High risk of lung cancer in surfactant-related gene variant carriers.

BACKGROUND: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

Similarities and differences of interstitial lung disease associated with pathogenic variants in SFTPC and ABCA3 in adults.

BACKGROUND AND OBJECTIVE: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults. METHODS: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed. RESULTS: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group. CONCLUSION: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions.

Pulmonary function test results are correlated with 6-minute walk distance, distance-saturation product, and 6-minute walk work in patients with lymphangioleiomyomatosis.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare multicystic lung disease. Although a correlation between pulmonary function test (PFT) results and exercise capacity appears probable, it has not yet been demonstrated. The aim of this study was to assess whether PFT results correlate with 6-minute walk test (6MWT) results in patients with LAM. METHODS: We conducted a retrospective study of all patients with a diagnosis of LAM followed in a French reference centre over a 13-year period. PFT and 6MWT data were collected. Distance-saturation product (DSP) and 6-minute walk work (6MWORK) were calculated. RESULTS: A total of 62 patients were included. Their median forced expiratory volume in 1 s (FEV1) was 82.7 % predicted and their median forced vital capacity (FVC) was 96.7 % predicted. The median diffusing capacity of the lungs for carbon monoxide (DLCO) was 58.5 % predicted and was decreased in 79 % of the patients. The median 6-minute walk distance was 535 m, which was 90.9 % of the 602 m predicted distance. The median DSP was 497.4 m % and the median 6MWORK was 32,910 kg.m. The distance walked during the 6MWT was significantly correlated with FVC%predicted (R = 0.435), FEV1 %predicted (R = 0.303), TLC%predicted (R = 0.345), FRC%predicted (R = 0.262), RV/TLC ratio (R = -0.271), and DLCO%predicted (R = 0.279). DSP and 6MWORK were each significantly correlated with different PFT results. CONCLUSION: The present study shows that PFT results are potential predictors of the exercise capacity in patients with LAM. Additional studies are required to evaluate the interest of DSP and 6MWORK in LAM.

Changes in the management of chronic thromboembolic pulmonary hypertension over a 10-year period, in a French expert regional competence centre.

Over the last few years, the advent of balloon pulmonary angioplasty (BPA) had led to changes in the management of chronic thromboembolic pulmonary hypertension (CTEPH). We reviewed data from 98 CTEPH patients diagnosed during the last decade in a pulmonary hypertension (PH) expert centre. The management modalities of 2 periods (Period A: 2011-15 and Period B: 2016-20) were compared. Age (period A: 72 [58-80] years; period B: 69 [62-79] years), clinical (New York Heart Association (NYHA) functional class III-IV: 25/41, 61% vs 39/57, 68%), and hemodynamic assessments (pulmonary vascular resistance: 7.5 [6.2-8.7] WU vs 8.0 [6.0-10.2] WU) at baseline were not significantly different. Pulmonary endarterectomy was performed in less than one third of patients (12, 29.3% vs 15, 26.3%). For patients not eligible for surgery, medical therapy was mostly prescribed alone during period A (medical therapy alone, patients diagnosed in period A: 61% vs in period B: 17.5%) while it was associated with BPA during period B (medical therapy + BPA, 12% vs 61.4%). The 5-year survival rate was excellent for patients who underwent surgery (96.3%) or BPA (95.2%), but was only 42.1% for patients under oral medication only (p < 0.0001). Patients diagnosed with CTEPH who cannot be operated should undergo BPA. The survival rate after BPA is as good as after surgery and significantly better than that of oral medication only.

The world of rare interstitial lung diseases.

The world of rare interstitial lung diseases (ILDs) is diverse and complex. Diagnosis and therapy usually pose challenges. This review describes a selection of rare and ultrarare ILDs including pulmonary alveolar proteinosis, pulmonary alveolar microlithiasis and pleuroparenchymal fibroelastosis. In addition, monogenic ILDs or ILDs in congenital syndromes and various multiple cystic lung diseases will be discussed. All these conditions are part of the scope of the European Reference Network on rare respiratory diseases (ERN-LUNG). Epidemiology, pathogenesis, diagnostics and treatment of each disease are presented.

Role of the occupational disease consultant in the multidisciplinary discussion of interstitial lung diseases.

BACKGROUND: Diffuse interstitial lung diseases (ILD) constitute a heterogeneous group of conditions with complex etiological diagnoses requiring a multidisciplinary approach. Much is still unknown about them, particularly their relationship with occupational exposures. The primary objective of this study was to investigate the distribution of occupational exposures according to type of ILD. The secondary objectives were to estimate the proportion of ILDs possibly related to occupational exposure and to evaluate the added value of the participation of an occupational disease consultant in ILD multidisciplinary discussions (MDD). METHODS: From May to December 2020, all consecutive patients with ILD whose cases were reviewed during a MDD in a referral centre for ILD were prospectively offered a consultation with an occupational disease consultant. RESULTS: Of the 156 patients with ILD whose cases were reviewed in MDD during the study period, 141 patients attended an occupational exposure consultation. Occupational exposure was identified in 97 patients. Occupational exposure to asbestos was found in 12/31 (38.7%) patients with idiopathic pulmonary fibrosis (IPF) and in 9/18 (50.0%) patients with unclassifiable fibrosis. Occupational exposure to metal dust was found in 13/31 (41.9%) patients with IPFs and 10/18 (55.6%) patients with unclassifiable fibrosis. Silica exposure was found in 12/50 (24.0%) patients with autoimmune ILD. The link between occupational exposure and ILD was confirmed for 41 patients after the specialist occupational consultation. The occupational origin had not been considered (n = 9) or had been excluded or neglected (n = 4) by the MDD before the specialised consultation. A total of 24 (17%) patients were advised to apply for occupational disease compensation, including 22 (15.6%) following the consultation. In addition, a diagnosis different from the one proposed by the MDD was proposed for 18/141 (12.8%) patients. CONCLUSIONS: In our study, we found a high prevalence of occupational respiratory exposure with a potential causal link in patients with ILD. We suggest that a systematic specialised consultation in occupational medicine could be beneficial in the ILD diagnostic approach.

Pleuroparenchymal fibroelastosis.

PURPOSE OF REVIEW: Pleuroparenchymal fibroelastosis (PPFE) is a clinico-radiologic-pathologic interstitial lung disease (ILD) characterized by fibrosis that has upper lobe and subpleural predominance, involving both the visceral pleura and the subjacent subpleural lung parenchyma, and comprises dense fibroelastic changes with prominent elastosis of the alveolar walls together with fibrous thickening of the visceral pleura. The goal of this review is to summarize the state-of-the-art understanding in PPFE. RECENT FINDINGS: PPFE was described in an increasing number of conditions. The course of disease is heterogeneous. Idiopathic PPFE, cases associated with telomerase-related gene mutations, cases related to a history of chemotherapy, and cases combining PPFE with a pattern of usual interstitial pneumonia, may have a particularly poor prognosis. Well-conducted retrospective studies identified marked PPFE features in approximately 10% of patients with idiopathic pulmonary fibrosis, 11% of patients with systemic sclerosis-associated ILD, 6.5% of patients with rheumatoid arthritis-associated ILD, and 23% of patients with hypersensitivity pneumonitis. Drug therapy has not been evaluated prospectively. A small retrospective study suggests that nintedanib may slow disease progression. However, whether the efficacy of antifibrotics is comparable in PPFE and in other forms of progressive pulmonary fibrosis warrants further evaluation. SUMMARY: Accumulating data indicate that PPFE features are associated with poor prognosis in fibrosing ILDs. Further research on the management of PPFE is warranted.

Pulmonary fibrosis associated with rheumatoid arthritis: from pathophysiology to treatment strategies.

INTRODUCTION: Rheumatoid arthritis (RA) is the most common inflammatory autoimmune disease, characterized by symmetric destructive arthritis and synovitis. Lung involvement is frequent, including in the form of interstitial lung disease (ILD). RA-ILD often presents with a radiologic and pathologic pattern of usual interstitial pneumonia, similar to idiopathic pulmonary fibrosis, highlighting the similarities between the two diseases, but other patterns and pathological associations are described. AREAS COVERED: This article reviews the pathogenesis of pulmonary fibrosis in the setting of rheumatoid arthritis as well as the current and future therapeutic options. EXPERT OPINION: Pulmonary fibrosis in the setting of RA-ILD is an example of genotype-environment interaction and involves multiple mechanisms including autoimmunity, inflammation, and fibrogenesis. Although ILD conveys most of the exceeding mortality in RA patients, there are no official guidelines for the management of RA-ILD. Attention should be paid to potential lung toxicity of RA treatment even though some of them might help stabilize the ILD. Current standard of care is often composed of glucocorticoids that may be associated with immunosuppressive therapy. Following the approval of antifibrotic therapy for ILDs with a progressive fibrosing phenotype, current works are evaluating the benefit of such treatment in RA-ILD.