Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

Haematological features of telomere biology disorders diagnosed in adulthood: A French nationwide study of 127 patients.

Data on haematological features of telomere biology disorders (TBD) remain scarce. We describe haematological, extra-haematological characteristics and prognosis of 127 genetically confirmed TBD patients diagnosed after the age of 15. Ninety-three index cases and 34 affected relatives were included. At diagnosis of TBD, 76.3% of index cases had haematological features, half pulmonary features and a third liver features. At diagnosis, bone marrow failure (BMF) was present in 59 (46.5%), myelodysplastic syndrome (MDS) in 22 (17.3%) and acute myeloid leukaemia (AML) in 2 (1.6%) while 13 (10.2%) developed or worsened bone marrow involvement during follow-up. At diagnosis, compared to MDS/AML patients, BMF patients were younger (median 23.1 years vs. 43.8, p = 0.007), and had a better outcome (4-year overall survival 76.3% vs. 31.8%, p < 0.001). While frequencies and burden of cytogenetical and somatic mutations increased significantly in myeloid malignancies, some abnormalities were also observed in patients with normal blood counts and BMF, notably somatic spliceosome variants. Solid cancers developed in 8.7% patients, mainly human papillomavirus-related cancers and hepatocellular carcinomas. TBD is a multiorgan progressive disease. While BMF is the main haematological disorder, high-risk myeloid malignancies are common, and are, together with age, the only factors associated with a worse outcome.

Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study.

BACKGROUND: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. METHODS: We used two-sample bidirectional Mendelian randomisation (MR) to test the hypothesis of a causal effect of RA on UIP and of UIP on RA, using variants from genome-wide association studies (GWAS) of RA (separately for seropositive (18 019 cases and 991 604 controls) and seronegative (8515 cases and 1 015 471 controls) RA) and of IPF (4125 cases and 20 464 controls) as genetic instruments. Sensitivity analyses were conducted to assess the robustness of the results to violations of the MR assumptions. FINDINGS: IPF showed a significant causal effect on seropositive RA, with developing IPF increasing the risk of seropositive RA (OR=1.06, 95% CI: 1.04 to 1.08, p<0.001) which was robust under all models. For the MR in the other direction, seropositive RA showed a significant protective effect on IPF (OR=0.93; 95% CI: 0.87 to 0.99; p=0.032), but the effect was not significant when sensitivity analyses were applied. This was likely because of bias due to exclusion of patients with RA from among the cases in the IPF GWAS, or possibly because our genetic instruments did not fully capture the effect of the complex human leucocyte antigen region, the strongest RA genetic risk factor. INTERPRETATION: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between UIP and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The significant causal effect of IPF on seropositive RA suggests that pathomechanisms involved in the development of UIP may promote RA, and this may help inform future guidelines on screening for ILD in patients with RA.

Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

European Respiratory Society guidelines for the Diagnosis and Management of Pulmonary Alveolar Proteinosis.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage, evaluation of antibodies against granulocyte macrophage colony stimulating factor (GM-CSF), genetic testing, and, eventually, lung biopsy. The management options are focused at removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis, and lung transplantation. The presented diagnostic and management guideline aim to provide guidance to physicians managing patients with PAP. METHODS: A European Respiratory Society Task Force committee composed of clinicians, methodologists, and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of the evidence and strength of recommendations. The committee formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions, and two narrative questions to develop specific evidence-based recommendations. RESULTS: The Task Force committee developed recommendations for five PICOs. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis, and lung transplantation. Also, the committee made recommendations regarding the use of GM-CSF antibody testing, diagnostic bronchoalveolar lavage (BAL) and biopsy based on narrative questions.In addition to the recommendations, the committee provided information on the hierarchy of diagnostic interventions and therapy. CONCLUSIONS: The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited.

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.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

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.

Effect of antifibrotic agents on postoperative complications after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Antifibrotic agents (AFAs) are now standard-of-care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx). METHODS: We performed a multi-centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri-operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post-operative complications and the survival of patients according to AFA exposure. RESULTS: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6-24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90-day mortality was lower (7% vs. 18%, p = 0.046). CONCLUSIONS: AFA therapy did not increase airway, bleeding or wound post-operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90-day mortality.