Pleuroparenchymal fibroelastosis from a consecutive database: a rare disease entity?

To the Editor:

Pleuroparenchymal fibroelastosis (PPFE) is a rare condition characterised by predominantly upper lobe involvement with pleural fibrosis and subjacent parenchymal fibroelastosis [1, 2]. Idiopathic PPFE (IPPFE), which was included in the rare idiopathic interstitial pneumonias (IIPs) in the update of the international multidisciplinary classification of IIPs published in 2013 [3], was first described in the Japanese literature by Amitani et al. in 1992 [4]. PPFE has been reported to be associated with drugs, chronic hypersensitivity pneumonia, collagen vascular diseases, infections, and bone marrow transplantations [5–8]. However, the frequency of PPFE occurrence has been uncertain. We hypothesised that PPFE was not a rare disease entity and conducted this study. Informed consent was obtained from all patients, and the Institutional Review Board of the National Hospital Organization Kinki-Chuo Chest Medical Center (KCCMC) (Sakai City, Japan) approved this study.

To prove the hypothesis, we retrospectively reviewed our database of diagnostic pathology archives from 205 consecutive patients who had undergone a surgical lung biopsy (SLB) to diagnose diffuse lung diseases at the KCCMC from 2004 to 2012, and selected 14 cases in which the key words “atelectatic fibrosis”, “pleuroparenchymal fibroelastosis” or “parenchymal fibroelastosis” were identified. The 14 cases were re-evaluated in multidisciplinary discussions using histopathological and radiological criteria for the diagnosis of PPFE [1, 2, 5]. Two cases were excluded from a diagnosis of PPFE; one did not fulfil the radiological criteria and the other showed a pathological pattern of usual interstitial pneumonia (UIP), with only focal elastosis.

We evaluated the pathology according to the report by Reddy et al. [5]. Patients with upper zone subpleural elastosis, intra-alveolar collagen deposition and pleural thickening with fibrosis were categorised as definite PPFE. Patients without pleural thickening were categorised as consistent with PPFE. For the radiological findings from high-resolution computed tomography (HRCT) pleural thickening associated with subpleural fibrosis was observed mainly in the upper lobes, with less marked or no involvement of the lower lobes. Features suggesting comorbid disease were allowed to be present elsewhere in the lung. Pathological and radiological patterns of interstitial lung diseases (ILDs) were determined by the criteria previously reported [3, 9, 10]. A radiological pattern of nonspecific interstitial pneumonia (NSIP) was defined according to a previous report [11].

Of the 205 consecutive patients who had undergone a SLB for ILDs, 12 (5.9%) cases were identified as PPFE after multidisciplinary discussion (definite PPFE: eight cases; consistent with PPFE: four cases). In the same period, the number of patients presenting ILDs on HRCT and receiving bronchoalveolar lavage was 1622, including the 205 (12.6%) cases with SLB. Of the 205 cases, 77 cases were diagnosed as IIPs. Clinical characteristics of the PPFE cases are summarised in table 1. Seven (58%) were male and the median age was 62 years old. Seven (58%) had never-smoked. Eight (67%) developed spontaneous pneumothoraces during the course of their disease and six (50%) experienced pneumothoraces repeatedly. Eight (3.9%) patients undergoing SLB were categorised as IPPFE, while four (2.0%) were categorised as secondary PPFE (SPPFE). Thus, the frequency of IPPFE was not rare among IIPs (10.4%).

The HRCT findings of patients with PPFE are summarised in table 1. All 12 patients revealed bilateral irregular pleuroparenchymal thickening in the upper zone. 10 demonstrated elevated hilar shadows suggesting volume reduction in the upper lobes. Notably, 11 (92%) demonstrated coexistent ILD in the lower lobes (UIP pattern: five cases; possible UIP pattern: four cases; NSIP pattern: one case; and an undefined pattern: one case).

Follow-up HRCT images were available for 10 patients (follow-up period: 13–69 months, median 22.5 months). Of these patients, seven (70%) demonstrated progression of pleuroparenchymal thickening, and four (40%) had increased or newly apparent honeycombing at their last HRCT. In seven (70%) out of the 10 discrete cysts increased or enlarged. In one of these cases, a ball of fungus appeared in the upper lobe cyst.

For pathological findings, 10 patients underwent SLBs in the upper lobes, with the remaining two undergoing biopsies in the middle lobes. All patients exhibited subpleural elastosis and intra-alveolar collagen deposition; however, four (33%) did not have pleural thickening with fibrosis. Notably, nine (75%) showed coexistent ILDs (eight with UIP pattern and one with non-classifiable interstitial pneumonia pattern) (table 1).

Pulmonary function test data were available for eight patients without the complication of pneumothoraces. The baseline levels of median forced vital capacity (FVC) and total lung capacity (TLC) were 70.6 and 71.7 % predicted, respectively. There was a marked decline in FVC and TLC.

Eight patients received medication. Six were treated with low-dose corticosteroids. Four out of these six patients received additional immunosuppressant therapy (cyclosporine (n=2) and azathioprine (n=2)). The other two of these six patients received both immunosuppressant therapy (azathioprine) and pirfenidone. Of the remaining two patients, one received both immunosuppressant therapy (azathioprine) and pirfenidone, while the other was treated only with pirfenidone (table 1). However, we did not find any improvement in pulmonary function tests, HRCT or symptoms.

The median survival time for PPFE patients from the first hospital visit and from the SLB were 2459 days and 838 days, respectively. The survival from SLB seemed to be poor. The number of patients was too small to tell the difference between the survival time for IPPFE and SPPFE patients, and of those with definite PPFE and consistent with PPFE. Seven patients were alive at the last follow-up (four of whom required home oxygen therapy), while the remaining five died from respiratory failure due to disease progression.

Although fibrotic thickening of the pleura is one of the features of PPFE patients [1], four patients (three IPPFE and one cyclophosphamide-induced case) did not have pleural thickening in the present study. These four cases were diagnosed as consistent with PPFE. The three IPPFE cases among these four cases did not have radiotherapy, chemotherapy or inhalational injuries, which are known aetiologies of intra-alveolar fibrosis with septal elastosis. Some reports have included PPFE cases without pleural thickening [4, 5, 8, 12, 13]. Further studies are required to clarify the significance of pleural thickening in the diagnosis of PPFE.

Patients with a coexistent ILD other than fibroelastosis were observed in the present study as previously reported [5, 12–14]. The frequency of such cases was 75% in our report and might be higher than the report by Reddy et al. [5] (43%); however, the patients in the other reports did not always accept SLB of the lower lobe. Watanabe et al. [13] mentioned eight out of nine cases of idiopathic upper lobe fibrosis, which is similar to PPFE, showed lower lobe lesions on HRCT although they were not pathologically evaluated. Thus, coexistent ILD is supposedly more frequently observed when histologically examined.

In pulmonary function tests FVC declined rapidly in most patients. In the report by Watanabe et al. [13] respiratory function also declined remarkably in PPFE patients. These findings suggest that PPFE is a progressive disease. However, in the current study drug therapies including pirfenidone were not effective. Given this, at present, lung transplantation would be the only effective treatment for PPFE.

From these findings, IPPFE is an acceptable disease entity among IIPs, and is not as rare as previously reported. PPFE is a progressive disease with the frequent complication of pneumothorax and there is no effective therapy. Development of effective anti-fibrotic and/or anti-elastotic treatment is required.