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EUROPEAN RESPIRATORY JOURNAL EDITORIAL P. BONNIAUD ET AL. Pleuroparenchymal fibroelastosis: so many unmet needs Philippe Bonniaud1, Vincent Cottin 2 and Guillaume Beltramo 1 1 Constitutive Reference Center for Rare Pulmonary Diseases, OrphaLung, Department of Pulmonary Medicine and Intensive Ca...

EUROPEAN RESPIRATORY JOURNAL EDITORIAL P. BONNIAUD ET AL. Pleuroparenchymal fibroelastosis: so many unmet needs Philippe Bonniaud1, Vincent Cottin 2 and Guillaume Beltramo 1 1 Constitutive Reference Center for Rare Pulmonary Diseases, OrphaLung, Department of Pulmonary Medicine and Intensive Care Unit, Dijon-Bourgogne Universitary Hospital, Inserm U1231, University of Bourgogne-Franche Comté, Dijon, France. 2National Reference Centre for Rare Pulmonary Diseases, OrphaLung, Louis Pradel Hospital, Hospices Civils de Lyon, UMR 754, Claude Bernard University Lyon 1, Lyon, France. Corresponding author: Philippe Bonniaud ( [email protected]) Shareable abstract (@ERSpublications) With numerous unanswered questions and clinical challenges, significant challenges remain for the management of pleuroparenchymal fibroelastosis. Registries and prospective trials should be encouraged for the future. https://bit.ly/3Tlq6gb Cite this article as: Bonniaud P, Cottin V, Beltramo G. Pleuroparenchymal fibroelastosis: so many unmet needs. Eur Respir J 2022; 60: 2201798 [DOI: 10.1183/13993003.01798-2022]. Copyright ©The authors 2022. For repr duction rights and permissions contact [email protected] Pleuroparenchymal fibroelastosis (PPFE) is a severe clinical entity that was only identified at the turn of the 21st century. There are so many unanswered questions and clinical challenges for this “new” disease that one may ask: what issues do we need to tackle as a priority? Received: 14 Sept 2022 Accepted: 2 Oct 2022 Though sparse cases have been identified retrospectively in the literature [1], FRANKEL et al. [2] recognised and labelled PPFE as a disease in its own right in 2004. They described a severe idiopathic condition suggestive of interstitial pneumonia but with distinguishing features that included predominant upper lobe involvement, fibrosis of the visceral pleura, uniform subpleural fibroelastosis, mild lymphoplasmacytic infiltrates, and few fibroblastic foci along the transitional fibrotic areas. In 2012, REDDY et al. [3] performed a landmark retrospective study. They extended the understanding of the disease by highlighting non-idiopathic cases (autoimmune and genetic). They further suggested that PPFE of various aetiologies may have varying disease progression patterns, and may also benefit from tailored disease management. Although PPFE is still a rare diagnosis, more and more cases are being identified, and the understanding of this condition has progressed on several fronts. The presentation, including clinical and imaging features (table 1), is now well-known [4]. Risk factors and conditions predisposing to PPFE, such as bone marrow transplant [5], medications, particularly alkylating drugs [6], and lung transplantation [7], have been clearly identified. PPFE may be familial or associated with autoimmune diseases. Other factors, for instance infections, exposure (to asbestos, aluminium or silica) or radiation treatment are strongly suspected, but the evidence is not yet conclusive. It is now also recognised that patients who are diagnosed with PPFE often present additional interstitial lung diseases, such as usual interstitial pneumonia (UIP), with a more severe outcome than patients with UIP alone [4]. The prognosis of PPFE is generally poor but obviously heterogenous. Retrospective studies suggest that certain aetiologies (idiopathic PPFE, and PPFE associated with telomeropathy or related to the use of alkylating drugs) have particularly poor outcomes. Despite the advances and the exponentially growing number of related publications over the past 18 years, significant challenges remain for the management of PPFE (figure 1). Patients tend to be diagnosed only at late stages, when most are already experiencing significant respiratory dysfunction, especially for idiopathic PPFE. In fact, there is a notable lack of tools for diagnosing PPFE, especially in the early stages of disease. When the disease was first identified, the primarily diagnostic criteria were based on histological samples obtained through lung biopsy [2, 3, 8]. However, because patients with PPFE are at a high risk of pneumothorax, pneumomediastinum, persistent air leak, bronchopleural fistula and other complications [9, 10], most experts consider that lung biopsies should be avoided whenever possible. So, while ENOMOTO et al. [11] found that biopsy-based elastic fibre scores could be used to evaluate prognosis, they recognised that the use of biopsy often resulted in refractory pneumothorax in patients who were already fragile. https://doi.org/10.1183/13993003.01798-2022 Eur Respir J 2022; 60: 2201798 Lung function Imaging Search for secondary PPFE □ Platythorax*** Occurs in about 50% of cases • May be clinically obvious • Very suggestive of PPFE diagnosis • if present □ Restriction*** Low TLC • Low FVC • Elevated RV/TLC ratio • Normal or moderately altered • DLCO/VA □ HRCT: criteria proposed by ENOMOTO et al. [13] in the absence of histopathology (all three criteria are necessary) Bilateral subpleural dense consolidation with or without pleural thickening in • the upper lobes and less marked or absent involvement of the lower lobes Radiologic confirmation of disease progression#,*** • Exclusion of other lung diseases with identifiable causes¶ • Or criteria proposed by REDDY et al. [3] (these radiological criteria were initially to be associated with the results of histopathology examination+) □ Past history of chemotherapy/drug Mainly alkylating drugs • (cyclophosphamide, carmustine) Search for other culprit drugs in • www.pneumotox.com Declare adverse effect to • pharmacovigilance □ Low BMI*** Nonspecific yet suggestive of PPFE • Cachexia possible in very advanced • disease □ The functional profile may vary depending on the possible association of fibrosing ILD in the lower lobes □ Pleural pain Infrequent, difficult to alleviate • □ Hypercapnic chronic respiratory failure at late stage □ HRCT (or chest radiograph): spontaneous pneumothorax or pneumomediastinum □ Haematopoietic stem cell transplantation Frequent (∼50%) • Heterologous or homologous Can be bilateral • • Often asymptomatic • Often small size (need for chest drainage is rare) • Often resolves spontaneously or comes and goes • □ HRCT: Platythorax (flat chest index)*** □ Lung transplantation Anteroposterior diameter to transverse diameter ratio of the thoracic cage Restrictive chronic allograft • • at the level of the sixth thoracic vertebra§ dysfunction □ HRCT: 3D-CT assessment of upper lobe volume [23] □ Associated diseases and ILDs Marked loss of upper lobe volume with increased lower lobe volume in PPFE*** Connective tissue disease • • May help to evaluate disease severity and mortality risk Fibrotic HSP • • Fibrotic idiopathic ILD • □ Chest radiograph: upper lobe pleural thickening with progressive □ Clinical or biological sign of telomere volume loss and upward shift of hilar structures disorders Premature hair greying • Haematological disorders • Liver disorders • Nail abnormalities • □ Other patterns of fibrotic ILD may coexist with PPFE □ Familial history of PPFE or other ILD Mainly UIP, less frequently NSIP or chronic HSP • Occurs most frequently in the lower lobes • □ Environmental exposures (asbestosis, silica, aluminium) Likely but still unclear relationship • □ Chronic respiratory infections i.e. chronic aspergillosis or • nontuberculous mycobacteria Relationship still unclear: cause or • consequence? □ Radiation therapy Unclear role; may be a differential • diagnosis □ Age PPFE may be present at any age • □ Dyspnoea*** Nonspecific and progressive • Nonspecific cough may be associated • □ No link to cigarette smoking □ Clubbing Nonspecific and often absent • □ No crackles Usually absent (except in the presence of • another associated ILD pattern) Strong orientation criteria for the diagnosis of PPFE are in bold. Progression is also a key criterion for the diagnosis of PPFE; criteria worth monitoring to assess disease progression are identifiable with asterisks (***). This checklist may help in the preparation of multidisciplinary discussion. #: defined as an increase in the upper lobe consolidation with or without pleural thickening and/or a decrease in upper lobe volume on serial radiologic assessment. ¶: such as connective tissue disease-related interstitial lung disease (ILD), chronic hypersensitivity pneumonitis (HSP), pulmonary sarcoidosis, pneumoconiosis and active pulmonary infection. This last criterion is debatable as PPFE may be associated with the presence of other fibrosing ILD patterns. +: definite PPFE: 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 distribution of these changes not concentrated in the upper lobes or no features of coexistent disease elsewhere. §: the flat chest index at the diagnosis of PPFE was found to be 0.57 in the study from IKEDA et al. [22] with a reference value for idiopathic pulmonary fibrosis of 0.65 [12]. BMI: body mass index; TLC: total lung capacity; FVC: forced vital capacity; RV: residual volume; DLCO: diffusing capacity of the lung for carbon monoxide; VA: alveolar volume; HRCT: high-resolution computed tomography; 3D-CT: three-dimensional computed tomography; UIP: usual interstitial pneumonia; NSIP: nonspecific interstitial pneumonia. 2 EDITORIAL | P. BONNIAUD ET AL. Clinical characteristics EUROPEAN RESPIRATORY JOURNAL https://doi.org/10.1183/13993003.01798-2022 TABLE 1 Main criteria checklist proposed for diagnosing pleuroparenchymal fibroelastosis (PPFE), either idiopathic or non-idiopathic in the absence of pathology EUROPEAN RESPIRATORY JOURNAL EDITORIAL | P. BONNIAUD ET AL. Diagnosis Pathophysiology Management and evolution Imaging Therapy KL6 Elastine Serum latent TGFB binding protein 4 Biomarkers Pathology Follow-up FIGURE 1 Unmet needs in pleuroparenchymal fibroelastosis diagnosis and management: there are many unanswered questions and clinical challenges concerning diagnostic tools ( physiopathology; biomarkers; imaging, remaining key for diagnosis; and biopsy, with high risk of pneumothorax) and management (therapy and follow-up). Better understanding of pathophysiology and the identification of biomarkers should lead to management improvement. The same authors and others later proposed non-pathological diagnostic criteria to confirm PPFE [12], circumventing the need for invasive sampling and also incorporating disease progression into the disease definition [13]. Imaging continues to be the main avenue for the non-invasive diagnosis of PPFE. A simple chest radiograph shows key features of the condition, including thickening of the pleura, especially in the upper lobes, distinctive flattening of the thorax, and an elevation of the hilar structures of the lungs [14]. However, it is not an imaging technique that can be used to confirm suspected cases. There are no pleural ultrasound criteria to support a diagnosis of PPFE, even though the examination can be a supplementary tool for initial phenotyping of the disease [15]. Chest high-resolution computed tomography (HRCT) remains the key examination in the recognition and validation of the diagnosis of PPFE in referral centres in the context of systematic multidisciplinary discussion. HRCT can identify additional features that include symmetrical or asymmetrical dense pleural and subpleural consolidations with a reticular pattern, and architectural distortions concentrated in the upper lobes. While the upward shift in the hilar structures, which is now recognised as a distinctive imaging feature, can be used for diagnosis, it was not found to be an effective means of evaluating stage [16]. Analysing lung volume, especially in order to reveal diminished or diminishing volume in the upper lobes, was previously suggested to be an important approach [17]. Beyond diagnostic considerations, it is urgently needed to identify criteria of disease progression, which can help assess prognosis and can be used as end-points in prospective therapeutic studies. However, even for more common conditions, such as pulmonary fibrosis, such criteria are not easy to establish [18]. There are no specific and robust clinical criteria for PPFE prognosis or progression apart from platythorax, which is frequent but not systematic, and low body mass index (BMI) [12]. The combination of low BMI, decreased forced vital capacity (FVC) and increased residual volume to total lung capacity ratio may be related to the progressive flattening of the rib cage which is one of the most striking features of the condition [19]. Moreover, a score using FVC, a history of pneumothorax, the presence of a lower lobe interstitial lung disease, and the level of Krebs von der Lungen 6 (KL6) may predict mortality [20]. While PPFE patients have impaired lung function with a marked restrictive https://doi.org/10.1183/13993003.01798-2022 3 EUROPEAN RESPIRATORY JOURNAL EDITORIAL | P. BONNIAUD ET AL. profile, definitive criteria to assess disease progression by lung function analysis alone remain elusive, and imaging might be a better alternative. In 2014, HARADA et al. [21] explored the possibility that the flattening of the thorax could be used to evaluate disease progression. However, assessments of the progression of the ratio of the anteroposterior diameter to the transverse diameter of the thoracic cage using CT imaging revealed that it was not suitable as an endpoint [22]. More recent publications have turned to pulmonary volume as a way to potentially assess progression. NASSER et al. [17] were the first to measure the decline in upper lung volume by HRCT to assess the efficacy of nintedanib treatment in a retrospective study. In this issue of the European Respiratory Journal, FUKADA et al. [23] bring exciting new perspectives. In a large retrospective study, they analysed three-dimensional computed tomography (3D-CT) to measure the lung volume specifically in the upper lobes in patients with idiopathic PPFE. They quantitatively measured each lobe with 3D-CT and standardised the volume using predicted FVC. Beyond confirming that there are 3D-CT “volume” specificities for PPFE, the novel findings demonstrate that the standardised measurement of upper lung volume could be used to assess severity and mortality risk. The authors suggest that a change in standardised upper lung volume could indeed be considered a marker of disease severity, and that variations over time could potentially be used to assess disease progression. Furthermore, they found a significant association between increased annual relative decline of standardised upper lobe volume and mortality. Thus, clinicians could potentially use this relatively simple, safe and patient-friendly method to assess and monitor disease progression, and also to start narrowing in on prognosis. There is still a need in the future to validate this method in prospective studies and in non-idiopathic PPFE. Biological biomarkers including serum levels of KL6, surfactant protein-D (SPD), urinary desmosines (a breakdown product of elastin) or latent transforming growth factor-β binding protein 4 are candidates to assess disease progression but are not ready for prime time [20, 24–27]. Genetics, with rare genetic variants, especially telomere-related gene mutations, is a promising avenue for the understanding of PPFE, but there is also much left to explore in this field [28]. Finally, a better understanding of the factors driving the condition would provide researchers with further resources to tackle the more practical aspects of disease management, including treatment, which is desperately missing. Lung transplantation faces many challenges, which include the flattened thorax and highly disturbed ventilatory mechanics in PPFE. The only medications that have been tested so far with varying results in retrospective studies are anti-fibrotic medications, which by extrapolation were thought to have a potential effect considering their indication for use in progressive pulmonary fibrosis [17, 29]. Is it however logical or even reasonable to start anti-fibrotic therapy in patients with PPFE complicated by pneumothorax? Wouldn’t it run the risk of slowing down the hope for pleural symphysis? Alas, as mentioned above, there have been limited investigations into the underlying mechanisms of the disease, partly due to the limited availability of human tissue. Questions remain as to why the principal extracellular matrix component in PPFE is elastin, and not collagen, as in most diseases with pulmonary fibrosis [30]. Alveolar epithelial denudation may be involved in the pathogenesis of the disease [31]. Mesothelial cells from the pleural surface might play a role in the pathogenesis of PPFE in addition to alveolar cell injury. Our team has developed pleural and subpleural fibrosis rodent models either by local TGF-β1 overexpression or in the presence of carbon particles after bleomycin stimulation with a demonstration of mesothelial-to-mesenchymal transition [32, 33]. These findings are reinforced by the presence of podoplanin-positive myofibroblast ( podoplanin is expressed in mesothelial cells) in PPFE but not in UIP human biopsies [34]. More recently, in an animal model and human pleural mesothelial cells, induced pleural fibroelastosis was successfully treated with metformin in an attempt to inhibit the production of extracellular matrix [35]. Nevertheless, the data remains limited and we do not yet have any solid mechanistic targets warranting prospective trials in patients with idiopathic or secondary PPFE. So, where should we go from here? In spite of these numerous challenges, the growing body of literature for PPFE provides a number of promising leads that should now be followed up in more depth. There is so much yet to do, but there are relatively few patients with PPFE and therefore few opportunities to compile meaningful datasets. In the future, large registries and prospective trials, ideally through the international community, are going to be necessary to improve our understanding of PPFE and therefore our ability to diagnose and manage it. Acknowledgements: The authors warmly thank Suzanne Rankin for her help with drafting, editing and proofreading the text. Some images from the figure were created with BioRender.com https://doi.org/10.1183/13993003.01798-2022 4 EUROPEAN RESPIRATORY JOURNAL EDITORIAL | P. BONNIAUD ET AL. Conflict of interest: P. Bonniaud reports grants from AstraZeneca; travel support from Roche, Boehringer, AstraZeneca, Novartis, Chiesi, Stallergenes and Sanofi; advisory board participation for Roche, Boehringer, AstraZeneca, Novartis, Sanofi and GSK; outside the submitted work. V. Cottin reports grants from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, Roche, Shionogi, RedX, Pure Tech, Celgene/BMS, AstraZeneca, CSL Behring, Sanofi, United Therapeutics/Ferrer and Pliant; lecture fees and travel support from Boehringer Ingelheim and Roche; participation on data and safety monitoring boards for Galapagos and Galecto; role on adjudication committee for Fibrogen; outside the submitted work. G. Beltramo reports lecture fees from Bristol-Myers Squibb and Sanofi; travel support from Novartis and Boehringer Ingelheim; outside the submitted work. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Amitani R, Niimi A, Kuse F. Idiopathic pulmonary upper lobe fibrosis (IPUF). 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