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Melatonin (Mel) serves as the central regulator for maintaining circadian rhythms and plays a crucial role not only in controlling the rhythmic clock, but also in several functional domains such as immunomodulation and anti-inflammation. In this study, we explored the clinical relevance of Mel and rheumatoid arthritis comorbid with interstitial lung disease (RA-ILD), and its potential therapeutic effects on arthropathy and pulmonary fibrosis (PF) in mice with collagen-induced arthritis (CIA). The results demonstrated that low serum levels of Mel were correlated with disease activity and severity of PF in RA-ILD patients. In addition, Mel was potentially efficacious in alleviating arthritis, bone destruction, and PF in a mouse model of CIA. Meanwhile, we observed that in lung tissues, the circadian-clock genes (CCGs) period circadian regulator 2 (PER2) and cryptochrome circadian regulator 2 (CRY2) were predominantly expressed in epithelial cells (ECs), and the regulation of their expression in ECs was closely correlated with Mel-mediated suppression of inflammatory responses and a significant reduction in macrophagic inflammatory activity. These results implied that Mel and its associated CCGs might play important regulatory roles in RA-ILD and its associated pathological processes., Competing Interests: Declaration of competing interest All authors declare that No conflict of interest exists., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is an increasingly recognized extra-articular manifestations (EAMs) in the RA, with highly morbidity and mortality. The identification of key molecules involved in RA-ILD has a high requirement in clinic, and the role of their transcriptional regulation in the etiology of RA-ILD is great significant for investigation. In this study, we collected the whole peripheral blood samples of RA-ILD and RA only patients to bulk RNA-sequence. Differential gene expression analysis was employed to identify key genes, common pathways, and potential drug targets for RA-ILD. Furthermore, RT-qPCR was conducted to verify potential biomarkers in RA-ILD. Four hundred seventy-eight differentially expressed genes (DEGs) were identified that related to chromatin-modifying enzymes. A robust correlation with immune and inflammation biological processes and pathways was indicated through enrichment analyses of these shared DEGs, like B cell receptor signaling pathway, complement activation, NF-kappa B signaling pathway. Protein-protein interaction network analysis further emphasized the significance of 12 hub genes, including CHD4, MUS81, CXCL8, NSUN6, RAD9A, CCL4, B3GAT1, KAT2A, TBX21, HDAC2, ERBB2, and ITGAL. Notably, NSUN6 expression was statistically significant in RA-ILD by the machine learning LASSO regression analysis and RT-qPCR. Our study provides novel insights into the molecular mechanisms of RA-ILD, identifies potential biomarkers, and lays the groundwork for future therapeutic strategies., (© 2024 John Wiley & Sons Ltd.)

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. In addition, we performed single-cell RNA sequencing (scRNA-seq) in PBMCs (10x Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low-, intermediate-, or high-risk of mortality and with significant differences in proinflammatory and profibrotic cytokines. Patients with COVID-19 in the high-risk group had increased expression of seven genes in CD14 + HLA-DR low CD163 + monocytic-myeloid-derived suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSCs and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, patients with IPF had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF. NEW & NOTEWORTHY Changes in the 50-gene signature, reflective of increase in CD14 + HLA-DR low CD163 + monocytes and decrease in CD4 and CD8 T cells, are associated with increased mortality in COVID-19. A reversal of this pattern can be seen in post-COVID-19-ILD, whereas its persistence can be seen in IPF. Modulating the imbalance between HLA-DR low monocytes and T cell subsets should be investigated as a potential strategy to treat pulmonary fibrosis associated with severe COVID-19 and progressive IPF.

Although relatively rare, interstitial lung diseases may present with respiratory distress in the newborn period. Most commonly these include developmental and growth disorders, disorders of surfactant synthesis and homeostasis, pulmonary interstitial glycogenosis, and neuroendocrine cell hyperplasia of infancy. Although the diagnosis of these disorders is sometimes made based on clinical presentation and imaging, due to the significant overlap between disorders and phenotypic variability, lung biopsy or, increasingly genetic testing is needed for diagnosis. These diseases may result in significant morbidity and mortality. Effective medical treatment options are in some cases limited and/or invasive. The genetic basis for some of these disorders has been identified, and with increased utilization of exome and whole genome sequencing even before lung biopsy, further insights into their genetic etiologies should become available., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Patients with familial fibrotic interstitial lung disease (ILD) experience worse survival than patients with sporadic disease. Current guidelines do not consider family aggregation or genetic information in the diagnostic algorithm for idiopathic pulmonary fibrosis or other fibrotic ILDs. Better characterizing familial cases could help in diagnostic and treatment decision-making., Methods: This retrospective cohort study included 222 patients with fibrotic ILD (104 familial and 118 sporadic) from Bellvitge University Hospital. Clinical, radiological, pulmonary functional tests (PFT), and histological evaluations were performed at diagnosis and follow-up. Telomere shortening and disease-associated variants (DAVs) in telomerase-related genes were analysed in familial patients and sporadic patients with telomeric clinical signs. Primary outcomes were the presence of a UIP histological pattern and disease progression., Results: Patients with idiopathic pulmonary fibrosis (IPF) (52%), fibrotic hypersensitivity pneumonitis (23%), and other fibrotic ILDs (25%) were included. 42% of patients underwent lung biopsy. Patients with family aggregation were younger and less frequently associated comorbidities, male sex, and smoking history. However, usual interstitial pneumonia (UIP) was more frequent on pathology (p = 0.005; OR 3.37), especially in patients with indeterminate or non-UIP radiological patterns. Despite similar PFT results at diagnosis, familial patients were more likely to present with progressive disease (p = 0.001; OR 3.75). Carrying a DAV increased the risk of fibrotic progression in familial and sporadic patients (p = 0.029, OR 5.01)., Discussion: Familial patients diagnosed with different fibrotic ILDs were more likely to exhibit a histological UIP pattern and disease progression than sporadic patients, independent of radiological findings and pulmonary function at diagnosis., Conclusion: Considering the diagnostic likelihood of the histological UIP pattern and disease outcome, the presence of family aggregation would be useful in the decision making of multidisciplinary committees., Competing Interests: Declarations. Ethics approval and consent to participate: The Ethics Committee of HUB approved the study (PR307/16), and all patients provided written informed consent before inclusion, including written informed consent for genetic testing if needed. Consent for publication: Not applicable. Clinical trial number: Not applicable. Competing interests: MMM has received grants for research purposes and fees for scientific advice outside this work from Boehringer Ing, Ferrer, Roche, Veracyte and Chiesi. The other authors of this work have no conflicts of interest to disclose., (© 2024. The Author(s).)

Rationale: Relatives of patients with familial pulmonary fibrosis (FPF) are at increased risk to develop FPF. Interstitial lung abnormalities (ILAs) are a radiologic biomarker of subclinical disease, but the implications of very mild abnormalities remain unclear. Objectives: To quantify the progression risk among FPF relatives with abnormalities below the threshold for ILAs as described by the Fleischner Society and to describe the characteristics of participants with new or progressive ILAs during observation. Methods: Asymptomatic FPF relatives undergo serial screening high-resolution chest computed tomography. For this analysis, early ILAs (no minimum threshold of lung involvement) were subclassified as mild (all interstitial abnormalities involve <5% of a lung zone) or moderate (any abnormality involves >5%). Identification of new or progressive ILAs on high-resolution chest computed tomography and the development of pulmonologist-diagnosed clinical FPF were defined as progression. Covariate-adjusted logistic regression identified progression-associated characteristics. Measurements and Main Results: From 2008 to 2023, 273 participants in follow-up procedures were 53.2 ± 9.4 years of age at enrollment, 95 (35%) were men, and 73 of 268 (27%) were ever-smokers. During a mean follow-up period of 6.2 ± 3.0 years, progression occurred among 31 of 211 (15%) of those with absence of ILAs at enrollment, 32 of 49 (65%) of those with mild ILAs, and 10 of 13 (77%) of those with moderate ILAs. Subjects with mild ILAs had 9.15 (95% confidence interval, 4.40-19.00; P  < 0.0001) times and those with moderate ILAs had 17.14 (95% confidence interval, 4.42-66.49; P  < 0.0001) times the odds of progression as subjects without ILAs. Conclusions: In persons at risk for FPF, minor interstitial abnormalities, including reticulation that is unilateral or involves <5% of a lung zone, frequently represent subclinical disease.

Introduction: Interstitial lung disease (ILD) is the most common extra-articular manifestation in rheumatoid arthritis (RA). Studies have concluded that there is an association between rs35705950 polymorphism of the MUC5B gene and RA-ILD., Aim: To explore this polymorphism in a cohort of Tunisian patients suffering from RA with or without ILD and stufdy its association to ILD during RA., Methods: A case-control study involving 61 patients followed for RA, 26 with ILD and 35 without pulmonary involvement and 62 healthy controls. This was an association study between genetic marker and RA-ILD by genotyping the rs35705950 polymorphism using PCR-RFLP., Results: No association was found between rs35705950 polymorphism and RA. However, the comparison of RA-ILD patients with controls showed a significant association with the allele frequencies of rs35705950 polymorphism (p=0.008; OR=2.61; CI [1.2-5.66]). Indeed, the minor T allele increased the risk of developing ILD by 2.61 for RA patients compared to the controls. Comparison of allele frequencies in RA-ILD patients and RA patients without ILD showed a significant association between the minor T allele of the studied polymorphism and RA-ILD (p= 0.02; OR= 2.66; CI [1.09-6.5]). In the adjusted model, this risk increased in case of smoking (p=0.025; OR=3,84; CI [1,13-13,08]) and/or female gender (p=0.013; OR = 4,63; CI [1,33-16,17])., Conclusion: Our work has confirmed the role of the polymorphism of MUC5B promoter in the appearance of ILD during RA in Tunisian patients. This variant could be used to early detect preclinical ILD in patients with RA.

Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a common complication of rheumatoid arthritis (RA) that result in significant morbidity and mortality. Understanding the molecular mechanisms underlying RA-ILD is crucial for effective prevention. This study aims to identify the specific molecule that mediate the causal association between RA and ILD, as well as to explore its potential mechanisms in the pathogenesis of RA-ILD., Methods: Using two-sample Mendelian randomization (MR) analyses, we investigated the causal relationship among 16,987 blood genes, RA and ILD. Subsequently, a two-step MR technique was employed to identify significant genes that mediate the association between RA and ILD, and to quantify their proportion of mediation effect. To validate the genes as mediators, the replication MR analysis was conducted and the in vivo experiment was performed using an established animal model of RA-ILD. Furthermore, integrated bioinformatic analyses were conducted to elucidate the specific biological functions of the determined mediator in pathogenesis of RA-ILD., Results: Nine genes, namely MAPK8IP2, TAF11, SLAMF1, DAB2IP, GLUL, SLC4A10, PRSS35, NFX1, and PLK3, were identified as mediators. Among them, SLAMF1 was validated as the most significant mediator, accounting for 4.693% of the mediating effect on the causal relationship between RA and ILD. Upregulated mRNA expression of SLAMF1 was observed in the animal model of RA-ILD compared to controls. Bioinformatic analyses revealed that SLAMF1 was overexpressed in patients with lung fibrosis and correlated with a poor prognosis. Specifically, SLAMF1 was found to be predominantly overexpressed in T cells in lung tissues of patients with lung fibrosis. Additionally, the functional role of SLAMF1 was associated with multiple immune cell infiltrations and the biological process of extracellular matrix synthesis in pulmonary tissues from patients with lung fibrosis., Conclusion: SLAMF1 may play a crucial role as a molecular mediator in the causal association between RA and ILD, and participate in multiple mechanisms underlying the pathogenesis of RA-ILD. This research provides insights into how the development of RA influences the risk of ILD and offers potential interventional targets against RA-ILD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fibrotic interstitial lung diseases (ILDs) result from excessive deposition of extracellular matrix (ECM) proteins in the lung, causing irreversible damage to the lung architecture. Clinical management of ILDs differs depending on the diagnosis, but differentiation between subtypes can be difficult and better clinical biomarkers are needed. In this study, we use a 166-gene NanoString assay to investigate whether there are ILD subtype-specific transcripts in whole blood. We identified one transcript, killer cell lectin like receptor 1 (KLRF1), as differentially expressed between idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD), and identified two transcripts (VCAN, LTK) associated with IPF expression against other ILD subtypes. These findings were validated by examining their expression in ILD lung, with KLRF1 expression significantly higher in SSc-ILD compared to IPF and hypersensitivity pneumonitis (HP) samples. Taken together, this pilot study provides support for the use of the peripheral transcriptome in identifying diagnostic biomarkers of ILD with biological relevance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Acute Interstitial Pneumonia (AIP) represents a severe form of diffuse lung injury within the idiopathic interstitial pneumonia spectrum. Given the limited understanding of its molecular basis, this study aims to elucidate AIP's genomic and transcriptomic profiles to uncover its pathophysiological underpinnings and identify potential therapeutic targets. We conducted a comprehensive analysis of genomic and transcriptomic data from lung tissues of 15 AIP patients. This included assessing differentially expressed genes (DEGs) and identifying mutations in exonic coding variants, as well as analysing expression quantitative trait loci (eQTL) profiles to link non-coding SNP genotypes with gene expression levels. Transcriptomic analysis revealed a significant upregulation of genes linked to the Type I interferon receptor and keratin filament, and a downregulation of genes related to focal adhesion and endothelial integrity, compared to healthy individuals. These patterns were distinct from those observed in idiopathic pulmonary fibrosis (IPF) and non-IPF interstitial lung diseases (ILDs). Genomic analysis highlighted mutations in genes associated with keratin and the extracellular matrix. Additionally, eQTL profiling provided insights into the genetic regulation of gene expression in AIP. Our findings reveals AIP's unique molecular landscape, differentiating it from other ILDs and laying the groundwork for future diagnostic and therapeutic research., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Purpose of Review: Telomere biology disorders (TBD) are a group of genetic disorders characterized by premature shortening of telomeres, resulting in accelerated aging of somatic cells. This often leads to major multisystem organ dysfunction, and TBDs have become increasingly recognized as a significant contributor to numerous disease processes within the past 10-15 years. Both research and clinical practice in this field are rapidly evolving., Recent Findings: A subset of patients with TBD suffers from interstitial lung disease, most commonly pulmonary fibrosis. Often, the clinical presentation is indistinguishable from other forms of lung fibrosis. There are no pathognomonic radiographic or histological features, and a high level of suspicion is therefore required. Telomere evaluation is thus crucial to establishing the diagnosis. This review details the clinical presentation, objective evaluation, indicated genetic testing, and recommended management strategies for patients affected by interstitial lung disease associated with TBDs. Our goal is to empower pulmonologists and other healthcare professionals who care for these patients to provide appropriate and personalized care for this population., Competing Interests: Compliance  with Ethical Standards Competing Interests The authors declare no competing interests. Conflict of Interest Dr. Eva M. Carmona reports providing consultation to Boehringer Ingelheim for sarcoidosis. This is unrelated to the submitted work. Dr. Kathryn T. del Valle has nothing to disclose. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. Ethical Approval Not applicable., (© 2023. The Author(s).)

Background: Biallelic ATP-binding cassette subfamily A member 3 (ABCA3) variants can cause interstitial lung disease in children and adults, for which no proven treatments exist. Recent in vitro evidence suggested that cyclosporine A (CsA) could correct some ABCA3 variants, however for other variants this is unknown and no data in patients exist., Methods: We retrieved the clinical data of two children aged 2 and 4 years carrying homozygous ABCA3 variants (G210C and Q1045R, respectively) and empiric CsA treatment from the Kids Lung Register database. In vitro experiments functionally characterized the two variants and explored the effects of CsA alone or combined with hydroxychloroquine (HCQ) in a human alveolar epithelial cell line (A549) derived from adenocarcinoma cells., Results: Six weeks following the introduction of CsA, both children required a reduced O 2 flow supply, which then remained stable on CsA. Later, when CsA was discontinued, the clinical status of the children remained unchanged. Of note, the children simultaneously received prednisolone, azithromycin, and HCQ. In vitro, both ABCA3 variants demonstrated defective lysosomal colocalization and impaired ABCA3 + vesicle size, with proteolytic cleavage impairment only in Q1045R. CsA alone corrected the trafficking impairment and ABCA3 + vesicle size of both variants with a variant-specific effect on phosphatidylcholine recycling in G210C. CsA combined with HCQ were additive for improving trafficking of ABCA3 in G210C, but not in Q1045R., Conclusions: CsA treatment might be helpful for certain patients with ABCA3 deficiency, however, currently strong clinical supporting evidence is lacking. Appropriate trials are necessary to overcome this unmet need., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Recent advances in genetics and epigenetics have provided critical insights into the pathogenesis of both idiopathic and non-idiopathic interstitial lung diseases (ILDs). Mutations in telomere-related genes and surfactant proteins have been linked to familial pulmonary fibrosis, while variants in MUC5B and TOLLIP increase the risk of ILD, including idiopathic pulmonary fibrosis and rheumatoid arthritis-associated ILD. Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs such as miR-21 and miR-29, regulate fibrotic pathways, influencing disease onset and progression. Although no standardized genetic panel for ILD exists, understanding the interplay of genetic mutations and epigenetic alterations could aid in the development of personalized therapeutic approaches. This review highlights the genetic and epigenetic factors driving ILD, emphasizing their potential for refining diagnosis and treatment.

Background: Genetic polymorphisms in Toll-interacting protein (TOLLIP) have been documented in relation to clinical manifestations of interstitial lung disease (ILD). Nevertheless, the findings across studies present inconsistencies. The present meta-analysis endeavors to elucidate the nexus between genetic variations in TOLLIP and the onset and prognosis of interstitial lung disease (ILD), with the overarching aim of providing insight into the pathophysiological underpinnings of ILD., Method: This systematic review was registered in PROSPERO. The OVID MEDLINE, OVID EMBASE, and Web of Science electronic databases were searched., Results: Fourteen studies with a total of 4821 cases and 9765 controls were examined. The final TOLLIP variants to be included in this meta-analysis were rs5743890, rs111521887, and rs3750920. There were significantly fewer TOLLIP rs5743890 minor allele C carriers among individuals with interstitial lung disease (ILD) than among those without this condition (11.42% vs. 18.92%). Conversely, patients with ILD exhibited higher frequencies of rs111521887 minor allele G carriers (28.92% vs. 22.44%) and rs3750920 minor allele T carriers (40.06% vs. 34.00%). A potential association between rs5743890&#95;C and a reduced incidence of ILD was plausible (p = 0.04, OR = 0.72, 95% CI = 0.53-0.99). Furthermore, a stratified analysis revealed that rs5743890&#95;C was significantly associated with a decreased risk of IPF (p = 0.004, OR = 0.62, 95% CI = 0.44-0.86). There was a significant correlation between susceptibility to ILD and rs111521887 G (p < 0.00001, OR = 1.48, 95% CI = 1.33-1.65) and rs3750920 T (p < 0.00001, OR = 1.34, 95% CI = 1.26-1.44). The survival of IPF patients was correlated with the TOLLIP rs5743890 SNP, and patients with the rs5743890&#95;C genotype had worse survival (p = 0.02, HR = 1.59, 95% CI = 1.07-2.36)., Conclusion: This study showed that rs5743890&#95;C was associated with a lower incidence of ILD and a worse survival rate in patients with IPF. Rs111521887&#95;G and rs3750920&#95;T were found to be associated with an elevated risk of ILD incidence, while no significant association was observed with ILD prognosis. Furthermore, studies are warranted to validate our results and assess the effects of TOLLIP genetic variants on ILD., Competing Interests: Declarations. Ethics approval and consent to participate: This study does not involve ethics, as it is a systematic review and meta-analysis. Consent for publication: All the authors have agreed to be listed and have read and approved the manuscript for publication. Competing interests: The authors have declared no conflicts of interest., (© 2024. The Author(s).)

The main monogenic causes of pulmonary fibrosis in adults are mutations in telomere-related genes. These mutations may be associated with extrapulmonary signs (hepatic, haematological and dermatological) and typically present radiologically as usual interstitial pneumonia or unclassifiable fibrosis. In children, the monogenic causes of pulmonary fibrosis are dominated by mutations in surfactant-related genes. These mutations are not associated with extrapulmonary signs and often manifest radiologically as unclassifiable fibrosis with cysts that can lead to chest wall deformities in adults. This review discusses these mutations, along with most of the monogenic causes of interstitial lung disease, including interferon-related genes, mutations in genes causing cystic lung disease, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lysinuric protein intolerance and lysosomal storage disorders, and their pulmonary and extrapulmonary manifestations., Competing Interests: Conflict of interest: R. Borie reports consultancy fees from Boerhinger Ingelheim, Ferrer and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, and support for attending meetings from Boehringer Ingelheim. L. Berteloot and C. Kannengiesser have nothing to disclose. M. Griese reports grants from Deutsche Forschungsgemeinschaft, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim. A. Cazes reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim. B. Crestani reports grants from Boehringer Ingelheim, consultancy fees from BMS, Boehringer Ingelheim, Chiesi, CSL Behring, GSK and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, BMS, Boehringer Ingelheim, GSK, Novartis, Roche and Sanofi, support for attending meetings from AstraZeneca, BMS, Boehringer Ingelheim, Roche and Sanofi, participation on a data safety monitoring board or advisory board with BMS, Boehringer Ingelheim, Horizon and Sanofi, and a leadership role with Fondation du Souffle (President of the board of trustees). A. Hadchouel has nothing to disclose. M.P. Debray reports consultancy fees from Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, Sanofi and Bracco, and support for attending meetings from Boehringer Ingelheim., (Copyright ©The authors 2024.)

Fibrosing interstitial lung diseases (ILDs) encompass a diverse range of scarring disorders that lead to progressive lung failure. Previous gene expression profiling studies focused on idiopathic pulmonary fibrosis (IPF) and bulk tissue samples. We employed digital spatial profiling to gain new insights into the spatial resolution of gene expression across distinct lung microenvironments (LMEs) in IPF, chronic hypersensitivity pneumonitis (CHP) and non-specific interstitial pneumonia (NSIP). We identified differentially expressed genes between LMEs within each condition, and across histologically similar regions between conditions. Uninvolved regions in IPF and CHP were distinct from normal controls, and displayed potential therapeutic targets. Hallmark LMEs of each condition retained distinct gene signatures, but these could not be reproduced in matched lung tissue samples. Based on these profiles and unsupervised clustering, we grouped previously unclassified ILD cases into NSIP or CHP. Overall, our work uniquely dissects gene expression profiles between LMEs within and across different types of fibrosing ILDs., (© 2024. The Author(s).)

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm 2 in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; P  < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.

Background: Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown., Research Question: What is the clinical impact of TL testing on the management of ILD?, Study Design and Methods: Patients were evaluated in the Columbia University ILD clinic and underwent Clinical Laboratory Improvement Amendments-certified TL testing by flow cytometry and fluorescence in situ hybridization (FlowFISH) as part of clinical treatment. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared with research quantitative polymerase chain reaction (qPCR) TL measurement., Results: A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR, 2.00; 95% CI, 1.27-3.32). TL testing led to clinical treatment changes for 35 patients (32%), most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n = 34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 patients (29%). Inclusion of TL testing below the 1st percentile helped reclassify eight of nine variants of uncertain significance into actionable findings. The quantitative polymerase chain reaction test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays., Interpretation: Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. Z. reports grant support from the Francis Family Foundation and the National Institutes of Health, and consulting fees from Boehringer Ingelheim. C. M. E. reports grant support from the National Institutes of Health. C. K. G. reports grant support from the Pulmonary Fibrosis Foundation, National Institutes of Health, and the Department of Defense; nonfinancial support from AstraZeneca; consulting fees from Rejuveron Telomere Therapeutics; and equity or stocks from Rejuvenation Technologies. None declared (C. M., S. B., J. P., C. D., K. B., J. W., A. T.-W., V. J.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

We describe a late preterm neonate presenting with respiratory distress syndrome (RDS), homozygous for the E292V missense mutation in the ATP-binding cassette subfamily A, member 3 gene. The neonate improved with supportive care. The E292V variant is the most common mutation in ABCA3, which is essential in surfactant synthesis. This variant has variable penetrance and is associated with increased prevalence of RDS and childhood interstitial lung disease and adult-onset interstitial lung disease. Homozygous E292V mutations have been associated with fatal neonatal lung disease and lung fibrosis in adulthood. This case highlights the association of homozygous E292V with non-fatal RDS that is more severe than predicted based on gestational age. Early genetic diagnosis permits the implementation of preventative health strategies and screening for lung disease throughout life and furthers knowledge of genetic risks for RDS and interstitial lung disease., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The most common mutation in surfactant protein C gene (SFTPC), SFTPCI73T, causes interstitial lung disease with few therapeutic options. We previously demonstrated that EMC3, an important component of the multiprotein endoplasmic reticulum membrane complex (EMC), is required for surfactant homeostasis in alveolar type 2 epithelial (AT2) cells at birth. In the present study, we investigated the role of EMC3 in the control of SFTPCI73T metabolism and its associated alveolar dysfunction. Using a knock-in mouse model phenocopying the I73T mutation, we demonstrated that conditional deletion of Emc3 in AT2 cells rescued alveolar remodeling/simplification defects in neonatal and adult mice. Proteomic analysis revealed that Emc3 depletion reversed the disruption of vesicle trafficking pathways and rescued the mitochondrial dysfunction associated with I73T mutation. Affinity purification-mass spectrometry analysis identified potential EMC3 interacting proteins in lung AT2 cells, including valosin containing protein (VCP) and its interactors. Treatment of SftpcI73T knock-in mice and SFTPCI73T-expressing iAT2 cells derived from SFTPCI73T patient-specific iPSCs with the VCP inhibitor CB5083 restored alveolar structure and SFTPCI73T trafficking, respectively. Taken together, the present work identifies the EMC complex and VCP in the metabolism of the disease-associated SFTPCI73T mutant, providing therapeutical targets for SFTPCI73T-associated interstitial lung disease.

To investigate the causal relationship between rheumatoid arthritis (RA) and interstitial lung disease (ILD) in the East Asian population, we utilized Mendelian randomization (MR). Publicly available summarized data from genome-wide association studies on RA (4199 cases and 208,254 controls), and the data on ILD (1046 cases and 176,974 controls) were obtained from BioBank Japan. Eligible single nucleotide polymorphisms from East Asian populations were obtained from genome-wide association studies as instrumental variables, and 11 RA-related single nucleotide polymorphisms (P < 5 × 10-8) were selected as instrumental variables. MR analysis was performed using inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO with RA as the exposure data and ILD as the outcome data. Reliability was evaluated using Cochran Q test, MR-Egger intercept, leave-one-out analysis, and funnel plot. Inverse variance weighted results showed an odds ratio (95% confidence interval) of 1.29 (1.18-1.41), P = 3.99 × 10-8, indicating a positive association between RA and ILD. The reliability evaluation could adopt the fixed-effect model, and the absolute value of the MR-Egger regression intercept was 0.021, P > 0.05, and P value of Global Test in MR-PRESSO was 0.573. The test results of the leave-one-out showed that the results are robust, and the funnel plot indicated that the instrumental variables were not affected by potential factors. In conclusion, this study demonstrates that RA is a risk factor for ILD in the East Asian population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

In lung disease, persistence of KRT8-expressing aberrant basaloid cells in the alveolar epithelium is associated with impaired tissue regeneration and pathological tissue remodeling. We analyzed single cell RNA sequencing datasets of human interstitial lung disease and found the profibrotic Interleukin-11 (IL11) cytokine to be highly and specifically expressed in aberrant KRT8 + basaloid cells. IL11 is similarly expressed by KRT8 + alveolar epithelial cells lining fibrotic lesions in a mouse model of interstitial lung disease. Stimulation of alveolar epithelial cells with IL11 causes epithelial-to-mesenchymal transition and promotes a KRT8-high state, which stalls the beneficial differentiation of alveolar type 2 (AT2)-to-AT1 cells. Inhibition of IL11-signaling in AT2 cells in vivo prevents the accumulation of KRT8 + cells, enhances AT1 cell differentiation and blocks fibrogenesis, which is replicated by anti-IL11 therapy. These data show that IL11 inhibits reparative AT2-to-AT1 differentiation in the damaged lung to limit endogenous alveolar regeneration, resulting in fibrotic lung disease., (© 2024. The Author(s).)

Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in SLC7A7 and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the SLC7A7, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, HPGD and SLCO2A1. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with SLC7A7 may be attributed to the mechanism of increased PGE2 production., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To investigate the clinicopathological features and genetic mutation status of pulmonary intravascular large B cell lymphoma. Methods: The clinicopathological data of eight patients diagnosed with pulmonary intravascular large B cell lymphoma, from April 2018 to May 2023, were retrospectively analyzed. The genetic profile of six patients was detected via next-generation sequencing (NGS) and followed up. Results: All patients included one male and seven females, with a median age of 64 years (ranging from 45 to 66 years). Respiratory symptoms were the most common (7 cases), B symptoms in two cases, hemophagocytic syndrome in two cases. Multiple diffuse ground-glass opacities in both lungs were observed based on the high-resolution chest CT scan. Six cases of mild to moderate ventilation or diffusion dysfunction were observed based on the pulmonary function tests. Moreover, two cases of hypoxemia and two cases with type Ⅰ respiratory failure were recorded. The serum lactate dehydrogenase level increased (7/8), β2-MG level increased (2/8), neuron-specific enolase level increased (7/8), total number of peripheral blood lymphocytes decreased (7/8), and clinical stages were all stage Ⅳ. The neoplastic lymphoid cells were lodged in the lumina of venules and capillaries of the alveolar septum; the tumor cells were large, with prominent nucleoli and frequent mitotic figures. The malignant cells were detected in the extravascular surrounding lung tissue in all cases. The tumor cells expressed mature B cell-associated antigens CD20 and CD79a, and the vascular endothelial markers CD31 and CD34 showed that the tumor cells were filled in the blood vessels, infiltrated blood vessel walls, and perivascular areas. One case was germinal center-type, seven cases were non-germinal center-type, two cases were double-expressing lymphoma, and all cases were EBER-negative. Furthermore, the top five genes with mutation frequencies detected by NGS were MYD88 (5/6), PIM1 (5/6), CD79B (4/6), TCF3 (4/6), and TP53 (3/6). Of the eight cases, seven patients received R-CHOP-based chemotherapy, six cases had complete remission after chemotherapy, one case died, and one case was lost to follow-up. Conclusions: Pulmonary vascular large B cell lymphoma is rare, which shares similar patterns with interstitial lung disease on imaging. Transbronchial lung biopsy is an effective method to confirm the diagnosis. Immunochemotherapy with BTK inhibitors can provide a survival advantage for patients in the future based on molecular typing.

Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology., (© 2024 Valeri et al.)

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in SSc, affecting around 50 % of the patients. Lung tissue of patients with early-stage SSc-ILD is characterized by a predominant inflammatory response with inconspicuous fibrosis, which may progress to honeycombing fibrosis. Hence, a better understanding of the molecular mechanisms underpinning SSc-ILD pathogenesis is needed to improve treatment options and progression prediction. This transcriptomic study aims to reveal the differential gene expression between control (ctrl) lung tissue and inflammatory, prefibrotic and fibrotic lung tissue to capture progression of early to late phase SSc-ILD., Methods: Twelve explanted lungs from patients with SSc-ILD were used to analyze gene expression from formalin-fixed paraffin-embedded lung tissues with varying stages of ILD (n = 18) and control lung tissue (n = 6). The SSc-ILD tissues were stratified into three ROIs: inflammatory, prefibrotic, and fibrotic using histological assessments to define a longitudinal simulation of early to late phases of SSc-ILD. The nanoString (nS) nCounter Human Fibrosis Panel was used to profile the transcriptome in the regions of interest. Validation of potential targetswas performed with immunohistochemistry in the same tissues that were used for transcriptome analysis., Results: To validate our simulation model, we performed subgroup analysis that showed an incremental increase in pathway scores related to the severity of fibrosis. Ctrl vs SSc-ILD comparison demonstrated 24 differentially expressed genes, two of which had the most pronounced p-values. Cyclin-dependent kinase inhibitor (cdkn2c) was overexpressed (P = 0.00052) in SSc-ILD compared to ctrl, while expression of Pellino E3 ubiquitin-protein ligase 1 (peli1) showed lower expression (P = 0.0012). Additionally, in all four groups, cdkn2c and peli1 gene expression showed an incremental increase and decrease, respectively. Immunohistochemistry of cdkn2c showed consistent results with the nS analysis., Conclusion: More cdkn2c and less peli1 expression were associated with more advanced stages of SSc-ILD on histologic assessment. We report the potential of the cell cycle inhibitor and senescence marker, cdkn2c (p18) to be associated with fibrosis progression., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although recent decades have seen the identification, classification and discovery of the genetic basis of many children's interstitial and rare lung disease (chILD) disorders, detailed understanding of pathogenesis and specific therapies are still lacking for most of them. Fortunately, a revolution of technological advancements has created new opportunities to address these critical knowledge gaps. High-throughput sequencing has facilitated analysis of transcription of thousands of genes in thousands of single cells, creating tremendous breakthroughs in understanding normal and diseased cellular biology. Spatial techniques allow analysis of transcriptomes and proteomes at the subcellular level in the context of tissue architecture, in many cases even in formalin-fixed, paraffin-embedded specimens. Gene editing techniques allow creation of "humanized" animal models in a shorter time frame, for improved knowledge and preclinical therapeutic testing. Regenerative medicine approaches and bioengineering advancements facilitate the creation of patient-derived induced pluripotent stem cells and their differentiation into tissue-specific cell types which can be studied in multicellular "organoids" or "organ-on-a-chip" approaches. These technologies, singly and in combination, are already being applied to gain new biological insights into chILD disorders. The time is ripe to systematically apply these technologies to chILD, together with sophisticated data science approaches, to improve both biological understanding and disease-specific therapy., (© 2023 Wiley Periodicals LLC.)

Newly developing genomic technologies are an increasingly important part of clinical care and thus, it is not only important to understand the technologies and their limitations, but to also interpret the findings in an actionable fashion. Clinical geneticists and genetic counselors are now an integral part of the clinical team and are able to bridge the complexities of this rapidly changing science between the bedside clinicians and patients. This manuscript reviews the terminology, the current technology, some of the known genetic disorders that result in lung disease, and indications for genetic testing with associated caveats. Because this field is evolving quickly, we also provide links to websites that provide continuously updated information important for integrating genomic technology results into clinical decision-making., (© 2023 Wiley Periodicals LLC.)

Combined pulmonary fibrosis and emphysema (CPFE) presents a unique challenge in respiratory disorders, merging features of interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). Using the random forest algorithm, our study thoroughly examines the molecular details of CPFE. Analyzing gene expression datasets from GSE47460 (ILD: 254, COPD: 220, control: 108), we identify key genes namely ADRB2, CDH3, IRS2, MATN3, CD38, PDIA4, VEGFC, and among twenty others, crucial in airway regulation, lung function, and apoptosis, shaping the complex pathogenesis of CPFE. Additionally, miRNAs (hsa-mir-101-3p, hsa-mir-1343-3p, hsa-mir-27a-3p, and miR-16-5p) showcase regulatory impacts on CPFE-related molecular pathways. Our machine learning model unveils these intricate interactions, offering a comprehensive insight into CPFE's molecular mechanisms. This research not only pinpoints potential therapeutic targets and biomarkers but also opens avenues for innovative approaches in managing CPFE, linking ILD and COPD within this complex respiratory condition., (© 2024. International Federation for Medical and Biological Engineering.)

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and interstitial lung diseases are frequently occurring disorders with a polygenic basis that account for a large global burden of morbidity and mortality. Recent large-scale genetic epidemiology studies have identified associations between genetic variation and individual respiratory diseases and linked specific genetic variants to quantitative traits related to lung function. These associations have improved our understanding of the genetic basis and mechanisms underlying common lung diseases. Moreover, examining the overlap between genetic associations of different respiratory conditions, along with evidence for gene-environment interactions, has yielded additional biological insights into affected molecular pathways. This genetic information could inform the assessment of respiratory disease risk and contribute to stratified treatment approaches., (© 2024. Springer Nature Limited.)

The ATP-binding cassette subfamily A member 3 (ABCA3) protein plays a fundamental role in surfactant homeostasis. Most children with ABCA3 gene mutations develop pulmonary interstitial fibrosis leading to the development of interstitial lung disease. Since traditional medicine does not offer effective therapy, the best option is lung transplantations, especially bilateral lung transplantations. We are reporting the case of a successful bilateral lung transplantation in a five-year-old child with pulmonary interstitial fibrosis caused by ABCA3 gene mutations. This successful transplantation enabled the patient to get rid of chronic cough and tachypnea., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Gain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). Patients with SAVI develop interstitial lung disease (ILD) and produce autoantibodies that are commonly associated with systemic autoimmune diseases. Mice expressing the most common SAVI mutation, STING V154M (VM), similarly develop ILD but exhibit severe T and B cell lymphopenia and low serum Ig titers, and they lack autoantibodies. Importantly, lethally irradiated VM hosts reconstituted with WT stem cells (WT→VM) still develop ILD. In this study, we find that WT→VM chimeras had restored B cell function, produced autoantibodies, and thereby recapitulated the loss of tolerance seen in patients with SAVI. Lymphocytes derived from both WT and BCR or TCR transgenic (Tg) donors accumulated in the extravascular lung tissue of WT+Tg→VM mixed chimeras, but lymphocyte activation and germinal center formation required WT cells with a diverse repertoire. Furthermore, when T cells isolated from the WT→VM chimeras were adoptively transferred to naive Rag1-deficient secondary hosts, they trafficked to the lung and recruited neutrophils. Overall, these findings indicated that VM expression by radioresistant cells promoted the activation of autoreactive B cells and T cells that then differentiated into potentially pathogenic effector subsets.

Introduction: Interstitial lung diseases are a varied group of diseases associated with chronic inflammation and fibrosis. With the emerging and current treatment options, survival rates have vastly improved. Having in mind that the most common type is idiopathic pulmonary fibrosis and that a significant proportion of these patients will develop lung cancer as the disease progresses, prompt diagnosis and personalized treatment of these patients are fundamental., Scope and Methods: The scope of this review is to identify and characterize molecular and pathogenetic pathways that can interconnect Interstitial Lung Diseases and lung cancer, especially driver mutations in patients with NSCLC, and to highlight new and emerging treatment options in that view., Results: Common pathogenetic pathways have been identified in sites of chronic inflammation in patients with interstitial lung diseases and lung cancer. Of note, the expression of driver mutations in EGFR, BRAF, and KRAS G12C in patients with NSCLC with concurrent interstitial lung disease is vastly different compared to those patients with NSCLC without Interstitial Lung Disease., Conclusions: NSCLC in patients with Interstitial Lung Disease is a challenging diagnostic and clinical entity, and a personalized medicine approach is fundamental to improving survival and quality of life. Newer anti-fibrotic medications have improved survival in IPF/ILD patients; thus, the incidence of lung cancer is going to vastly increase in the next 5-10 years.

Background: Prior observational studies have suggested a potential direct link between psoriasis (PSO) and interstitial lung disease (ILD). Consequently, we applied Mendelian randomization (MR) to further evaluate the bidirectional causal relationships between PSO and its different phenotypes [psoriatic arthritis (PSA)/psoriasis vulgaris (PSV)] and ILD., Methods: Data regarding PSO/PSA/PSV and ILD were sourced from publicly accessible genome-wide association studies (GWAS) databases, focusing on European populations. We used five algorithms- MR Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode- to evaluate the causal relationships between PSO/PSA/PSV and ILD, with a primary emphasis on the IVW method., Results: The analysis indicated a potential association between PSA and an elevated risk of ILD [IVW odds ratio (OR): 1.035 (95% CI 1.008, 1.064; P = 0.012)], with no evidence of a direct relationship between total PSO and PSV with ILD. Conversely, no substantial evidence emerged from the reverse MR analysis to suggest that ILD significantly affects total PSO or the specific PSA/PSV phenotypes., Conclusion: Our findings provide genetic evidence supporting the notion that PSA may be a contributory risk factor for ILD. Further investigations are warranted to explore the underlying mechanisms of this potential causal relationship between PSA and ILD., (© 2024. The Author(s).)

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently characterized disease associated with somatic mutations in the UBA1 gene, which cause dysregulation of ubiquitin-mediated processes. This case describes a 71-year-old male patient with VEXAS syndrome who presented with refractory lung inflammation with a pattern similar to computed tomography hypersensitivity pneumonitis, a novel finding in VEXAS syndrome. The presented clinical case highlights the protean involvement of the lung in VEXAS syndrome and emphasizes the importance of considering interstitial lung disease in the differential diagnosis.

Mesenchymal-epithelial transition (MET) exon 14-skipping mutation (METex14) is rare in pulmonary invasive mucinous adenocarcinomas (IMAs), and the clinical impact of MET-tyrosine kinase inhibitors (TKIs) remains unknown. We herein report a 75-year-old woman with IMA harboring METex14 who was treated with the MET-TKI tepotinib. The lung tumor regressed over six months; however, the patient ultimately died of exacerbated interstitial lung disease (ILD), possibly associated with tepotinib. An autopsy revealed diffuse alveolar damage in pre-existing chronic fibrosis. We discuss how to pre-evaluate ILD deterioration risks and monitor TKI-induced lung toxicity during treatment.

Cystic fibrosis (CF) is a monogenic disorder cause by mutations in the CF Transmembrane Regulator (CFTR) gene. The prognosis of cystic fibrosis has been transformed by the discovery of highly effective modulator therapies (HEMT). Treatment has changed from reactive therapy dealing with complications of the disease to pro-active correction of the underlying molecular functional abnormality. This has come about by discovering the detailed biology of the different CF molecular sub-endotypes; the development of biomarkers to assess response even in mild disease or young children; the performance of definitive large randomised controlled trials in patients with a common mutation and the development of in vitro testing systems to test efficacy in those patients with rare CFTR mutations. As a result, CF is now an umbrella term, rather than a specific diagnostic label; we have moved from clinical phenotypes to molecular subendotypes. Children's Interstitial Lung Diseases (chILDs) comprise more than 200 entities, and are a diverse group of diseases, for an increasing number of which an underlying gene mutation has been discovered. Many of these entities are umbrella terms, such as pulmonary alveolar proteinosis or hypersensitivity pneumonitis, for each of which there are multiple and very different endotypes. Even those chILDs for which a specific gene mutation has been discovered comprise, as with CF, different molecular subendotypes likely mandating different therapies. For most chILDs, current treatment is non-specific (corticosteroids, azithromycin, hydroxychloroquine). The variability of the different entities means that there is little evidence for the efficacy of any treatment. This review considers how some of the lessons of the success story of CF are being applied to chILD, thus opening the opportunities for truly personalised medicine in these conditions. Advances in knowledge in the molecular biology of surfactant protein C and Adenosine triphosphate binding cassette subfamily A member 3 (ABCA3), and the possibilities of discovering novel therapies by in vitro studies will especially be highlighted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus., Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak., Findings: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response., Interpretation: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms., Funding: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists., Competing Interests: Declaration of interests The authors declare that they have no financial conflict of interests for this study., (Copyright © 2024. Published by Elsevier B.V.)

Background: To determine the predictive value of interstitial lung abnormalities (ILA) for epidermal growth factor receptor (EGFR) mutation status and assess the prognostic significance of EGFR and ILA in patients with non-small cell lung cancer (NSCLC)., Methods: We reviewed 797 consecutive patients with a histologically proven diagnosis of primary NSCLC from January 2013 to October 2018. Of these, 109 patients with NSCLC were found to have concomitant ILA. Multivariate logistic regression analysis was used to identify the significant clinical and computed tomography (CT) findings in predicting EGFR mutations. Cox proportional hazard models were used to identify significant prognostic factors., Results: EGFR mutations were identified in 22 of 109 tumors (20.2%). Multivariate analysis showed that the models incorporating clinical, tumor CT and ILA CT features yielded areas under the receiver operating characteristic curve (AUC) values of 0.749, 0.838, and 0.849, respectively. When combining the three models, the independent predictive factors for EGFR mutations were non-fibrotic ILA, female sex, and small tumor size, with an AUC value of 0.920 (95% confidence interval[CI]: 0.861-0.978, p < 0.001). In the multivariate Cox model, EGFR mutations (hazard ratio = 0.169, 95% CI = 0.042-0.675, p = 0.012; 692 days vs. 301 days) were independently associated with extended overall survival compared to the wild-type., Conclusion: Non-fibrotic ILA independently predicts the presence of EGFR mutations, and the presence of EGFR mutations rather than non-fibrotic ILA serves as an independent good prognostic factor for patients with NSCLC., (© 2024. The Author(s).)

Objectives: To systemically analyse the heterogeneity in the clinical manifestations and prognoses of patients with antisynthetase syndrome (ASS) and evaluate the transcriptional signatures related to different clinical phenotypes., Methods: A total of 701 patients with ASS were retrospectively enrolled. The clinical presentation and prognosis were assessed in association with four anti-aminoacyl transfer RNA synthetase (ARS) antibodies: anti-Jo1, anti-PL7, anti-PL12 and anti-EJ. Unsupervised machine learning was performed for patient clustering independent of anti-ARS antibodies. Transcriptome sequencing was conducted in clustered ASS patients and healthy controls., Results: Patients with four different anti-ARS antibody subtypes demonstrated no significant differences in the incidence of rapidly progressive interstitial lung disease (RP-ILD) or prognoses. Unsupervised machine learning, independent of anti-ARS specificity, identified three endotypes with distinct clinical features and outcomes. Endotype 1 (RP-ILD cluster, 23.7%) was characterised by a high incidence of RP-ILD and a high mortality rate. Endotype 2 (dermatomyositis (DM)-like cluster, 14.5%) corresponded to patients with DM-like skin and muscle symptoms with an intermediate prognosis. Endotype 3 (arthritis cluster, 61.8%) was characterised by arthritis and mechanic's hands, with a good prognosis. Transcriptome sequencing revealed that the different endotypes had distinct gene signatures and biological processes., Conclusions: Anti-ARS antibodies were not significant in stratifying ASS patients into subgroups with greater homogeneity in RP-ILD and prognoses. Novel ASS endotypes were identified independent of anti-ARS specificity and differed in clinical outcomes and transcriptional signatures, providing new insights into the pathogenesis of ASS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

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., Competing Interests: Conflict of interest: P. Bonniaud reports grants from AstraZeneca, lecture honoraria from Sanofi and AstraZeneca, travel support from AstraZeneca, Novartis, Sanofi, Boehringer and Stallergenes, and advisory board membership with AstraZeneca, Novartis, Sanofi, GSK and Boehringer. J. Cadranel had a patent planned, received consulting fees and participated on a data safety monitoring board or advisory board for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Daichi, Lilly, Pfizer, Novartis, MSD, Roche and Takeda. A. Cazes reports lecture honoraria and travel support from Boehringer Ingelheim. B. Crestani reports grants from Boehringer Ingelheim, consulting fees from Apellis, BMS, Boehringer Ingelheim and Sanofi, lecture honoraria from Apellis, AstraZeneca, BMS, Boehringer Ingelheim, Novartis and Sanofi, support for attending meetings or travel from AstraZeneca, BMS, Boehringer Ingelheim and Sanofi, participated on a data safety monitoring board or advisory board for Apellis, BMS, Boehringer Ingelheim and Sanofi, and had a leadership role as President of the Board of Trustees of the Fondation du Souffle. R. Epaud reports consulting fees from AstraZeneca, lecture honoraria from GSK, AstraZeneca and Menarini, travel support from GSK and AstraZeneca, and advisory board membership with AstraZeneca and Novartis. M-P. Debray reports lecture honoraria and travel support from Boehringer Ingelheim. E. Manali reports lecture honoraria from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, support for attending meetings or travel from Boehringer Ingelheim, CLS Behring, Hoffman-La Roche and Elpen, and had a leadership role as a Chair in the ERS Task Force for transition of chILD to adult care. S. Papiris reports lecture honoraria from Boehringer Ingelheim and Hoffmann-La Roche, and travel support from Boehringer Ingelheim and Elpen. N. Nathan reports grants from Legs poix de la Chancellerie des Universités 2022 (number 2022000594). C. Andréjak participated on a data safety monitoring board or advisory board for the EVER-ILD2 study (rituximab in diffuse interstitial pneumonia) and received funding via a grant from the French Research Ministry. S. Jouneau reports grants from AIRB, Boehringer Ingelheim and Roche, lecture honoraria from AIRB, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chiesi, Genzyme, GSK, LVL, Novartis, Pfizer, Roche and Sanofi, travel support from Boehringer Ingelheim, Roche and AIRB, and advisory board participation for Boehringer Ingelheim, GSK and Sanofi. G. Beltramo reports lecture honoraria from Bristol Myers Squibb, and support for attending meetings or travel from Sanofi Aventis France and Boehringer Ingelheim France. S. Hirschi reports research grants from Agence de la Biomedécine, CSL Behring and Adiral medical assistance, lecture honoraria from Boehringer Ingelheim, travel support from CSL Behring, Boehringer Ingelheim and ISIS Medical, and received medical equipment from ISIS Medical. C. Picard reports lecture honoraria and consulting fees from Boehringer Ingelheim. G. Prévot reports honoraria for presentations and educational event from Boehringer Ingelheim, Sanofi, Jansen and MSD. G. Zalcman reports consulting fees from AstraZeneca, BMS, Pfizer and Sanofi, lecture honoraria from BMS, AstraZeneca and Sanofi, support for attending meetings or travel from AstraZeneca and BMS, and participated on a data safety monitoring board or advisory board for AstraZeneca and BMS. V. Cottin reports grants from Boehringer Ingelheim, consulting fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, CSL Behring, Ferrer/United Therapeutics, GSK, Pliant, Pure Tech, RedX, Roche, Sanofi and Shionogi, lecture honoraria from Boehringer Ingelheim, Ferrer/United Therapeutics and Roche, support for attending meetings or travel from Boehringer Ingelheim and Roche, participated on a data safety monitoring board or advisory board for Galapagos, Galecto and GSK, and had a leadership role in an adjudication committee for Fibrogen. R. Borie reports consulting fees from Boehringer Ingelheim, Ferrer and Sanofi, lecture honoraria from Boehringer Ingelheim and Roche, travel support from Boehringer Ingelheim, Roche and Chiesi, and advisory board participation for Savara. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Squamous cell carcinoma (SCC) is a common histological type of lung carcinoma that is associated with interstitial pneumonia (IP). We hypothesized that identifying specific genetic alterations or molecular markers of SCC with IP may aid the development of novel therapeutic strategies for the same. Therefore, in the present study, we aimed to identify tumorigenic genetic alterations and molecular markers in cases of SCC with IP. We included 28 lung SCC cases (14 cases with IP and 14 cases without IP). We performed immunohistochemistry for STAT3, STAT5, and TLE1, and next-generation sequencing was performed using an iSeq 100 system. The panel used in this study targeted 50 cancer-associated genes. Immunohistochemically, the rate of TLE1 positivity was higher in the SCC without IP group (93 %) than in the SCC with IP group (29 %), while that of STAT5 was higher in the SCC with IP group (79 %) than in the SCC without IP group (14 %). STAT3 expression was high in both the groups (SCC with IP, 64 %; SCC without IP, 71 %). Eighteen genes were mutated in more than six samples, and FBXW7 mutation was mainly observed in the SCC with IP group (p < 0.01). Mechanisms underlying tumorigenesis in SCC with IP included STAT5 activation via inflammation, while that in SCC without IP included squamous TLE1-mediated metaplasia. These findings are based on smoking-induced STAT3 activation; therefore, patients with IP who smoke are more likely to have progressive SCC. We also found that FBXW7 mutations may be associated with SCC with IP and keratinization. ERBB4 and KDR mutations were observed in both with or without IP, and these genes may be tumor-related genes in SCC. These molecular markers may help determine the prognoses of patients with SCC with IP and direct the development of treatment approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Rationale: Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood. Objectives: To identify novel protein biomarkers of QIAs using high-throughput plasma proteomic panels within two multicenter cohorts. Methods: We measured the plasma proteomics of 4,383 participants in an older, ever-smoker cohort (COPDGene [Genetic Epidemiology of Chronic Obstructive Pulmonary Disease]) and 2,925 participants in a younger population cohort (CARDIA [Coronary Artery Disease Risk in Young Adults]) using the SomaLogic SomaScan assays. We measured QIAs using a local density histogram method. We assessed the associations between proteomic biomarker concentrations and QIAs using multivariable linear regression models adjusted for age, sex, body mass index, smoking status, and study center (Benjamini-Hochberg false discovery rate-corrected P  ⩽ 0.05). Measurements and Main Results: In total, 852 proteins were significantly associated with QIAs in COPDGene and 185 in CARDIA. Of the 144 proteins that overlapped between COPDGene and CARDIA, all but one shared directionalities and magnitudes. These proteins were enriched for 49 Gene Ontology pathways, including biological processes in inflammatory response, cell adhesion, immune response, ERK1/2 regulation, and signaling; cellular components in extracellular regions; and molecular functions including calcium ion and heparin binding. Conclusions: We identified the proteomic biomarkers of QIAs in an older, smoking population with a higher prevalence of pulmonary disease and in a younger, healthier community cohort. These proteomics features may be markers of early precursors of advanced lung diseases.

Competing Interests: GR reports consulting fees from Sanofi. JMT received partial funding for her paid fellowship training during the writing of this Comment from the Warren Alpert Foundation fellowship. RLB declares no competing interests. We thank Gail P Jarvik (Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA) for kindly reviewing the article and providing valuable input.

Numerous SARS-CoV-2 variant strains with altered characteristics have emerged since the onset of the COVID-19 pandemic. Remdesivir (RDV), a ribonucleotide analogue inhibitor of viral RNA polymerase, has become a valuable therapeutic agent. However, immunosuppressed hosts may respond inadequately to RDV and develop chronic persistent infections. A patient with respiratory failure caused by interstitial pneumonia, who had undergone transplantation of the left lung, developed COVID-19 caused by Omicron BA.5 strain with persistent chronic viral shedding, showing viral fusogenicity. Genome-wide sequencing analyses revealed the occurrence of several viral mutations after RDV treatment, followed by dynamic changes in the viral populations. The C799F mutation in nsp12 was found to play a pivotal role in conferring RDV resistance, preventing RDV-triphosphate from entering the active site of RNA-dependent RNA polymerase. The occurrence of diverse mutations is a characteristic of SARS-CoV-2, which mutates frequently. Herein, we describe the clinical case of an immunosuppressed host in whom inadequate treatment resulted in highly diverse SARS-CoV-2 mutations that threatened the patient's health due to the development of drug-resistant variants., (© 2024. The Author(s).)

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STING V154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders., Competing Interests: Declaration of interests K.A.F. is a Scientific Founder of Danger Bio, a Related Sciences company and is a member of the Scientific Advisory Board for Vesigen Therapeutics, NodThera, Janssen, and Generation Bio., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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 DL CO 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 DL CO , 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., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)