Suspected pleuroparenchymal fibroelastosis relapse after lung transplantation: a case report and literature review

Pleuroparenchymal fibroelastosis (PPFE) is a very rare lung disease characterized by dense fibrous thickening of the visceral pleura and intraalveolar fibrosis containing prominent elastosis, with typical upper lobe predominance. PPFE usually shows progressive restrictive ventilatory impairment refractory to medical treatment; bilateral lung transplantation currently remains the only available therapeutic option. In this report, we describe a case of suspected PPFE relapse after lung transplantation that, to our knowledge, has never been described in the medical literature. A 48-year-old male with idiopathic pleuroparenchymal fibroelastosis underwent a bilateral lung transplant in our department. 8 months later, he presented with progressively worsening clinical condition, his respiratory state gradually deteriorated. High-resolution CT again showed bilateral diffused parenchymal consolidations, with prevalence in the upper lobes and subpleural regions. A PPFE relapse was therefore suspected, so he was listed for lung retransplantation, which was performed ten months after the first transplant. Histopathological analysis of the second explanted lung again confirmed the diagnosis of PPFE. The case highlights the possibility of PPFE relapse after lung transplantation, that may add to the increasing evidence of an underlying auto-immune mechanism contributing to its pathogenesis.

Pleuroparenchymal Fibroelastosis (PPFE) is a rare interstitial lung disease that is characterized by upper lobes pleural thickening and subpleural fibrosis. 1 Differently from other more common patterns of pulmonary fibrosis, like usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP), PPFE typically shows prominent elastotic fibrosis of the pleura and subjacent lung, with sparing of the parenchyma distant from the pleura. 2 PPFE pathogenesis is still poorly understood, as it can either be idiopathic or secondary to many underlying diseases. In the updated American Thoracic Society-European Respiratory Society classification of the idiopathic interstitial pneumonias (IIPs), idiopathic PPFE (iPPFE) has been recognized as a separate entity, and categorized as a rare form of interstitial pneumonia. 1 The clinical course of this severe disease is characterized by slowly progressive restrictive ventilatory impairment. No effective medical treatment has been identified, as both secondary and idiopathic form of PPFE are refractory to steroids or immunosuppressive drugs. As such, bilateral lung transplantation is the only currently available therapeutic option. 2 In this report, we describe a case of suspected iPPFE relapse after lung transplantation.

Case pResentation
A 48-years-old male with iPPFE was referred to our department for a lung transplantation consultation. He received a diagnosis of iPPFE 2 years before with surgical lung biopsy after a few months of cough and dyspnea ( Figure 1). His past medical history was silent, except for a previous Ravitch procedure for pectus excavatum.
abstRaCt Pleuroparenchymal fibroelastosis (PPFE) is a very rare lung disease characterized by dense fibrous thickening of the visceral pleura and intraalveolar fibrosis containing prominent elastosis, with typical upper lobe predominance. PPFE usually shows progressive restrictive ventilatory impairment refractory to medical treatment; bilateral lung transplantation currently remains the only available therapeutic option. In this report, we describe a case of suspected PPFE relapse after lung transplantation that, to our knowledge, has never been described in the medical literature. A 48-year-old male with idiopathic pleuroparenchymal fibroelastosis underwent a bilateral lung transplant in our department. 8 months later, he presented with progressively worsening clinical condition, his respiratory state gradually deteriorated. High-resolution CT again showed bilateral diffused parenchymal consolidations, with prevalence in the upper lobes and subpleural regions. A PPFE relapse was therefore suspected, so he was listed for lung retransplantation, which was performed ten months after the first transplant. Histopathological analysis of the second explanted lung again confirmed the diagnosis of PPFE. The case highlights the possibility of PPFE relapse after lung transplantation, that may add to the increasing evidence of an underlying auto-immune mechanism contributing to its pathogenesis.
At admission, the patient presented with wheezes, diffuse inspiratory crackles and reduced vescicular murmur, predominantly in the upper lobes. SpO 2 was 94% at rest.
Chest high-resolution CT (HRCT) showed bilateral parahilar fibrotic interstitial thickening with architectural distortion, dorsal pleural thickening and subpleural consolidations, predominantly in the upper lobes ( Figure 1). Pulmonary function testing (PFTs) progressively worsened; 3 months later, PFTs showed severe restrictive ventilatory impairment [forced vital capacity (FVC), 0.93 L; % FVC, 23%] with poor diffusing capacity of carbon monoxide (%DLCO, 21%), so he was listed for lung transplantation. The patient underwent a bilateral lung transplant 3 months after being included on the waiting list.
The postoperative course was uneventful, and the patient was discharged on postoperative day 20. The histopathological analysis confirmed the diagnosis of iPPFE, as it showed diffuse areas of dense and homogeneous fibrosis, rich in elastic fibers, partially extending into alveolar and interlobular septa; fibroblastic foci at the edge of the fibrosis were incospicuous or absent ( Figure 2).  BJR|case reports Case Report: Suspected PPFE relapse after lung transplantation: a case report After 1 month, his lung function steadily declined, so he was listed for lung retransplantation, which was performed 10 months after the first transplant ( Figure 3). He did not show any significant postoperative complications and he was discharged on postoperative day 23.
Histopathological analysis of the second explanted lung again confirmed the diagnosis of PPFE, as it revealed fibrosis with a more diffuse pattern of distribution, predominantly in the subpleural regions, with a prominent elastotic component, together with foci of obliterative bronchiolitis (Figure 4). 12 months later, he is doing well without oxygen supplementation.

disCussion
PPFE is a very rare clinicopathological entity consisting of a form of progressive pulmonary fibrosis involving the pleura and subpleural lung parenchyma, with upper lobe predominance. 1 Amitani et al first described some form of idiopathic pulmonary upper lobe fibrosis in 1992, 3  Chest HRCT shows dense subpleural consolidation with pleural thickening, traction bronchiectasis, architectural distortion, and volume loss predominantly in the upper lobes. 5,6 A final diagnosis of PPFE may require surgical lung biopsy, showing peculiar histopathology consisting of marked visceral pleural thickening and prominent subpleural fibrosis with both elastic tissue and dense collagen. 7 PPFE may have a long, asymptomatic subclinical stage, in which lesions are limited to the apex, 2 whereas in most cases it manifests with dyspnea, recurrent respiratory infections, pneumothorax, and disease progression with death in 40% of cases.
The clinical course of this disease is slowly progressive (median survival 11 years), refractory to steroids or immunosuppressive drugs, with lung transplantation being the only currently available therapeutic option. 2 PPFE is a complex disease that can either be idiopathic or secondary to many underlying diseases or conditions, e.g. anticancer chemotherapy, bone marrow or stem cell-transplantation, occupational dust exposure (asbestos, aluminum). 4 No connection with gender or smoking history has been detected so far. Patients with PPFE frequently show a flattened thoracic cage, 2 as in our case.
As PPFE pathogenesis is still poorly understood, a contributing auto-immune mechanism has been proposed by some authors: PPFE has been reported in siblings, in a pair of parents and child and in patients with other autoimmune diseases like ankylosing spondylitis, ulcerative colitis, and psoriasis. 8 Recently, PPFE has been also identified as a phenotype of chronic rejection of lung transplantation, as it represents a major histopathological correlate in restrictive allograft syndrome (RAS). [8][9][10] Transplantation-associated PPFE seems to have some peculiar histopathological differences from iPPFE, and appears to have a poorer prognosis than other secondary causes of PPFE. 8,11,12 Konen et al 10  In our case, only 5 months passed between the transplantation and the first clinical symptoms of lung function decline, and only 10 between the two lung transplantations. This may suggest the contribution of an underlying process accelerating the development of PPFE in the transplanted lung.
In conclusion, our case highlights the possibility of PPFE relapse after lung transplantation, that may add to the increasing evidence of an underlying auto-immune mechanism contributing to its pathogenesis. More studies are needed to further understand PPFE pathogenesis and to identify potential alternative effective treatments; more importantly, potential causes of lung transplantation failure for disease relapse need to be addressed, to better identify potential candidates to transplantation.

leaRning points
1. Pleuroparenchymal Fibroelastosis is a rare and progressive form of pulmonary fibrosis with upper lobe predominance, and its pathogenesis is still poorly understood 2. The case highlights the possibility of PPFE relapse after lung transplantation, adding to the increasing evidence of an underlying auto-immune mechanism contributing to its pathogenesis. 3. PPFE may also represent a histopathological and radiological pattern of chronic lung allograft dysfunction after lung transplantation.

Consent foR publiCation
Written informed consent was obtained from the patient for publication of this report, including accompanying images.