteristics. Curr Respir Med Rev. 2013;9:229-237. 21. Iwasawa T, Ogura T, Takahashi H, et al. Pneumothorax and idiopathic pulmonary fibrosis. Jpn J Radiol. 2010;28(9): 672-679. 22. Picado C, Gómez de Almeida R, Xaubet A, Montserrat J, Letang E, Sánchez-Lloret J. Spontaneous pneumothorax in cryptogenic fibrosing alveolitis. Respiration. 1985;48(1):77-80. 23. Kim JH, Lee JH, Ryu YJ, Chang JH. Clinical predictors of survival in idiopathic pulmonary fibrosis. Tuberc Respir Dis (Seoul). 2012;73(3):162-168. 24. Butler C II, Kleinerman J. The pulmonary apical cap. Am J Pathol. 1970;60(2): 205-216. 25. Yousem SA. Pulmonary apical cap: a distinctive but poorly recognized lesion in pulmonary surgical pathology. Am J Surg Pathol. 2001;25(5): 679-683. 26. Travis WD, Costabel U, Hansell DM, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. 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. 2013;188(6):733-748.
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Original Research Diffuse Lung Disease
]
Distinct Characteristics of Pleuroparenchymal Fibroelastosis With Usual Interstitial Pneumonia Compared With Idiopathic Pulmonary Fibrosis Tsuneyuki Oda, MD; Takashi Ogura, MD; Hideya Kitamura, MD, PhD; Eri Hagiwara, MD, PhD; Tomohisa Baba, MD; Yasunori Enomoto, MD; Tae Iwasawa, MD, PhD; Koji Okudela, MD, PhD; Tamiko Takemura, MD, PhD; Fumikazu Sakai, MD, PhD; and Yoshinori Hasegawa, MD, PhD, FCCP
BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia and sometimes coexists with a histologic usual interstitial pneumonia (UIP) pattern. This study aimed to describe the distinct clinical features of PPFE with UIP pattern compared with idiopathic pulmonary fibrosis (IPF).
We conducted a retrospective review of the medical records of 110 consecutive patients with IPF with a histologic UIP pattern on surgical lung biopsy specimen. Patients meeting radiologic criteria for the diagnosis of PPFE based on high-resolution CT scan and with a histologic UIP pattern were included.
METHODS:
Nine of eleven patients meeting radiologic criteria for the diagnosis of PPFE were histologically confirmed as having PPFE with UIP pattern. The PPFE with UIP pattern group showed a significantly higher residual volume (1.8 L vs 1.3 L, P , .01), higher Paco2 (44.6 mm Hg vs 41.7 mm Hg, P 5 .04), and higher complication rate of pneumothorax and pneumomediastinum than the 99 patients with IPF/UIP. The ratio of anteroposterior to transthoracic diameter in patients with PPFE with UIP pattern was significantly lower than that in patients with IPF/UIP (P 5 .04). Survival time tended to be shorter in patients with PPFE with UIP pattern.
RESULTS:
The results support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP and may well be classified as PPFE. CHEST 2014; 146(5):1248-1255
CONCLUSIONS:
Manuscript received December 4, 2013; revision accepted May 26, 2014; originally published Online First June 19, 2014. ABBREVIATIONS: APDT 5 anteroposterior diameter of the thorax; ATS 5 American Thoracic Society; ERS 5 European Respiratory Society; HRCT 5 high-resolution CT; IPF 5 idiopathic pulmonary fibrosis; PPFE 5 pleuroparenchymal fibroelastosis; RV 5 residual volume; TDT 5 transthoracic diameter of the thorax; TLC 5 total lung capacity; UIP 5 usual interstitial pneumonia AFFILIATIONS: From the Department of Respiratory Medicine (Drs Oda, Ogura, Kitamura, Hagiwara, Baba, and Enomoto) and Department of Radiology (Dr Iwasawa), Kanagawa Cardiovascular and Respiratory Center, Yokohama; Department of Pathobiology (Dr Okudela), Yokohama City University Graduate School of Medicine, Yokohama; Department of Pathology (Dr Takemura), Japan Red Cross Medical Center, Tokyo; Department of Diagnostic Radiology (Dr Sakai), Inter-
1248 Original Research
national Medical Center of Saitama Medical University, Saitama; and Department of Respiratory Medicine (Drs Oda and Hasegawa), Nagoya University Graduate School of Medicine, Nagoya, Japan. FUNDING/SUPPORT: This study was supported in part by a grant-in-aid for interstitial lung diseases from the Japanese Ministry of Health, Labor and Welfare [Grant H23-Nanchi-Ippan-023]. CORRESPONDENCE TO: Takashi Ogura, MD, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomioka-higashi, Kanazawa-ku, Yokohama 236-0051, Japan; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2866
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Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare form of interstitial pneumonia. In 2004, five cases were reported of a unique idiopathic pleuroparenchymal lung disease characterized by a chronic idiopathic interstitial pneumonia with upper lobe-predominant marked pleural and parenchymal involvement.1 The disease shares common features with idiopathic pulmonary upper lobe fibrosis proposed by Amitani et al.2 Since, several case reports of PPFE have been published,3-13 but no consensus has been reached regarding disease entity, characteristics, and diagnostic criteria. Lobar histologic variability is frequent in patients with idiopathic interstitial pneumonia, and multiple histologic and high-resolution CT (HRCT) image patterns may coexist in the same patient. Cases with coexisting usual interstitial pneumonia (UIP) pattern and fibrotic nonspecific interstitial pneumonia pattern named as discordant UIP appear to behave similarly to those of
Materials and Methods Study Population We retrospectively reviewed medical records of 291 consecutive patients with idiopathic interstitial pneumonia who underwent surgical lung biopsy between January 2001 and December 2011 at Kanagawa Cardiovascular and Respiratory Center. Included were 110 consecutive patients with IPF diagnosed according to the 2002 ATS/ERS statement,18 with histologic UIP pattern shown in the biopsy specimen from the lower lobe. This study was approved by an institutional review board of Kanagawa Cardiovascular and Respiratory Center (approval number 24-14). Radiologic Criteria for PPFE Two expert pulmonary radiologists (T. I. and F. S.) identified patients according to the following radiologic criteria for the diagnosis of PPFE as previously reported in the literature16 and without knowledge of their clinical background or histologic findings:
concordant UIP.14,15 One study on PPFE reported that HRCT imaging could show other interstitial lung disease patterns in other locations in some patients.16 Indeed, specimens from patients with PPFE occasionally show a UIP pattern in the lower lobe (ie, PPFE with UIP pattern). Because PPFE with UIP pattern is regarded as inconsistent with UIP on HRCT scan and as UIP by histopathologic analysis, it is considered possible idiopathic pulmonary fibrosis (IPF) in accordance with the 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/Latin American Thoracic Association official statement on IPF.17 However, whether this diagnosis is appropriate when PPFE coexists with UIP pattern is not clear. This retrospective study has two objectives: to define the clinical and radiologic features of PPFE with UIP pattern compared with IPF/UIP by identifying PPFE with UIP pattern from surgically proven IPF/UIP and to determine whether PPFE with UIP pattern is a disease entity distinct from IPF/UIP.
bacterial infection, and connective tissue disease-related lung disease on biopsy specimens were excluded. Histologic UIP pattern was diagnosed according to the 2002 ATS/ERS consensus classification of idiopathic interstitial pneumonias.18 Histologic criteria for the diagnosis of PPFE were previously described in the literature as follows16: • Definite PPFE: upper zone pleural fibrosis with subjacent intraalveolar fibrosis accompanied by alveolar septal elastosis. • Consistent with PPFE: intraalveolar fibrosis present but (1) not associated with pleural fibrosis, (2) not predominantly beneath the pleura, or (3) not observed in an upper lobe biopsy specimen. • Inconsistent with PPFE: lacking the requisite features just described. If the two pathologists disagreed, the final diagnosis was reached by consensus. In this study, only patients with definite or consistent with PPFE by histologic criteria were included.
• Definite PPFE: demonstrating pleural thickening with associated subpleural fibrosis concentrated in the upper lobes, with involvement of lower lobes being less marked or absent. • Consistent with PPFE: upper lobe pleural thickening with associated subpleural fibrosis present, but (1) distribution of these changes not concentrated in the upper lobes or (2) features of coexistent disease present elsewhere. • Inconsistent with PPFE: lacking the requisite features just described. In this study, only patients with definite or consistent with PPFE by radiologic criteria were included. If the two radiologists disagreed, the final diagnosis was reached by consensus. HRCT scan had been performed within 2 months before surgical lung biopsy.
Clinical and Radiologic Review The pulmonologists reviewed the medical records, pulmonary function data, and laboratory data, analyzing pulmonary function data obtained within 6 months before surgical lung biopsy. Radiologic features such as dense subpleural consolidation, honeycombing, and degree of flattened thoracic cage were also analyzed. The anteroposterior diameter of the thorax (APDT) was measured on HRCT scan as the longest distance of the anterior-posterior dimension of the thoracic cage at the level of the sixth thoracic vertebra.19 The transthoracic diameter of the thorax (TDT) was measured as the longest transverse diameter of the thoracic cage at the level of the sixth thoracic vertebra.19 The ratio of anteroposterior to transthoracic diameter was then derived. Survival analysis was performed from the time of initial consultation. Patients with clinical connective tissue disease, autoimmune disease, or hypersensitivity pneumonitis were excluded.
Histologic Criteria for PPFE Surgical biopsies of multiple lobes were performed in all patients. All available slides were reviewed independently by two expert pulmonary pathologists (K. O. and T. T.) who were not aware of the clinical and radiologic findings for the patients. Patients with a possibility of chronic hypersensitivity pneumonitis, pneumoconiosis, fungal or myco-
Statistical Analysis Data are presented as mean ⫾ SD unless otherwise stated. Fisher exact test or Mann-Whitney U test was used for between-group comparisons as appropriate. Survival time from initial consultation was analyzed by the Kaplan-Meier method and log-rank test, with the end points being death or last contact. P , .05 was considered significant.
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1250 Original Research
[
Dead Dead Dead Alive Outcome
Dead
42.7
Normal Restrictive
28.3 24.3
Restrictive Restrictive
31.5 29.6
Restrictive
Survival, mo
PFT
None
None None
None None
None None None
Sister Mother/aunt Family history
Autoantibody
PT
10 Never
PM PT/PM
Never Never
PT PT
33
PT or PM
Smoking history, pack-y
Male
Cough Cough
Female Male
Cough/DOE Cough Symptoms
Female Male
Cough
Sex
5
69 71
4 3
65 64
2 1
46
Characteristic
Chest HRCT images and histopathology of a typical case, patient 8, are shown in Figures 1 and 2. An HRCT image in the coronal plane showed bilateral dense subpleural consolidation. Upper lobe volume loss and hilar elevation were observed bilaterally. Less marked subpleural reticulation and ground glass opacities were observed in the lower lobes. Biopsy specimens from the upper lobe revealed subpleural fibroelastosis and abrupt transition from fibroelastosis to normal lung parenchyma, with no evidence of pleural fibrosis. A UIP pattern was seen in the lower lobe.
Age, y
Imaging and Histopathology of PPFE With UIP Pattern
] Clinical Characteristics in Nine Patients With PPFE With UIP Pattern
Biopsy specimens from multiple lobes were performed in the nine patients. The histology of all patients with PPFE with UIP pattern showed subpleural fibroelastosis and intraalveolar fibrosis in the upper lobes and UIP pattern in the lower lobes. Six had histologic UIP features along with PPFE in the upper lobes. Pleural fibrosis was present in two patients.
TABLE 1
The clinical features of the nine patients (five men) with PPFE with UIP pattern are described in Table 1. Median age was 64 years (range, 46-71 years) at the time of biopsy. Four patients died of respiratory failure between 24.3 and 42.7 months after the initial evaluation. Spontaneous pneumothorax or pneumomediastinum developed in six patients during the follow-up period. None of the patients had a significant history of anticancer drug therapy, radiotherapy, bone marrow transplantation, or connective tissue disorders.
Patient
Clinical Findings in the Nine Patients With PPFE With UIP Pattern
DOE 5 dyspnea on exertion; PFT 5 pulmonary function test; PM 5 pneumomediastinum; PPFE 5 pleuroparenchymal fibroelastosis; PT 5 pneumothorax; UIP 5 usual interstitial pneumonia.
Alive Alive Alive Alive
Normal
30.8 14.9
Restrictive Restrictive
24.7 47.8
Normal
None
Mother/sister None
None None
None None
None
None
Never Never
PT None
7 23
None
DOE
9
Female Female
Cough DOE
Male Male
Check up
65
8 7 6
53
Eleven of the 110 consecutive patients with IPF met radiologic criteria for PPFE. Of these, nine fulfilled the histologic criteria of PPFE. Two patients were excluded because their upper lobe biopsy specimens showed marked interstitial inflammatory cell infiltrates within the intraalveolar fibrosis, and we found it difficult to completely rule out other interstitial pneumonia, such as connective tissue disease-related UIP. Accordingly, the nine patients meeting both radiologic and histologic criteria for PPFE comprised the final study group. The remaining 99 patients were given a diagnosis of IPF/UIP after multidisciplinary discussion among radiologists, pathologists, and pulmonologists.
64
Patient Identification
60
Results
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Figure 1 – High-resolution CT imaging of patient 8, a 65-y-old woman. A, Coronal image showing bilateral, apical, irregular pleural thickening. B, Subpleural thickening with fibrotic changes in the upper lobes. C, Less marked subpleural reticulation and ground glass opacities in the lower lobes.
Clinical, Laboratory, and Radiologic Findings of PPFE With UIP Pattern Compared With IPF/UIP
The clinical characteristics of the nine patients with PPFE with UIP pattern were compared with those of the 99 patients with IPF/UIP and are summarized in Table 2. Age, sex, and symptoms at initial consultation were not significantly different between the groups. Significant differences were observed in terms of BMI (P , .01) and complication rates of pneumothorax or pneumomediastinum (P 5 .01) between the groups. These complications all occurred during the follow-up period.
Radiologic findings in patients with PPFE with UIP pattern and those with IPF/UIP are shown in Table 3. The ratio of APDT to TDT was significantly lower in patients with PPFE with UIP pattern than in those with IPF/UIP (P 5 .04). The presence of honeycombing was not significantly different between the groups. Physiologic testing indicated that % predicted diffusing capacity of lung for carbon monoxide was not decreased in the PPFE group in contrast to a significant decrease observed in the IPF group (P , .01) (Table 4). Compared with the IPF group, the PPFE group showed
Figure 2 – Histopathologic findings in patient 8. A, A biopsy specimen from the upper lobe at low-power magnification shows subpleural fibroelastosis and abrupt transition from fibroelastosis to normal lung parenchyma (hematoxylin-eosin staining). B, A biopsy specimen from the upper lobe at high-power magnification shows an abundance of elastic fiber (elastic van Gieson staining); however, there was no evidence of pleural fibrosis. C and D, A biopsy specimen from the lower lobe at lowpower magnification (hematoxylineosin staining) (C) and high-power magnification (hematoxylin-eosin staining) (D) shows subpleural fibrosis and fibroblastic foci adjacent to established fibrosis.
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TABLE 2
] Clinical Characteristics in Patients With PPFE With UIP Pattern and Those With IPF/UIP
Characteristic
PPFE With UIP Pattern (n 5 9)
IPF/UIP (n 5 99)
64 (46-71)
67 (37-80)
.26
5
76
.22
5
23
Median age (range), y Male sex Smoking history
.049
Never Former and current, pack-y BMI, kg/m
2
P Value
4 (18 ⫾ 12)
76 (41 ⫾ 28)
18.6 ⫾ 1.8
25.1 ⫾ 3.6
, .01
Initial symptoms Cough
5
34
.28
DOE
2
18
.67
DOE and cough
1
22
.68
No symptoms
1
22
.68
Clubbing
0
22
.20
PT/PM
6
23
.01
Acute exacerbation
1
23
.68
Data are presented as counts or mean ⫾ SD unless otherwise indicated. IPF 5 idiopathic pulmonary fibrosis. See Table 1 legend for expansion of other abbreviations.
higher residual volume (RV) and ratio of RV to total lung capacity (TLC). The PPFE group also showed significantly higher Paco2 (P 5 .04). In contrast, alveolararterial oxygen tension differences were within the normal range in the PPFE group. The PPFE group had lower levels of serum biomarkers, such as Krebs von den Lungen-6, than the IPF group. BAL fluid yielded lower cell counts in the PPFE group. No significant difference was found between groups in cell fraction and the CD4/ CD8 ratio. Survival Analysis of PPFE With UIP Pattern and IPF/UIP
Survival analysis in patients with PPFE with UIP pattern compared with patients with IPF/UIP is shown in Figure 3. The median survival time was 31.5 and 82.1 months, respectively. Although the survival time tended to be TABLE 3
shorter in the PPFE group, the difference was not significant (P 5 .13).
Discussion To our knowledge, this study is the first to describe the clinical characteristics of PPFE with UIP pattern compared with IPF/UIP. We identified nine patients with PPFE with UIP pattern among 110 consecutive patients with surgically proven IPF/UIP diagnosed according to the 2002 ATS/ERS statement.18 We identified three characteristic features of PPFE with UIP pattern. Compared with patients with IPF/UIP, patients with PPFE with UIP pattern had (1) a higher complication rate of pneumothorax or pneumomediastinum and lower BMI; (2) a flattened chest (ie, lower APDT/TDT ratio); and (3) distinct features of pulmonary function in the form of restrictive pattern and alveolar hypoventilation, including
] Radiologic Findings of Patients With PPFE With UIP Pattern and Those of IPF/UIP
Characteristic
PPFE With UIP Pattern (n 5 9)
IPF/UIP (n 5 99)
P Value
Image ¿nding Dense subpleural consolidation
9
30
, .01
Honeycombing
2
25
.07
APDT, cm
13.2 ⫾ 1.4
14.7 ⫾ 1.2
, .01
TDT, cm
22.7 ⫾ 1.9
23.1 ⫾ 1.5
.49
APDT/TDT, %
58.4 ⫾ 6.8
63.8 ⫾ 5.6
.04
Thoracic dimensions
Data are presented as counts or mean ⫾ SD. APDT 5 anteroposterior diameter of the thorax; TDT 5 transverse diameter of the thorax. See Table 1 and 2 legends for expansion of other abbreviations.
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TABLE 4
] Pulmonary Function, Arterial Blood Gas Analysis, Laboratory Data, and BAL Fluid Findings in Patients With PPFE With UIP Pattern and Those With IPF/UIP
Parameter
PPFE With UIP Pattern (n 5 9)
IPF/UIP (n 5 99)
76.5 ⫾ 15.0
80.8 ⫾ 16.8
.36
P Value
Pulmonary function FVC, % predicted FEV1, % predicted
90.1 ⫾ 19.1
90.4 ⫾ 18.7
.79
FEV1/FVC ratio
87.1 ⫾ 7.8
82.3 ⫾ 6.8
.08
DLCO, mL/min/mm Hg
17.5 ⫾ 5.7
DLCO, % predicted
14.2 ⫾ 4.2
109 ⫾ 25.5
78.7 ⫾ 20.5
.12 , .01
DLCO/VA, mL/min/mm Hg/L
5.1 ⫾ 0.8
4.6 ⫾ 1.1
.16
DLCO/VA, % predicted
111 ⫾ 15.9
101 ⫾ 23.7
.16
92.4 ⫾ 18.1
79.5 ⫾ 15.4
1.8 ⫾ 0.5
1.3 ⫾ 0.4
, .01
42.6 ⫾ 8.7
33.1 ⫾ 7.6
, .01
pH
7.39 ⫾ 0.02
7.41 ⫾ 0.02
.12
PaO2, mm Hg
87.2 ⫾ 10.7
81.0 ⫾ 8.2
.15
PaCO2, mm Hg
44.6 ⫾ 4.1
41.7 ⫾ 3.5
.04
7.7 ⫾ 6.3
16.8 ⫾ 8.9
, .01
TLC, % predicted RV, L RV/TLC, %
.05
Blood gas test
P(A-a)O2, mm Hg Laboratory data LDH, International Units/L
238 ⫾ 32.2
KL-6, International Units/mL
600 ⫾ 340
SP-D, ng/mL
177 ⫾ 86.7
238 ⫾ 53.3
.64
1213 ⫾ 784
, .01
299 ⫾ 233
.09
BAL Àuid ¿ndings Cell count, 3 104/mL
10.5 ⫾ 3.5
24.8 ⫾ 18.7
, .01
Macrophages, %
70.3 ⫾ 20.2
77.4 ⫾ 18.0
.36
Neutrophils, %
5.0 ⫾ 4.1
3.8 ⫾ 6.4
.14
22.0 ⫾ 19.5
15.6 ⫾ 15.5
.31
Eosinophils, %
2.6 ⫾ 3.0
2.8 ⫾ 4.2
.95
CD4/CD8 ratio
2.7 ⫾ 1.8
2.4 ⫾ 2.3
.34
Lymphocytes, %
Data are presented as mean ⫾ SD. DLCO 5 diffusing capacity of lung for carbon monoxide; KL-6 5 Krebs von den Lungen-6; LDH 5 lactate dehydrogenase; P(A-a)O2 5 alveolar-arterial oxygen tension difference; RV 5 residual volume; SP-D 5 surfactant protein-D; TLC 5 total lung capacity; VA 5 alveolar volume. See Table 1 and 2 legends for expansion of other abbreviations.
an increased RV/TLC ratio and Paco2. The results define the clinical and radiologic characteristics of PPFE with UIP pattern and support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP. A higher complication rate of pneumothorax or pneumomediastinum in the PPFE group was consistent with the results of previously published reports.1,2,4,11,12,16 It is true that findings similar to PPFE could be observed as sequelae of ordinary spontaneous pneumothorax. However, all the patients experienced pneumothorax or pneumomediastinum after the initial visit, and it is unlikely that the pneumothorax caused PPFE. journal.publications.chestnet.org
Flattened chest is a characteristic finding in idiopathic pulmonary upper lobe fibrosis and PPFE in the literature.2,13 It is also reported that the thoracic cage becomes flattened in the progression of PPFE.19,20 The present study showed that the APDT/TDT ratio and APDT in the PPFE group were lower than those in the IPF group. In addition, despite the PPFE group having upper lobe volume loss, TLC was increased in the PPFE group compared with the IPF group. These results imply that upper lobe volume loss led to flattened chest and the compensatory hyperinflation of the middle and lower lobes in the PPFE group. Respiratory function in PPFE with UIP pattern was characterized by a restrictive pattern and alveolar hypoventilation, 1253
The histopathologic features of PPFE, such as intraalveolar fibrosis and elastosis, correspond to the presence of an apical cap.24,25 Patients with PPFE with UIP pattern showed dense subpleural consolidation with more diffuse distribution in biopsy specimens not from the apex but mainly from the posterior segment in which apical cap is not usually observed. In addition, we confirmed progressive upper lobe volume loss in some patients, which is inconsistent with the natural course of the apical cap.
Figure 3 – Kaplan-Meier distribution of survival time in patients with PPFE with UIP pattern vs those with IPF/UIP. IPF 5 idiopathic pulmonary fibrosis; PPFE 5 pleuroparenchymal fibroelastosis; UIP 5 usual interstitial pneumonia.
as indicated by the increased RV/TLC ratio and Paco2. Although both the IPF and the PPFE groups showed a restrictive pattern, some differences existed. In the IPF group both TLC and RV were decreased as expected. In the PPFE group, however, TLC was somewhat decreased, whereas RV was increased. Because this type of restrictive change is common in patients with neuromuscular disorders or pleural diseases, there is a strong possibility that lung movement is being restricted in patients with PPFE with UIP pattern. In this study, none of the patients had neuromuscular or neurologic complications. It is possible that pleural and subpleural thickening causes restricted lung movement in patients with PPFE with UIP pattern, resulting in alveolar hypoventilation. The survival time tended to be shorter in patients with PPFE with UIP pattern than in patients with IPF/UIP. In the four patients who died, the cause of death was chronic respiratory failure with recurrent pneumothorax or pneumomediastinum; the incidence of pneumothorax or pneumomediastinum was significantly higher in the PPFE group. Pneumothorax in patients with IPF/UIP is reportedly associated with rapid deterioration on HRCT imaging21 and poor prognosis.22 Moreover, the PPFE group had a lower BMI than the IPF group. Low BMI at IPF diagnosis has been associated with poor prognosis.23 The present observation of poorer survival outcome in the PPFE group can be explained in the same way.
1254 Original Research
In the present study, the clinical and radiologic features of PPFE with UIP pattern were similar to those previously reported for PPFE. In the 2011 ATS/ERS/ Japanese Respiratory Society/Latin American Thoracic Association statement,17 upper or mid-lung-predominant distribution is one of the seven features of inconsistent with UIP on HRCT imaging. PPFE with UIP pattern has been judged inconsistent with UIP on HRCT imaging and as UIP by histopathologic analysis and then considered possible IPF. A certain number of patients with this disease may have been given a diagnosis of IPF/UIP. In a recently published ATS/ERS statement on the classification of idiopathic interstitial pneumonias, PPFE was mentioned for the first time, to our knowledge, as a rare form of independent idiopathic interstitial pneumonia.26 The present results show that the characteristics of PPFE with UIP pattern more closely resemble those previously reported for PPFE than those for IPF/UIP and support the idea that this disease is distinct from IPF/UIP and classifiable as PPFE. This study has several limitations. It was a singlecenter retrospective study, and the number of patients with PPFE with UIP pattern was small. However, PPFE is a rare form of interstitial lung disease, and, thus, prospective studies will prove difficult. Moreover, the patients with IPF/UIP in this study had a longer survival time compared with previous reports.17 A possible reason is that the present study only included patients able to undergo surgical lung biopsy; therefore, the survival result for IPF/UIP may exclude the more severe cases. In conclusion, the results support the view that PPFE with UIP pattern is a disease entity distinct from IPF/UIP. It may well be classified as PPFE rather than UIP.
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Acknowledgments Author contributions: T. Oda had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. T. Ogura contributed to the study concept and design, data analysis and interpretation, and final approval of the manuscript; H. K. and Y. H. contributed to the study concept and design and submission of the manuscript; E. H. contributed to the data collection, organization, and analysis and preparation, review, writing, and submission of the manuscript; and T. B., Y. E., T. I., K. O., T. T., and F. S. contributed to the data collection, organization, and analysis and preparation, review, and submission of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Others contributions: Editorial assistance was provided by Stephen L. Nishimura, PhD, Department of Pathology, University of California, San Francisco, California.
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