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.

Syndromic genetic causes of pulmonary fibrosis.

PURPOSE OF REVIEW: The identification of extra-pulmonary symptoms plays a crucial role in diagnosing interstitial lung disease (ILD). These symptoms not only indicate autoimmune diseases but also hint at potential genetic disorders, suggesting a potential overlap between genetic and autoimmune origins. RECENT FINDINGS: Genetic factors contributing to ILD are predominantly associated with telomere (TRG) and surfactant-related genes. While surfactant-related gene mutations typically manifest with pulmonary involvement alone, TRG mutations were initially linked to syndromic forms of pulmonary fibrosis, known as telomeropathies, which may involve hematological and hepatic manifestations with variable penetrance. Recognizing extra-pulmonary signs indicative of telomeropathy should prompt the analysis of TRG mutations, the most common genetic cause of familial pulmonary fibrosis. Additionally, various genetic diseases causing ILD, such as alveolar proteinosis, alveolar hemorrhage, or unclassifiable pulmonary fibrosis, often present as part of syndromes that include hepatic, hematological, or skin disorders. SUMMARY: This review explores the main genetic conditions identified over the past two decades.

Cystic lung in sarcoidosis: Clinico-radiologic characteristic and evolution.

BACKGROUND AND OBJECTIVE: Sarcoidosis can manifest with atypical findings on chest computed tomography (CT). Cysts are a rare manifestation of lung sarcoidosis. The aim of the study was to describe a series of patients with cystic sarcoidosis and their clinical-radiological characteristics and progression. METHODS: In this retrospective, bicentric study we recruited all patients affected by sarcoidosis with lung cystic lesions at chest CT. We collected clinical characteristics, pulmonary tests and tracked number, distribution and size of the cysts at diagnosis and at the last evaluation. RESULTS: Twelve patients (6 males, median age 53 years) were identified (prevalence: 1.9%; 95% Confidence Interval: 0.8%-2.9%). All patients presented multiple cystic lesions (median number: 14 [range: 2-216]) with a bilateral distribution in 10/12, micronodules and nodules in 11/12 and fibrotic lesions in 4/12. Seven patients had normal lung function test, three had an obstructive syndrome, one had a restrictive syndrome and one had coexistence of both. During follow-up (median: 10 years [range 1-16 years]), an increase of the number of cysts was observed in four patients. At last evaluation, 3/12 patients experienced a decline of forced vital capacity >10% and 3/12 patients a decline of diffusing capacity for carbon monoxide (DLCO) >10%. A lower DLCO at diagnosis, and the presence of nodules or fibrotic lesions on CT were associated with an increase in the number of cysts. CONCLUSION: Cystic lung lesions are rare in patients with sarcoidosis and do not influence long term prognosis.

Chronic interstitial lung disease associated with systemic lupus erythematosus: A multicentric study of 89 cases.

BACKGROUND AND OBJECTIVE: Chronic interstitial lung disease (ILD) occurs rarely with systemic lupus erythematosus (SLE) as compared with other connective tissue diseases. This multicentric retrospective study of patients with SLE-ILD from the OrphaLung and French SLE networks during 2005-2020 aimed to describe the characteristics of patients with SLE-ILD and analyse factors associated with prognosis. METHODS: We analysed data for 89 patients with SLE-ILD (82 women, 92.1%) (median age at SLE diagnosis: 35 years [interquartile range 27-47]). All patients met the 2019 EULAR/ACR criteria for the diagnosis of SLE. RESULTS: Forty two (47.2%) patients were positive for anti-ribonuclear protein antibodies and 45 (50.6%) for anti SSA/Ro antibodies. A total of 58 (65.2%) patients had another connective tissue disease: Sjögren's syndrome (n = 33, 37.1%), systemic sclerosis (n = 14, 15.7%), inflammatory myopathy (n = 6, 6.7%), or rheumatoid arthritis (n = 6, 6.7%). ILD was diagnosed along with SLE in 25 (28.1%) patients and at a median of 6 (0-14) years after the SLE diagnosis. The most frequent CT pattern was suggestive of non-specific interstitial pneumonia (n = 41, 46.0%) with or without superimposed organizing pneumonia. After a median follow-up of 86.5 [39.5-161.2] months, 18 (20.2%) patients had died and 6 (6.7%) underwent lung transplantation. The median 5-year and 10-year transplantation-free survival were 96% (92-100) and 87% (78-97). In total, 44 (49.4%) patients showed ILD progression. Cutaneous manifestations and Raynaud's phenomenon were associated with better survival. Only forced vital capacity was significantly associated with survival and ILD progression. CONCLUSION: ILD is a rare manifestation of SLE with good overall prognosis but with possible risk of ILD progression. Patients with SLE-ILD frequently have another connective tissue disease.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. METHODS: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. FINDINGS: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. INTERPRETATION: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection.

Strategies to safely rule out pulmonary embolism in COVID-19 outpatients: a multicenter retrospective study.

OBJECTIVES: The objective was to define a safe strategy to exclude pulmonary embolism (PE) in COVID-19 outpatients, without performing CT pulmonary angiogram (CTPA). METHODS: COVID-19 outpatients from 15 university hospitals who underwent a CTPA were retrospectively evaluated. D-Dimers, variables of the revised Geneva and Wells scores, as well as laboratory findings and clinical characteristics related to COVID-19 pneumonia, were collected. CTPA reports were reviewed for the presence of PE and the extent of COVID-19 disease. PE rule-out strategies were based solely on D-Dimer tests using different thresholds, the revised Geneva and Wells scores, and a COVID-19 PE prediction model built on our dataset were compared. The area under the receiver operating characteristics curve (AUC), failure rate, and efficiency were calculated. RESULTS: In total, 1369 patients were included of whom 124 were PE positive (9.1%). Failure rate and efficiency of D-Dimer > 500 µg/l were 0.9% (95%CI, 0.2-4.8%) and 10.1% (8.5-11.9%), respectively, increasing to 1.0% (0.2-5.3%) and 16.4% (14.4-18.7%), respectively, for an age-adjusted D-Dimer level. D-dimer > 1000 µg/l led to an unacceptable failure rate to 8.1% (4.4-14.5%). The best performances of the revised Geneva and Wells scores were obtained using the age-adjusted D-Dimer level. They had the same failure rate of 1.0% (0.2-5.3%) for efficiency of 16.8% (14.7-19.1%), and 16.9% (14.8-19.2%) respectively. The developed COVID-19 PE prediction model had an AUC of 0.609 (0.594-0.623) with an efficiency of 20.5% (18.4-22.8%) when its failure was set to 0.8%. CONCLUSIONS: The strategy to safely exclude PE in COVID-19 outpatients should not differ from that used in non-COVID-19 patients. The added value of the COVID-19 PE prediction model is minor. KEY POINTS: • D-dimer level remains the most important predictor of pulmonary embolism in COVID-19 patients. • The AUCs of the revised Geneva and Wells scores using an age-adjusted D-dimer threshold were 0.587 (95%CI, 0.572 to 0.603) and 0.588 (95%CI, 0.572 to 0.603). • The AUC of COVID-19-specific strategy to rule out pulmonary embolism ranged from 0.513 (95%CI: 0.503 to 0.522) to 0.609 (95%CI: 0.594 to 0.623).

Interstitial lung diseases associated with mutations of poly(A)-specific ribonuclease: A multicentre retrospective study.

BACKGROUND AND OBJECTIVE: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations. METHODS: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network. RESULTS: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation. CONCLUSION: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed.

Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia.

Increased blood fibrocytes are associated with a poor prognosis in fibrotic lung diseases. We aimed to determine whether the percentage of circulating fibrocytes could be predictive of severity and prognosis during coronavirus disease 2019 (COVID-19) pneumonia. Blood fibrocytes were quantified by flow cytometry as CD45+/CD15-/CD34+/collagen-1+ cells in patients hospitalized for COVID-19 pneumonia. In a subgroup of patients admitted in an intensive care unit (ICU), fibrocytes were quantified in blood and bronchoalveolar lavage (BAL). Serum amyloid P (SAP), transforming growth factor-ß1 (TGF-ß1), CXCL12, CCL2, and FGF2 concentrations were measured. We included 57 patients in the hospitalized group (median age = 59 yr [23-87]) and 16 individuals as healthy controls. The median percentage of circulating fibrocytes was higher in the patients compared with the controls (3.6% [0.2-9.2] vs. 2.1% [0.9-5.1], P = 0.04). Blood fibrocyte count was lower in the six patients who died compared with the survivors (1.6% [0.2-4.4] vs. 3.7% [0.6-9.2], P = 0.02). Initial fibrocyte count was higher in patients showing a complete lung computed tomography (CT) resolution at 3 mo. Circulating fibrocyte count was decreased in the ICU group (0.8% [0.1-2.0]), whereas BAL fibrocyte count was 6.7% (2.2-15.4). Serum SAP and TGF-ß1 concentrations were increased in hospitalized patients. SAP was also increased in ICU patients. CXCL12 and CCL2 were increased in ICU patients and negatively correlated with circulating fibrocyte count. We conclude that circulating fibrocytes were increased in patients hospitalized for COVID-19 pneumonia, and a lower fibrocyte count was associated with an increased risk of death and a slower resolution of lung CT opacities.

Study of Thoracic CT in COVID-19: The STOIC Project.

Background There are conflicting data regarding the diagnostic performance of chest CT for COVID-19 pneumonia. Disease extent at CT has been reported to influence prognosis. Purpose To create a large publicly available data set and assess the diagnostic and prognostic value of CT in COVID-19 pneumonia. Materials and Methods This multicenter, observational, retrospective cohort study involved 20 French university hospitals. Eligible patients presented at the emergency departments of the hospitals involved between March 1 and April 30th, 2020, and underwent both thoracic CT and reverse transcription-polymerase chain reaction (RT-PCR) testing for suspected COVID-19 pneumonia. CT images were read blinded to initial reports, RT-PCR, demographic characteristics, clinical symptoms, and outcome. Readers classified CT scans as either positive or negative for COVID-19 based on criteria published by the French Society of Radiology. Multivariable logistic regression was used to develop a model predicting severe outcome (intubation or death) at 1-month follow-up in patients positive for both RT-PCR and CT, using clinical and radiologic features. Results Among 10 930 patients screened for eligibility, 10 735 (median age, 65 years; interquartile range, 51-77 years; 6147 men) were included and 6448 (60%) had a positive RT-PCR result. With RT-PCR as reference, the sensitivity and specificity of CT were 80.2% (95% CI: 79.3, 81.2) and 79.7% (95% CI: 78.5, 80.9), respectively, with strong agreement between junior and senior radiologists (Gwet AC1 coefficient, 0.79). Of all the variables analyzed, the extent of pneumonia at CT (odds ratio, 3.25; 95% CI: 2.71, 3.89) was the best predictor of severe outcome at 1 month. A score based solely on clinical variables predicted a severe outcome with an area under the curve of 0.64 (95% CI: 0.62, 0.66), improving to 0.69 (95% CI: 0.6, 0.71) when it also included the extent of pneumonia and coronary calcium score at CT. Conclusion Using predefined criteria, CT reading is not influenced by reader's experience and helps predict the outcome at 1 month. ClinicalTrials.gov identifier: NCT04355507 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Rubin in this issue.

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

Radiation dose reduction with the wide-volume scan mode for interstitial lung diseases.

OBJECTIVES: The wide-volume mode, available on wide-area detector row CTs, has the advantage of reducing exposure time and radiation dose. It is infrequently used for lung diseases. The purpose of this study is to compare image quality and radiation dose of wide-volume chest CT to those of standard helical CT in the setting of interstitial lung diseases. METHODS: Retrospective monocentric study including 50 consecutive patients referred for follow-up or screening of interstitial lung diseases, requiring prone scan, acquired with the wide-volume mode, in addition to the routine supine scan, acquired with the helical mode. The optimal collimation in wide-volume mode (320 × 0.5mm or 240 × 0.5mm) was chosen according to the length of the thorax. Wide-volume acquisitions were compared to helical acquisitions for radiation dose (CTDIvol, DLP) and image quality, including analysis of normal structures, lesions, overall image quality, and artifacts (Wilcoxon signed-rank test). RESULTS: Median CTDIvol and DLP with wide volumes (3.1 mGy and 94.6 mGy·cm) were significantly reduced (p < 0.0001) as compared to helical mode (3.7mGy and 122.1 mGy·cm), leading to a median 21% and 32% relative reduction of CTDIvol and DLP, respectively. Image noise and quality were not significantly different between the two modes. Misalignment artifact at the junction of two volumes was occasionally seen in the wide-volume scans and, when present, did not impair the diagnostic quality in the majority of cases. CONCLUSIONS: Wide-volume mode allows 32% radiation dose reduction compared to the standard helical mode and could be used routinely for diagnosis and follow-up of interstitial lung diseases. KEY POINTS: • Retrospective monocentric study showed that wide-volume scan mode reduces radiation dose by 32% in comparison to helical mode for chest CT in the setting of interstitial lung diseases. • Mild misalignment may be observed at the junction between volumes with the wide-volume mode, without decrease of image quality in the majority of cases and without impairing diagnostic quality. • Wide-volume mode could be used routinely for the diagnosis and follow-up of interstitial lung diseases.

Observer agreement and clinical significance of chest CT reporting in patients suspected of COVID-19.

OBJECTIVES: To assess interobserver agreement and clinical significance of chest CT reporting in patients suspected of COVID-19. METHODS: From 16 to 24 March 2020, 241 consecutive patients addressed to hospital for COVID-19 suspicion had both chest CT and SARS-CoV-2 RT-PCR. Eight observers (2 thoracic and 2 general senior radiologists, 2 junior radiologists, and 2 emergency physicians) retrospectively categorized each CT into one out of 4 categories (evocative, compatible for COVID-19 pneumonia, not evocative, and normal). Observer agreement for categorization between all readers and pairs of readers with similar experience was evaluated with the Kappa coefficient. The results of a consensus categorization were correlated to RT-PCR. RESULTS: Observer agreement across the 4 categories was good between all readers (κ value 0.61 95% CI 0.60-0.63) and moderate to good between pairs of readers (0.54-0.75). It was very good (κ 0.81 95% CI 0.79-0.83), fair (κ 0.32 95% CI 0.29-0.34), moderate (κ 0.56 95% CI 0.54-0.58), and moderate (0.58 95% CI 0.56-0.61) for the categories evocative, compatible, not evocative, and normal, respectively. RT-PCR was positive in 97%, 50%, 31%, and 11% of cases in the respective categories. Observer agreement was lower (p < 0.001) and RT-PCR positive cases less frequently categorized evocative in the presence of an underlying pulmonary disease (p < 0.001). CONCLUSION: Interobserver agreement for chest CT reporting using categorization of findings is good in patients suspected of COVID-19. Among patients considered for hospitalization in an epidemic context, CT categorized evocative is highly predictive of COVID-19, whereas the predictive value of CT decreases between the categories compatible and not evocative. KEY POINTS: • In patients suspected of COVID-19, interobserver agreement for chest CT reporting into categories is good, and very good to categorize CT "evocative." • Chest CT can participate in estimating the likelihood of COVID-19 in patients presenting to hospital during the outbreak, CT categorized "evocative" being highly predictive of the disease whereas almost a third of patients with CT "not evocative" had a positive RT-PCR in our study. • Observer agreement is lower and CTs of positive RT-PCR cases less frequently "evocative" in presence of an underlying pulmonary disease.

Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer.

INTRODUCTION: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives. METHODS: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented. RESULTS: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic. DISCUSSION: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes.

Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5-9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0-80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.

Rituximab for auto-immune alveolar proteinosis, a real life cohort study.

BACKGROUND: Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody. METHODS: We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed. RESULTS: Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naïve to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced. CONCLUSIONS: These data do not support rituximab as a second line therapy for patients with refractory aPAP.

Early computed tomography modifications following bronchial thermoplasty in patients with severe asthma.

Bronchial thermoplasty (BT) is a recent, promising and well-tolerated technique for the treatment of severe asthma. By delivering thermal energy to the airway wall, this procedure can induce early pulmonary opacities seen on computed tomography (CT). We aimed to examine early CT modifications induced by BT and to determine their association with respiratory symptoms.Unenhanced chest CT was performed the day after each BT session in 13 patients with severe asthma, leading to the examination of 38 treated lobes. A total of 15 BT-treated lobes were evaluated in 11 patients at 1 month. The first two patients also underwent CT at 1 week.No symptoms suggestive of pulmonary infection were noted following BT in any patient. Peribronchial consolidations and ground-glass opacities were observed in all treated lobes on day 1, with three lower lobes showing complete collapse. Mild involvement of an adjacent untreated lobe was observed in 12 out of 38 (32%) cases. Opacities had decreased in 5 out of 15 (33%) and disappeared in 10 out of 15 (67%) at 1 month.BT induced early pulmonary peribronchial hyperdensities in all treated lobes. These alterations were unrelated to clinical symptoms and spontaneously decreased or disappeared after 1 month.

Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis.

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10-4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10-2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses.

BACKGROUND: Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). METHODS: Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. RESULTS: Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. CONCLUSIONS: This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.