Weakly-supervised learning-based pathology detection and localization in 3D chest CT scans.

BACKGROUND: Recent advancements in anomaly detection have paved the way for novel radiological reading assistance tools that support the identification of findings, aimed at saving time. The clinical adoption of such applications requires a low rate of false positives while maintaining high sensitivity. PURPOSE: In light of recent interest and development in multi pathology identification, we present a novel method, based on a recent contrastive self-supervised approach, for multiple chest-related abnormality identification including low lung density area ("LLDA"), consolidation ("CONS"), nodules ("NOD") and interstitial pattern ("IP"). Our approach alerts radiologists about abnormal regions within a computed tomography (CT) scan by providing 3D localization. METHODS: We introduce a new method for the classification and localization of multiple chest pathologies in 3D Chest CT scans. Our goal is to distinguish four common chest-related abnormalities: "LLDA", "CONS", "NOD", "IP" and "NORMAL". This method is based on a 3D patch-based classifier with a Resnet backbone encoder pretrained leveraging recent contrastive self supervised approach and a fine-tuned classification head. We leverage the SimCLR contrastive framework for pretraining on an unannotated dataset of randomly selected patches and we then fine-tune it on a labeled dataset. During inference, this classifier generates probability maps for each abnormality across the CT volume, which are aggregated to produce a multi-label patient-level prediction. We compare different training strategies, including random initialization, ImageNet weight initialization, frozen SimCLR pretrained weights and fine-tuned SimCLR pretrained weights. Each training strategy is evaluated on a validation set for hyperparameter selection and tested on a test set. Additionally, we explore the fine-tuned SimCLR pretrained classifier for 3D pathology localization and conduct qualitative evaluation. RESULTS: Validated on 111 chest scans for hyperparameter selection and subsequently tested on 251 chest scans with multi-abnormalities, our method achieves an AUROC of 0.931 (95% confidence interval [CI]: [0.9034, 0.9557], p $ p$ -value < 0.001) and 0.963 (95% CI: [0.952, 0.976], p $ p$ -value < 0.001) in the multi-label and binary (i.e., normal versus abnormal) settings, respectively. Notably, our method surpasses the area under the receiver operating characteristic (AUROC) threshold of 0.9 for two abnormalities: IP (0.974) and LLDA (0.952), while achieving values of 0.853 and 0.791 for NOD and CONS, respectively. Furthermore, our results highlight the superiority of incorporating contrastive pretraining within the patch classifier, outperforming Imagenet pretraining weights and non-pretrained counterparts with uninitialized weights (F1 score = 0.943, 0.792, and 0.677 respectively). Qualitatively, the method achieved a satisfactory 88.8% completeness rate in localization and maintained an 88.3% accuracy rate against false positives. CONCLUSIONS: The proposed method integrates self-supervised learning algorithms for pretraining, utilizes a patch-based approach for 3D pathology localization and develops an aggregation method for multi-label prediction at patient-level. It shows promise in efficiently detecting and localizing multiple anomalies within a single scan.

Evidence from recent clinical trials in fibrotic interstitial lung diseases.

PURPOSE OF REVIEW: Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrosing interstitial lung diseases. It is mirrored by progressive pulmonary fibrosis (PPF), an umbrella term which characterizes disease behavior of various fibrotic interstitial lung diseases with irreversible progression, accounting for loss of lung function, exercise intolerance and respiratory failure leading to early mortality. Pirfenidone and nintedanib halve the decline in lung function but do not halt disease progression. RECENT FINDINGS: Since the publication in 2014 of pivotal pirfenidone and nintedanib studies, a number of clinical trials were conducted, many of them did not reach their primary endpoints. In IPF, promising phase 2 trials were followed by large phase 3 trials that did not confirm a favorable efficacy to tolerability favorable profile, including those with ziritaxestat, an autotaxin-1 inhibitor, zinpentraxin-alpha (human recombinant pentraxin-2), and the monoclonal antibody pamrevlumab targeting connective tissue growth factor. Nevertheless, newer compounds that hold promise are currently being evaluated in phase 3 or phase 2b randomized controlled trials, including: nerandomilast, a preferential phosphodiesterase 4B inhibitor; admilparant, a lysophosphatidic acid receptor antagonist; inhaled treprostinil, a prostacyclin agonist; and bexotegrast, a dual-selective inhibitor of αvß6 and αvß1 integrins. Nerandomilast, admilparant, inhaled treprostinil, and inhaled AP01 (pirfenidone), are currently studied in patients with PPF. SUMMARY: Despite recent frustrating negative results, there is a growing portfolio of candidate drugs developed in both IPF and PPF.

Quantitative imaging methods in combined pulmonary fibrosis and emphysema.

TOPIC IMPORTANCE: Combined pulmonary fibrosis and emphysema (CPFE) is an underdiagnosed syndrome in which individuals have variable degrees of pulmonary fibrosis and emphysema. Patients with CPFE have high morbidity, including poor exercise tolerance and increased development of co-morbidities. CPFE mortality also appears to outpace lone emphysema and pulmonary fibrosis. A major limitation to rigorous, large-scale studies of CPFE has been the lack of a precise definition for this syndrome. A 2022 ATS/ERJ/JRS/ALAT Research Statement called attention to fundamental gaps in our understanding of CPFE and highlighted the potential use of quantitative imaging techniques to better define CPFE. REVIEW FINDINGS: Broadly, CPFE has been defined using visual interpretation of chest computed tomography (CT) documenting the presence of both emphysema and fibrosis, with varying distributions. When quantitative approaches were employed, varying thresholds of emphysema and fibrosis on imaging have been used across different studies. SUMMARY: This review is structured into three primary themes, starting with early imaging studies, then evaluating the use of quantitative methods and imaging-based thresholds both in large population studies and single center cohorts to define CPFE and assess patient outcomes, and concludes by discussing current challenges and how to focus our efforts so quantitative imaging methods can effectively address the most pressing clinical dilemmas in CPFE.

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.

Circulating biomarkers and progression of idiopathic pulmonary fibrosis: data from the INMARK trial.

Background: We used data from the INMARK trial to investigate associations between circulating biomarkers of extracellular matrix (ECM) turnover, inflammation and epithelial dysfunction and disease progression in subjects with idiopathic pulmonary fibrosis (IPF). Methods: Subjects with IPF and forced vital capacity (FVC) ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Associations between baseline biomarker levels and the proportion of subjects with disease progression (decline in FVC ≥10% predicted or death) over 52 weeks were assessed in subjects randomised to placebo using logistic regression. Associations between baseline demographic/clinical characteristics and biomarker levels and disease progression over 52 weeks were analysed using multivariate models. Results: Of 230 subjects who received placebo for 12 weeks then open-label nintedanib for 40 weeks, 70 (30.4%) had disease progression over 52 weeks. Baseline levels of CRPM (C-reactive protein (CRP) degraded by matrix metalloproteinase (MMP)-1/8), C3M (collagen 3 degraded by MMP-9), CRP, KL-6 (Krebs von den Lungen-6) and SP-D (surfactant protein D) were not significantly associated with disease progression over 52 weeks in analyses corrected for multiple comparisons. In models including only baseline demographic/clinical characteristics, 61.2-64.2% of subjects were correctly classified as having or not having disease progression over 52 weeks. When both demographic/clinical characteristics and biomarker levels were included in the models, 50.0-64.5% of the test set were correctly classified. Conclusions: Among subjects with IPF and preserved FVC, multivariate models based on demographic/clinical characteristics and biomarker levels at baseline did not provide an accurate prediction of which patients would progress.

Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

Bioreactance assessment of cardiac output lacks reliability for the follow-up of patients with pulmonary hypertension.

Cardiac output (CO) is one of the primary prognostic factors evaluated during the follow-up of patients treated for pulmonary hypertension (PH). It is recommended that it be measured using the thermodilution technique during right heart catheterization. The difficulty to perform iterative invasive measurements on the same individual led us to consider a non-invasive option. The aims of the present study were to assess the agreement between CO values obtained using bioreactance (Starling™ SV) and thermodilution, and to evaluate the ability of the bioreactance monitor to detect patients whose CO decreased by more than 15% during follow-up and, accordingly, its usefulness for patient monitoring. A prospective cohort study evaluating the performance of the Starling™ SV monitor was conducted in patients with clinically stable PH. Sixty patients referred for hemodynamic assessment were included. CO was measured using both the thermodilution technique and bioreactance during two follow-up visits. A total of 60 PH patients were included. All datasets were available at the baseline visit (V0) and 50 of them were usable during the follow-up visit (V1). Median [IQR] CO was 4.20 l/min [3.60-4.70] when assessed by bioreactance, and 5.30 l/min [4.57-6.20] by thermodilution (p<0.001). The Spearman correlation coefficient was 0.51 [0.36-0.64], and the average deviation on Bland-Altman plot was -1.25 l/min (95% CI [-1.48-1.01], p<0.001). The ability of the monitor to detect a variation in CO of more than 15% between two follow-up measurements, when such variation existed using thermodilution, was insufficient for clinical practice (AUC = 0.54, 95% CI [0.33-0.75]).

Interstitial Lung Disease Associated with Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by a tripod combining vasculopathy, fibrosis, and immune-mediated inflammatory processes. The prevalence of interstitial lung disease (ILD) in SSc varies according to the methods used to detect it, ranging from 25 to 95%. The fibrotic and vascular pulmonary manifestations of SSc, particularly ILD, are the main causes of morbidity and mortality, contributing to 35% of deaths. Although early trials were conducted with cyclophosphamide, more recent randomized controlled trials have been performed to assess the efficacy and tolerability of several medications, mostly mycophenolate, rituximab, tocilizumab, and nintedanib. Although many uncertainties remain, expert consensus is emerging to optimize the therapeutic management and to provide clinicians with evidence-based clinical practice guidelines for patients with SSc-ILD. This article provides an overview, in the light of the latest advances, of the available evidence for the diagnosis and management of SSc-ILD.

Phenotypes and outcome of diffuse pulmonary non-amyloid light chain deposition disease.

BACKGROUND: Light chain deposition disease (LCDD) is a very rare entity. Clinical manifestations of LCDD vary according to the organs involved. Data on pulmonary LCDD are scarce and limited to small series or case reports. This study aimed to describe the characteristics and outcome of diffuse pulmonary non-amyloid LCDD localized to the lungs. STUDY DESIGN AND METHODS: A multicenter retrospective cohort study was conducted. Clinical characteristics were collected, and chest CTs were centrally reviewed. The diagnosis of pulmonary non-amyloid LCDD was confirmed by immunohistochemistry. RESULTS: Thirty-one cases were identified (68% female), with a median age at diagnosis of 50 years (IQR 20). Baseline FEV1/FVC was < 0.70 in 45% of patients. Mean (± SD) FEV1 and DLCO were 86% ± 26.2 and 52% ± 23.9, respectively. CT revealed peculiar patterns of thin-walled cysts (58%) and thin-walled cystic bronchiectases (27%). Increased serum kappa light chain was found in 87% of patients. Histological analysis showed kappa light chain deposits in all patients, except one with lambda chain deposits. Median annual FEV1 decline was 127 ml (IQR 178) and median DLCO decline was 4.3% (IQR 4.3). Sixteen patients received immunomodulatory treatment or chemotherapy; serum light chain levels decreased in 9 cases (75%), without significant improvement in FEV1 (p = 0.173). Overall, 48% of patients underwent bilateral lung transplantation. Transplant-free survival at 5 and 10 years were 70% and 30%, respectively. An annual FEV1 decline greater than 127 ml/year was associated with increased risk of death or transplantation (p = 0.005). CONCLUSIONS: Diffuse pulmonary LCDD is characterised by female predominance, a peculiar imaging pattern with bronchiectasis and/or cysts, progressive airway obstruction and severe DLCO impairment, and poor outcome. Lung transplantation is a treatment of choice.

Mepolizumab and benralizumab in patients with severe asthma and a history of eosinophilic granulomatosis with polyangiitis.

Introduction: Asthma associated with eosinophilic granulomatosis with polyangiitis (EGPA) is often severe and corticosteroid-dependent, leading to significant morbidity. Mepolizumab and benralizumab are humanized monoclonal antibodies targeting interleukin 5 (IL-5) and its receptor, respectively. They have been shown to be effective in steroid-sparing in patients with severe eosinophilic asthma. Objective: Our aim was to evaluate the efficacy and safety of mepolizumab and benralizumab prescribed for severe asthma in patients with EGPA under "real-world" conditions. Methods: This was a retrospective analysis of patients with EGPA and persistent asthma who received either mepolizumab 100 or 300 mg administered every 4 weeks, or benralizumab 30 mg administered every 4 weeks for the initial 3 injections and followed by an injection every 8 weeks thereafter, whilst combined with oral glucocorticoids. The follow-up every 6 ± 3 months included an assessment of clinical manifestations, pulmonary function tests and eosinophil cell count. The primary outcome was the proportion of patients at 12 months receiving a daily oral dose of prednisone or equivalent of 4 mg or less with a BVAS of 0. Results: Twenty-six patients were included. After 12 months of treatment with mepolizumab or benralizumab, 32% of patients met the primary outcome and were receiving less than 4 mg of prednisone per day with a BVAS of 0. The median dose of prednisone was 10 mg per day at baseline, 9 mg at 6 months, and 5 mg at 12 months (p ≤ 0.01). At 12 months, 23% of patients were weaned off corticosteroids, while an increase or no change in dose was observed in 27% of patients. The median eosinophil count was significantly reduced from 365 cells/mm3 to 55 cells/mm3 at 6 months and 70 cells/mm3 at 12 months, respectively. No significant change was observed in FEV1. After 12 months of treatment, 14% of patients had had an average of 1 exacerbation of asthma, compared with 52% of patients before baseline. The tolerability profile was favorable. Conclusion: In this real-world study in patients with severe asthma and a history of EGPA asthma, mepolizumab and benralizumab had a significant steroid-sparing effect and reduced asthma exacerbation, but no significant effect on lung function.

Ultra-low dose chest CT for the diagnosis of pulmonary arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia.

PURPOSE: The purpose of this study was to compare ultra-low dose (ULD) and standard low-dose (SLD) chest computed tomography (CT) in terms of radiation exposure, image quality and diagnostic value for diagnosing pulmonary arteriovenous malformation (AVM) in patients with hereditary hemorrhagic telangiectasia (HHT). MATERIALS AND METHODS: In this prospective board-approved study consecutive patients with HHT referred to a reference center for screening and/or follow-up chest CT examination were prospectively included from December 2020 to January 2022. Patients underwent two consecutive non-contrast chest CTs without dose modulation (i.e., one ULD protocol [80 kVp or 100 kVp, CTDIvol of 0.3 mGy or 0.6 mGy] and one SLD protocol [140 kVp, CTDIvol of 1.3 mGy]). Objective image noises measured at the level of tracheal carina were compared between the two protocols. Overall image quality and diagnostic confidence were scored on a 4-point Likert scale (1 = insufficient to 4 = excellent). Sensitivity, specificity, positive predictive value and negative predictive value of ULD CT for diagnosing pulmonary AVM with a feeding artery of over 2 mm in diameter were calculated along with their 95% confidence intervals (CI) using SLD images as the standard of reference. RESULTS: A total of 44 consecutive patients with HHT (31 women; mean age, 42 ± 16 [standard deviation (SD)] years; body mass index, 23.2 ± 4.5 [SD] kg/m2) were included. Thirty-four pulmonary AVMs with a feeding artery of over 2 mm in diameter were found with SLD images versus 35 with ULD images. Sensitivity, specificity, predictive positive value, and predictive negative value of ULD CT for the diagnosis of PAVM were 100% (34/34; 95% CI: 90-100), 96% (18/19; 95% CI: 74-100), 97% (34/35; 95% CI: 85-100) and 100% (18/18; 95% CI: 81-100), respectively. A significant difference in diagnostic confidence scores was found between ULD (3.8 ± 0.4 [SD]) and SLD (3.9 ± 0.1 [SD]) CT images (P = 0.03). No differences in overall image quality scores were found between ULD CT examinations (3.9 ± 0.2 [SD]) and SLD (4 ± 0 [SD]) CT examinations (P = 0.77). Effective radiation dose decreased significantly by 78.8% with ULD protocol, with no significant differences in noise values between ULD CT images (16.7 ± 5.0 [SD] HU) and SLD images (17.7 ± 6.6 [SD] HU) (P = 0.07). CONCLUSION: ULD chest CT provides 100% sensitivity and 96% specificity for the diagnosis of treatable pulmonary AVM with a feeding artery of over 2 mm in diameter, leading to a 78.8% dose-saving compared with a standard low-dose protocol.

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.

Risk stratification refinements with inclusion of haemodynamic variables at follow-up in patients with pulmonary arterial hypertension.

BACKGROUND AND AIMS: Haemodynamic variables are prognostic factors in pulmonary arterial hypertension (PAH). However, right heart catheterization (RHC) is not systematically recommended to assess the risk-status during follow-up. This study aimed to assess the added value of haemodynamic variables in prevalent patients to predict the risk of death or lung transplantation according to their risk status assessed by the non-invasive 4 strata model as recommended by the European guidelines. METHODS: We evaluated incident patients with PAH enrolled in the French PAH Registry between 2009 and 2020 who had a first follow-up RHC. Cox regression identified, in each follow-up risk status, haemodynamic variables significantly associated with transplant-free survival (TFS). Optimal thresholds were determined by time-dependent Receiver-Operating Characteristics. Several multivariable Cox regression models were performed to identify the haemodynamic variables improving the non-invasive risk stratification model. RESULTS: We analysed 1240 incident patients reassessed within a year by RHC. None of haemodynamic variable were significantly associated with TFS among low-risk (n=386) or high-risk (n=71) patients. Among patients at intermediate (-low, n=483, -high, n=300) risk at first follow-up, multivariable models including either stroke volume index (SVi) or mixed venous oxygen saturation (SvO2) were the best. The prognostic performance of refined 6 strata risk stratification model including the non-invasive 4 strata model and SVi>37 mL·m-2 and/or SvO2>65% for patients at intermediate-risk (Area Under the Curve 0.81, c-index 0.74), was better than that of 4 strata model (0.79, p=0.009; c-index 0.72). CONCLUSIONS: Cardiopulmonary haemodynamics may improve risk stratification at follow-up in patients at intermediate-risk.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Pulmonary vascular phenotype identified in patients with GDF2 (BMP9) or BMP10 variants: an international multicentre study.

BACKGROUND: Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10, respectively, play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored. METHODS: We report the characteristics and outcomes of PAH patients in GDF2 and BMP10 carriers from the French and Dutch pulmonary hypertension registries. A literature review explored the phenotypic spectrum of these patients. RESULTS: 26 PAH patients were identified: 20 harbouring heterozygous GDF2 variants, one homozygous GDF2 variant, four heterozygous BMP10 variants, and one with both GDF2 and BMP10 variants. The prevalence of GDF2 and BMP10 variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30 years, with a female/male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise (median (range) pulmonary vascular resistance 9.0 (3.3-40.6) WU). Haemoptysis was reported in four patients; none met the HHT criteria. Two patients carrying BMP10 variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of GDF2 carriers developed isolated HHT, and identified cardiomyopathy and developmental disorders in BMP10 carriers. CONCLUSIONS: GDF2 and BMP10 pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among GDF2 carriers are limited according to the literature. BMP10 full phenotypic ramifications warrant further investigation.

Towards the adoption of quantitative computed tomography in the management of interstitial lung disease.

The shortcomings of qualitative visual assessment have led to the development of computer-based tools to characterise and quantify disease on high-resolution computed tomography (HRCT) in patients with interstitial lung diseases (ILDs). Quantitative CT (QCT) software enables quantification of patterns on HRCT with results that are objective, reproducible, sensitive to change and predictive of disease progression. Applications developed to provide a diagnosis or pattern classification are mainly based on artificial intelligence. Deep learning, which identifies patterns in high-dimensional data and maps them to segmentations or outcomes, can be used to identify the imaging patterns that most accurately predict disease progression. Optimisation of QCT software will require the implementation of protocol standards to generate data of sufficient quality for use in computerised applications and the identification of diagnostic, imaging and physiological features that are robustly associated with mortality for use as anchors in the development of algorithms. Consortia such as the Open Source Imaging Consortium have a key role to play in the collation of imaging and clinical data that can be used to identify digital imaging biomarkers that inform diagnosis, prognosis and response to therapy.

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.