Pleuroparenchymal Fibroelastosis (PPFE)

A Rare Idiopathic Interstitial Pneumonia - Complete 10-Mark Answer

1. Definition and Historical Background

• The term "PPFE" was first coined by Frankel in 2004, describing five patients with a previously uncategorized fibrotic pattern.
• It closely resembles Pulmonary Upper Lobe Fibrosis (PULF) described by Amitani et al. in 1992 - both are now accepted as the same entity.
• Formally recognized as an independent rare Idiopathic Interstitial Pneumonia (IIP) by the ATS/ERS consensus statement in 2013.
• Accounts for approximately 6-8% of all ILDs, though the true incidence is unknown due to lack of formal diagnostic criteria and frequent misdiagnosis.

2. Classification

3. Etiology and Associated Conditions

• Hematopoietic stem cell transplantation (HSCT) - most common secondary cause; resembles chronic graft-versus-host disease
• Lung transplantation

• Alkylating agents: carmustine, cyclophosphamide
• Amiodarone
• Bleomycin

• Rheumatoid arthritis (RA)
• Systemic sclerosis / primary Sjogren's syndrome
• Ankylosing spondylitis, ulcerative colitis

• Recurrent pulmonary infections (strong history in most patients)
• Aspergillus, Mycobacterium avium intracellulare

• Familial cases described (sibling pairs), suggesting genetic predisposition
• Mutations in telomere-regulating genes (TERT - telomere reverse transcriptase; TERC - telomerase RNA) identified; associated with more progressive disease

• Aluminosilicate dust, asbestos exposure implicated
• No association with cigarette smoking (a key distinguishing point)

4. Epidemiology

• Age of presentation: highly variable, 8 to 87 years; bimodal distribution - smaller peak in the 3rd decade, larger peak in the 6th decade
• No sex predilection overall (some reports show female predominance especially in young patients)
• Mean time from symptom onset to diagnosis: 2-3 years
• Most patients are non-smokers with a history of recurrent pulmonary infections

5. Clinical Features

• Progressive dyspnea on exertion (most common)
• Cough (may or may not be present)
• Weight loss (worsens with disease progression)

• Often normal in early disease
• Platythorax (flat chest): characteristic finding - reduced anteroposterior diameter of the thorax, visible as deepening of the suprasternal notch. Ratio of AP to transverse diameter is abnormally low. May worsen over time.
• Crackles appear when PPFE extends beyond upper zones, or when coexisting UIP/NSIP/HP is present
• Clubbing: in less than 25% of patients

• Spontaneous pneumothorax and pneumomediastinum - can be asymptomatic and recurrent; occur in both idiopathic and secondary forms

6. Laboratory Features

• No diagnostic laboratory tests exist for PPFE
• Elevated KL-6 (Krebs von den Lungen-6) antigen in some patients
• Elevated Surfactant Protein D (SP-D) in some
• Elevated urinary desmosine (a cross-link marker of elastin) found in biopsy-proven PPFE - not yet validated for clinical use

7. Pulmonary Function Tests (PFTs)

• Restrictive ventilatory defect: reduced TLC, decreased FVC, increased FEV1/FVC ratio
• Decreased DLCO
• FVC may decline rapidly, especially in those with telomere gene mutations
• A key distinguishing feature: decrease in FVC out of proportion to DLCO (in early disease, the main defect is pleural fibrosis - extrapulmonary restriction)
• Early stages may show hypercapnia with a normal A-a oxygen gradient (because the early defect is extrapulmonary/pleural restriction, not parenchymal gas exchange impairment)
• Residual volumes may be reduced; mixed ventilatory defects also possible
• Platythorax contributes to ventilation-perfusion mismatch as disease progresses

8. Radiological Features

Chest X-Ray:

• Early disease: may be normal, or show bilateral irregular thickening of apices
• With progression: reticular and nodular opacities in upper lung fields + bilateral hilar opacities
• Lateral view: narrowed AP dimension (platythorax)
• Upward retraction of hila due to upper lobe volume loss

HRCT (Diagnostic Hallmark):

• Upper lobe pleural thickening with subpleural fibrosis (required)
• Limited lower lobe involvement (required)
• Dense subpleural consolidations with traction bronchiectasis and architectural distortion - bilaterally in upper lobes
• Thickening of the pleura adjacent to subpleural fibrotic changes
• Sharp/clear delineation between areas of fibrosis and normal lung (characteristic)
• Volume loss with upward hilar retraction
• Cysts and bullae may be present
• Coexistent lower lobe changes in UIP-like or NSIP-like pattern are increasingly reported

HRCT of PPFE: (A) Axial lung windows showing reticulation (straight arrows) and traction bronchiectasis (curved arrow). (B) Soft tissue windows showing marked pleural thickening (arrowheads). (C) Coronal view demonstrating apical-predominant fibrosis with upward hilar retraction and marked pleural thickening.

9. Histopathological Features

1. Visceral pleural fibrosis - dense collagenous fibrosis of the visceral pleura, upper zone predominant (but all zones may be involved histologically even when not apparent on CT)
2. Subpleural intra-alveolar fibrosis and elastosis (IAFE) - fibrosis of subpleural lung with septal elastosis
3. Elastic fiber deposition - disordered elastic fibers with intervening collagen within alveolar septa

• Sharp delineation between involved subpleural region and normal lung parenchyma (homogeneous fibroelastosis)
• Rare fibroblastic foci may be present at the leading edge adjacent to normal parenchyma
• Upper lobe-predominant fibrotic and elastotic changes
• IAFE is not exclusive to PPFE (can also be seen in paraquat toxicity, radiation injury, ARDS, apical cap)

• H&E: Pink collagenous fibrous tissue with disordered elastic fibers
• Pentachrome (Movat) stain: mature collagen stains yellow; irregular, fragmented elastic fibers stain black

Photomicrograph of PPFE: (A) Low-power H&E showing subpleural-pleural fibroelastosis. (B) High-power H&E showing pink collagen interspersed with purple elastic fibers. (C) Movat pentachrome stain - mature collagen (yellow) and irregular elastic tissue fibers (black).

10. Diagnosis

• Clinical history + CT findings are often sufficient for confident diagnosis
• Transbronchial biopsy or transthoracic (CT-guided) biopsy: used when clinical/imaging data are insufficient; non-surgical sampling is preferred
• Surgical lung biopsy (SLB): can be used but is often avoided due to complication risk, especially in secondary PPFE

• Apical cap (localized fibrotic lesion vs. bilateral PPFE)
• Sarcoidosis (upper lobe predominance but different CT pattern)
• HP (can coexist)
• UIP/IPF (predominantly lower lobe)
• Post-radiation/paraquat changes

11. Treatment

• Corticosteroids and immunosuppressive therapy: generally not beneficial - a case series of 12 patients showed prednisone (with or without additional immunosuppression) had no beneficial effect
• Antifibrotic drugs (pirfenidone, nintedanib): currently under investigation; no established evidence yet
• Pleurodesis: may be considered for recurrent pneumothorax
• Lung transplantation: may be required in severe, progressive disease; however, PPFE can recur post-transplant, and secondary PPFE from transplantation itself is recognized
• Supportive care: oxygen therapy, pulmonary rehabilitation

12. Prognosis and Clinical Course

• Progressive disease in most patients
• In a series of 52 patients with idiopathic PPFE diagnosed after multidisciplinary discussion: 5-year mortality was 42%
• In patients with coexisting IIP (especially lower lobe UIP): more rapidly progressive course
• FVC decline is especially marked in patients with telomere gene abnormalities
• Some experience an indolent course; others have rapidly progressive and often fatal disease
• Recurrent pneumothorax is associated with higher morbidity

Summary Table for Quick Revision

• Murray & Nadel's Textbook of Respiratory Medicine (Chapters 90 & 112)
• Fishman's Pulmonary Diseases and Disorders (Chapter 55)
• Goldman-Cecil Medicine (Rare Interstitial Pneumonias)
• Recent reviews: Cottin V et al., Curr Opin Pulm Med 2022 [PMID 35855575]; Yamakawa H et al., J Clin Med 2024 [PMID 38999241]; Ishii H et al., Expert Rev Respir Med 2025 [PMID 40289399]