Health Sci Rep. 2025 Feb 6;8(2):e70328. doi: 10.1002/hsr2.70328. eCollection 2025 Feb.

ABSTRACT

BACKGROUND AND AIMS: Interactions between the lung microbiome and pulmonary epithelium plays a pivotal role in shaping immunity in the lung. Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD). Some patients with IPF develop episodic acute exacerbations often associated with microbial dysbiosis in the lungs. This study aimed to investigate etiologic agents as well as the lung microbiome in patients with ILDs and sarcoidosis.

METHODS: This study analyzed 31 patients divided into the IPF (IPF-stable, n = 12), acute exacerbation of ILDs (AE-ILDs, n = 6), and sarcoidosis (n = 13) groups. Bronchoalveolar lavage fluid (BALF) samples were analyzed by RNA-based metagenomic next-generation sequencing (NGS) on an Illumina platform.

RESULTS: In total, 87 pathogens were detected using metagenomic NGS at the genus level. Prevotella, Streptococcus, and Veillonella dominated the BALF microbial communities, and sequence reads of these bacteria were abundant, especially in the sarcoidosis group. Conversely, only a small number of bacterial reads were detected in the AE-ILDs group, and the overall proportion of microbial composition differed from that of the other groups. No significant difference was found in community diversity (α-diversity) among the groups, whereas the structural similarity of the microflora (β-diversity) differed significantly between the AE-ILDs and sarcoidosis groups.

CONCLUSIONS: Bacterial sequence reads in BALF were smaller in both the IPF-stable and AE-ILD groups than in the sarcoidosis group. Dysbiosis in the lung microbiome has been observed in patients with AE-ILD and may be related to the progression of inflammation.

PMID:39927182 | PMC:PMC11803077 | DOI:10.1002/hsr2.70328

Respir Med. 2025 Feb 5:107986. doi: 10.1016/j.rmed.2025.107986. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a distinctive chronic interstitial lung disease characterized by upper lobe-dominant elastofibrosis. Deepening of the suprasternal notch is a notable physical feature in patients with iPPFE. However, the anatomical explanation and clinical significance of iPPFE have not yet been studied in detail.

METHODS: We retrospectively examined 84 patients with iPPFE, 59 with idiopathic pulmonary fibrosis (IPF), 32 with chronic hypersensitivity pneumonitis (CHP), and 91 non-interstitial lung disease (ILD) controls. The depth of the suprasternal notch assessed on axial chest computed tomography and its association with clinical, radiological, and physiological parameters, and patient outcomes were investigated.

RESULTS: The depth of the suprasternal notch was anatomically correlated with the thickness of the pre-tracheal soft tissue and posterior or right deviation of the trachea in patients with iPPFE. The depth of the suprasternal notch effectively discriminated patients with iPPFE from those with IPF (sensitivity, 75%; specificity, 86.4%), CHP (sensitivity, 75%; specificity, 84.4%), and non-ILD controls (sensitivity, 75%; specificity, 83.5%), with a cutoff value of 9.5 mm. A log-rank test showed that patients with iPPFE with a deep suprasternal notch had significantly shorter survival than those without a deep suprasternal notch. In addition, a multivariate Cox regression analysis adjusted for age, sex, and %forced vital capacity showed that the depth of the suprasternal notch was an independent risk factor for mortality.

CONCLUSION: The suprasternal notch is a simple and useful indicator with diagnostic and prognostic implications for patients with iPPFE.

PMID:39921067 | DOI:10.1016/j.rmed.2025.107986

Cell Commun Signal. 2025 Feb 7;23(1):67. doi: 10.1186/s12964-025-02076-4.

ABSTRACT

Synchrotron-radiation nano-X-Ray Fluorescence (XRF) is a cutting-edge technique offering high-resolution insights into the elemental composition of biological tissues, shedding light on metabolic processes and element localization within cellular structures. In the context of Idiopathic Pulmonary Fibrosis (IPF), a debilitating lung condition associated with respiratory complications and reduced life expectancy, nano-XRF presents a promising avenue for understanding the disease's intricate pathology. Our developed workflow enables the assessment of elemental composition in both human and rodent fibrotic tissues, providing insights on the interplay between cellular compartments in chronic lung diseases. Our findings demonstrate trace element accumulations associated with anthracosis, a feature observed in IPF. Notably, Zn and Ca clusters approximately 750 nm in size were identified exclusively in IPF samples. While their specific role remains unclear, their presence may be associated with disease-specific processes. Additionally, we observed Fe and S signal colocalization in 650-nm structures within some IPF cells. Fe-S complexes in mitochondria are known to be associated with increased ROS production, suggesting a potential connection to the disease pathology. In contrast, a bleomycin-induced fibrosis rodent model exhibits a different elemental phenotype with low Fe and increased S, Zn, and Ca. Overall, our workflow highlights the effectiveness of synchrotron-based nano-XRF mapping in analyzing the spatial distribution of trace elements within diseased tissue, offering valuable insights into the elemental aspects of IPF and related chronic lung diseases.

PMID:39920750 | DOI:10.1186/s12964-025-02076-4

Cell Biol Toxicol. 2025 Feb 7;41(1):40. doi: 10.1007/s10565-025-09990-w.

ABSTRACT

Autophagy related genes (ATGs) play essential roles in maintaining cellular functions, although biological and pathological alterations of ATG phenotypes remain poorly understood. To address this knowledge gap, we utilized the single-cell sequencing technology to elucidate the transcriptomic atlas of ATGs in lung diseases, with a focus on lung epithelium and lymphocytes. This study conducted a comprehensive investigation into RNA profiles of ATGs in the lung tissues obtained from healthy subjects and patients with different lung diseases through single-cell RNA sequencing (scRNA-seq), including COVID-19 related acute lung damage, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), systemic sclerosis (SSC), and lung adenocarcinoma (LUAD). Our findings revealed significant variations of ATGs expression across lung epithelial cell subsets, e.g., over-expression of MAPK8 in basal cells, ATG10 in club cells, and BCL2 in a goblet cell subset. The changes of autophagy-related pathways varied between lung epithelial and lymphocyte subsets. We identified the disease-associated changes in ATG expression, including significant alterations in BCL2, BCL2L1, PRKCD, and PRKCQ in inflammatory lung diseases (COPD and IPF), and MAP2K7, MAPK3, and RHEB in lung cancer (LUAD), as compared to normal lung tissues. Key ligand-receptor pairs (e.g., CD6-ALCAM, CD99-CD99) and signaling pathways (e.g., APP, CD74) might serve as biomarkers for lung diseases. To evaluate ATGs responses to external challenges, we examined ATGs expression in different epithelial cell lines exposed to cigarette smoking extract (CSE), lysophosphatidylcholine (lysoPC), lipopolysaccharide (LPS), and cholesterol at various doses and durations. Notable changes were observed in CFLAR, EIF2S1, PPP2CA, and PPP2CB in A549 and H1299 against CSE and LPS. The heterogeneity of ATGs expression was dependent on cell subsets, pathologic conditions, and challenges, as well as varied among cellular phenotypes, functions, and behaviors, and the severity of lung diseases. In conclusion, our data might provide new insights into the roles of ATGs in epithelial biology and pulmonary disease pathogenesis, with implications for disease progression and prognosis.

PMID:39920481 | DOI:10.1007/s10565-025-09990-w

Respirology. 2025 Feb 7. doi: 10.1111/resp.14894. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. Antifibrotics slow the decline of pulmonary function after 12-months, but limited studies have examined the role of circulatory biomarkers in antifibrotic treated IPF patients.

METHODS: Serum from 98 IPF participants, from the Australian Idiopathic Pulmonary Fibrosis Registry were collected at four time-points over 1 year post-antifibrotic treatment and analysed as two separate cohorts. Patients were stratified as progressive, if they experienced ≥ 10% decline in FVC or ≥ 15% decline in DLCO or were deceased within 1 year of treatment initiation: or otherwise as stable. Ten molecules of interest were measured by ELISAs in patient serum.

RESULTS: Baseline MMP7 levels were higher in progressive than stable patients in Cohort 1 (p = 0.02) and Cohort 2 (p = 0.0002). Baseline MMP7 levels also best differentiated progressive from stable patients (Cohort 1, AUC = 0.74, p = 0.02; Cohort 2, AUC = 0.81, p = 0.0003). Regression analysis of the combined cohort showed that elevated MMP7 levels predicted 12-month progression (OR = 1.530, p = 0.010) and increased risk of overall mortality (HR = 1.268, p = 0.002). LASSO regression identified a multi-biomarker panel (MMP7, ICAM-1, CHI3L1, CA125) that differentiated progression more accurately than MMP7 alone. Furthermore, GAP combined with MMP7, ICAM-1, CCL18 and SP-D was more predictive of 3-year mortality than GAP alone.

CONCLUSION: MMP7 along with a multi-biomarker and GAP panel can predict IPF progression and mortality, with the potential for optimising management.

PMID:39919729 | DOI:10.1111/resp.14894

PLoS One. 2025 Feb 7;20(2):e0318877. doi: 10.1371/journal.pone.0318877. eCollection 2025.

ABSTRACT

BACKGROUND: The therapeutic role of antifibrotic therapy has been well-established in idiopathic pulmonary fibrosis (IPF). However, its efficacy and safety for interstitial lung diseases (ILDs) other than IPF are not fully understood.

METHODS: We updated a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials and prospective studies on antifibrotic drug (nintedanib or pirfenidone) vs other intervention (placebo, no intervention or conventional treatment) in non-IPF ILDs. The primary outcomes were absolute change in forced vital capacity (FVC), all-cause mortality and serious adverse events (SAEs). The risk of bias was rated with the RoB2 tool and certainty of evidence was assessed by the GRADE approach.

RESULTS: 17 studies with 1908 patients were included. For the primary outcomes, pooled analyses of four trials with low risk of bias showed that antifibrotic drugs significantly ameliorated FVC decline (mean difference 86.21; 95% CI 49.38 to 123.03; I2 = 64%; TSA-adjusted CI 40.86 to 131.56). Based on five trials with low risk of bias, no difference was observed in all-cause mortality (RR 0.87; 95% CI 0.53 to 1.43; I2 = 0%; TSA-adjusted CI 0.12 to 6.53) and SAEs (RR 0.97; 95% CI 0.83 to 1.13; I2 = 0%; TSA-adjusted CI 0.74 to 1.28) between groups. However, based on two studies with 324 patients, benefit of antifibrotic drugs in FVC was not shown in the subgroup taking mycophenolate (mean difference 17.08; 95% CI -56.22 to 90.37), which also had higher risk of SAEs (RR 1.71; 95% CI 1.09 to 2.70), although both were contested by TSA.

CONCLUSION: Our study suggests that antifibrotic drugs are beneficial for patients with non-IPF ILDs in slowing disease progression, whereas may not correlate to all-cause mortality and SAEs. However, for patients taking mycophenolate, antifibrotic drugs may do more harm than good. More investigations are warranted to validate current findings.

PMID:39919132 | DOI:10.1371/journal.pone.0318877

Cell Rep. 2025 Feb 6;44(2):115275. doi: 10.1016/j.celrep.2025.115275. Online ahead of print.

ABSTRACT

Mucosal-associated invariant T (MAIT) cells, the most abundant unconventional T cells in the lung, can exhibit a wide range of functional responses to different triggers via their T cell receptor (TCR) and/or cytokines. Their role, especially in sterile lung injury, is unknown. Using single-cell RNA sequencing (scRNA-seq), spectral analysis, and adoptive transfer in a bleomycin-induced sterile lung injury, we found that bleomycin activates murine pulmonary MAIT cells and is associated with a protective role against bleomycin-induced lung injury. MAIT cells drive the accumulation of type 1 conventional dendritic cells (cDC1s), limiting tissue damage in a DNGR-1-dependent manner. Human scRNA-seq data revealed that MAIT cells were activated, with increased cDC populations in idiopathic pulmonary fibrosis patients. Thus, MAIT cells enhance defense against sterile lung injury by fostering cDC1-driven anti-fibrotic pathways.

PMID:39918959 | DOI:10.1016/j.celrep.2025.115275

Expert Rev Respir Med. 2025 Feb 7. doi: 10.1080/17476348.2025.2464886. Online ahead of print.

NO ABSTRACT

PMID:39917880 | DOI:10.1080/17476348.2025.2464886

Epigenetics. 2025 Dec;20(1):2462898. doi: 10.1080/15592294.2025.2462898. Epub 2025 Feb 7.

ABSTRACT

Although N6-methyladenosine (m6A) may be related to the pathogenesis of fibrotic process, the mechanism of m6A modification in aging-related idiopathic pulmonary fibrosis (IPF) remains unclear. Three-milliliter venous blood was collected from IPF patients and healthy controls. MeRIP-seq and RNA-seq were utilized to investigate differential m6A modification. The expressions of identified m6A regulator and target gene were validated using MeRIP-qPCR and real-time PCR. Moreover, we established an animal model and a senescent model of A549 cells to explore the associated molecular mechanism. Our study provided a panorama of m6A methylation in IPF. Increased peaks (3756) and decreased peaks (4712) were observed in the IPF group. The association analysis showed that 749 DEGs were affected by m6A methylation in IPF. Among the m6A regulators, the expression of METTL14 decreased in IPF. The m6A level of our interested gene DDIT4 decreased significantly, but the mRNA level of DDIT4 was higher in IPF. This was further verified in bleomycin-induced pulmonary fibrosis. At the cellular level, it was further confirmed that METTL14 and DDIT4 might participate in the senescence of alveolar epithelial cells. The downregulation of METTL14 might inhibit the decay of DDIT4 mRNA by reducing the m6A modification level of DDIT4 mRNA, leading to high expression of DDIT4 mRNA and protein. Our study provided a panorama of m6A alterations in IPF and discovered METTL14 as a potential intervention target for epigenetic modification in IPF. These results pave the way for future investigations regarding m6A modifications in aging-related IPF.

PMID:39916577 | DOI:10.1080/15592294.2025.2462898

Expert Opin Investig Drugs. 2025 Feb 6. doi: 10.1080/13543784.2025.2462592. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease of unknown cause that occurs primarily in older adults and is associated with poor quality of life and substantial healthcare utilization. IPF has a dismal prognosis. Indeed, first-line therapy, which includes nintedanib and pirfenidone, does not stop disease progression and is often associated with tolerability issues. Therefore, there remains a high medical need for more efficacious and better tolerated treatments.

AREAS COVERED: Gene therapy is a relatively unexplored field of research in IPF that has the potential to mitigate a range of profibrotic pathways by introducing genetic material into cells. Here, we summarize and critically discuss publications that have explored the safety and efficacy of gene therapy in experimentally-induced pulmonary fibrosis in animals, as clinical studies in humans have not been published yet.

EXPERT OPINION: The application of gene therapy in pulmonary fibrosis requires further investigation to address several technical and biological hurdles, improve vectors' design, drug delivery, and target selection, mitigate off-target effects and develop markers of gene penetration into target cells. Long-term clinical data are needed to bring gene therapy in IPF one step closer to practice.

PMID:39916340 | DOI:10.1080/13543784.2025.2462592

Biofabrication. 2025 Feb 6. doi: 10.1088/1758-5090/adb338. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. Macrophages are implicated in the fibrotic process, but exhibit remarkable plasticity in the activated immune environment in vivo, presenting significant challenges as therapeutic targets. To explore the influence of macrophages on IPF and develop macrophage-targeted therapies, we engineered a micro-lung chip with a lung epithelium-interstitium tissue unit to establish a controlled immune environment containing only macrophages. We discovered that macrophages exacerbated inflammation and fibrosis by comparing microchips treated with bleomycin in the presence and absence of macrophages. Based on the duration of bleomycin treatment, we established pathological models corresponding to inflammation and fibrosis stages. Transcriptome analysis revealed that activation of the PI3K-AKT signaling pathway facilitates the transition from inflammation to fibrosis. However, LY294002, a PI3K inhibitor, not only suppressed fibrosis and decreased the accumulation of M2 macrophages but also intensified the severity of inflammation. These findings suggest that macrophages play a pivotal role in the potential development at the tissue level. The micro-lung chip cocultured with macrophages holds significant potential for exploring the pathological progression of IPF and elucidating the mechanisms of anti-fibrotic drugs.

PMID:39914008 | DOI:10.1088/1758-5090/adb338

Expert Rev Respir Med. 2025 Feb 6. doi: 10.1080/17476348.2025.2464035. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive scarring and reduced survival. The development of IPF is influenced by rare and common genetic variants, cigarette smoking, aging, and environmental exposures. Among the two dozen genetic contributors, the MUC5B promoter variant (rs35705950) is the dominant risk factor, increasing the risk of both familial and sporadic IPF and accounting for nearly 50% of the genetic predisposition to the disease.

AREAS COVERED: This review provides an expert perspective on the genetic underpinnings of IPF rather than a systematic analysis, emphasizing key insights into its genetic basis. The articles referenced in this review were identified through targeted searches in PubMed, Scopus, and Web of Science for studies published between 2000 and 2023, prioritizing influential research on the genetic factors contributing to IPF. Search terms included 'idiopathic pulmonary fibrosis,' 'genetics,' 'MUC5B,' 'telomere dysfunction,' and 'surfactant proteins.' The selection of studies was guided by the authors' expertise, focusing on the most relevant publications.

EXPERT OPINION: The identification of genetic variants not only highlights the complexity of IPF but also offers potential for earlier diagnosis and personalized treatment strategies targeting specific genetic pathways, ultimately aiming to improve patient outcomes.

PMID:39912527 | DOI:10.1080/17476348.2025.2464035

J Med Chem. 2025 Feb 5. doi: 10.1021/acs.jmedchem.5c00263. Online ahead of print.

ABSTRACT

Despite significant advancements in the treatment options for idiopathic pulmonary fibrosis (IPF), the disease remains aggressive and incurable. This viewpoint summarizes the discovery of a neutral, potent, and selective lysophosphatidic acid receptor 1 antagonist for the treatment of IPF. The lead optimization without the cocrystal structure guidance is worth it to highlight.

PMID:39909836 | DOI:10.1021/acs.jmedchem.5c00263

BMJ Open. 2025 Feb 5;15(2):e088604. doi: 10.1136/bmjopen-2024-088604.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease frequently complicated by gastro-oesophageal reflux disease. Although several observational studies and a pilot study have investigated the role of proton pump inhibitors (PPIs) in IPF, their efficacy is unknown and there is much debate in international IPF guidelines on their use. We aim to undertake an adequately powered double-blind placebo-controlled randomised multicentre clinical trial to assess the change in forced vital capacity (FVC), cough and other important patient-reported outcomes, following 12-month therapy with PPIs in people with IPF.

METHODS AND ANALYSIS: A total of 298 patients with IPF diagnosed by a multidisciplinary team according to international guidelines who are not receiving PPIs will be enrolled. Patients are randomised equally to receive two capsules of lansoprazole or two placebo capsules, two times per day for 12 months. The primary outcome for the trial is change in FVC, measured at home, between the first week and last week of the study period. Secondary assessments include cough frequency (in a subgroup) measured using the VitaloJAK cough monitor, the King's Brief Interstitial Lung Disease questionnaire, the Raghu Scale for Pulmonary Fibrosis, Medical Research Council dyspnoea score, EQ-5D-5L, Leicester Cough Questionnaire, modified DeMeester reflux symptoms questionnaire and opportunistically captured routine lung function measurements. High-resolution CT scoring will be undertaken in a subgroup. The trial is designed to determine whether treating people with IPF with lansoprazole will reduce the reduction in FVC over a year. The COVID-19 pandemic required the study to be undertaken as a remote trial.

ETHICS AND DISSEMINATION: This study received ethical approval from the East of England Cambridgeshire and Hertfordshire Research Ethics Committee (reference 20/EE/0043; integrated research application system number 269050). Trial results will be published in a peer-reviewed journal upon completion.

TRIAL REGISTRATION NUMBER: ISRCTN13526307; ClinicalTrials.gov NCT04965298.

PMID:39909521 | DOI:10.1136/bmjopen-2024-088604

Eur Respir Rev. 2025 Feb 5;34(175):240080. doi: 10.1183/16000617.0080-2024. Print 2025 Jan.

ABSTRACT

Interstitial lung disease (ILD) is a clinical term that refers to a diverse group of non-neoplastic lung diseases. This group includes idiopathic and secondary pulmonary entities that are often associated with progressive pulmonary fibrosis. Currently, therapeutic approaches based on specific structural targeting of pulmonary fibrosis are limited to nintedanib and pirfenidone, which can only slow down disease progression leading to a lower mortality rate. Lung transplantation is currently the only available curative treatment, but it is associated with high perioperative mortality. The pulmonary vasculature plays a central role in physiological lung function, and vascular remodelling is considered a hallmark of the initiation and progression of pulmonary fibrosis. Different patterns of pulmonary fibrosis commonly exhibit detectable pathological features such as morphomolecular changes, including intussusceptive and sprouting angiogenesis, vascular morphometry, broncho-systemic anastomoses, and aberrant angiogenesis-related gene expression patterns. Dynamic cellular interactions within the fibrovascular interface, such as endothelial activation and endothelial-mesenchymal transition, are also observed. This review aims to summarise the current clinical, radiological and pathological diagnostic algorithm for different ILDs, including usual interstitial pneumonia/idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, alveolar fibroelastosis/pleuroparenchymal fibroelastosis, hypersensitivity pneumonitis, systemic sclerosis-related ILD and coronavirus disease 2019 injury. It emphasises an interdisciplinary clinicopathological perspective. Additionally, the review covers current therapeutic strategies and knowledge about associated vascular abnormalities.

PMID:39909504 | DOI:10.1183/16000617.0080-2024

Eur J Radiol. 2025 Jan 30;184:111961. doi: 10.1016/j.ejrad.2025.111961. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the reliability, validity and applicability of ILD-RADS among readers with different levels of experience.

METHODS: This prospective tri-center study included 159 patients with clinically diagnosed ILD who underwent high-resolution CT (HRCT). Two experienced thoracic radiologists, two general radiologists, and one pulmonologist independently evaluated the HRCT images blinded to the patient's clinical data and assigned ILD-RADS category for each patient. The Fleiss kappa test was employed to estimate the inter-reader agreement among all readers. Cohen's kappa test was applied to measure the pairwise inter-reader agreement. The multi-disciplinary team discussion (MDD) was used as a reference test to estimate the validity of ILD-RADS for diagnosing idiopathic pulmonary fibrosis (IPF). A 5-point Likert short survey was accomplished by the pulmonologists about the applicability of ILD-RADS in clinical practice.

RESULTS: The current study included 124 non-IPF and 35 IPF cases. Based on the radiologists, the ILD-RADS showed moderate inter-reader agreement (K = 0.515, P < 0.001) while being fair after the inclusion of the pulmonologist's input (K = 0.333, P < 0.001). The agreement was substantial among thoracic radiologists (K = 0.716, p < 0.001) and moderate among general radiologists (K = 0.461, p < 0.001). ILD-RADS ≤ 2 was the optimal cut-off for predicting IPF, with an accuracy ranging from 62.84 % to 80.54 %. Seventy-five percent of pulmonologists rated ILD-RADS as highly applicable in practice.

CONCLUSIONS: ILD-RADS is reliable and valid among radiologists but requires further refinement to enhance consistency and applicability in diverse clinical settings. Moreover, pulmonologists support its use in clinical practice.

PMID:39908937 | DOI:10.1016/j.ejrad.2025.111961

Heliyon. 2024 Dec 30;11(2):e41311. doi: 10.1016/j.heliyon.2024.e41311. eCollection 2025 Jan 30.

ABSTRACT

Cumulative evidence suggests a link between specific autoimmune diseases (AD), including idiopathic inflammatory myopathies (IIM), and SARS-CoV-2 infection or COVID-19 vaccination. Anti-synthetase syndrome (ASS), a subset of IIM, is defined by the presence of autoantibodies against aminoacyl-tRNA synthetase (anti-ARS) and is strongly associated with interstitial lung disease (ILD), a major contributor to severe complications and reduced survival. We present four clinical cases of patients who developed autoantibodies against threonyl (PL-7) and alanyl (PL-12) synthetases associated with ASS-ILD shortly after SARS-CoV-2 infection or COVID-19 vaccination. Anti-ARS autoantibodies were identified using three complementary methods: immunoblotting, western blotting (WB) and the method considered the gold standard, immunoprecipitation (IP), which ensures accurate interpretation of results. The study highlights the clinical and pathogenic overlap between ASS-ILD and SARS-CoV-2-related lung involvement.Both conditions share similar high-resolution computed tomography (HRCT) patterns, including inflammation and pulmonary fibrosis (PF), driven by IFN-γ signaling, which complicates accurate diagnosis. Our results provide novel insights into the temporal association of SARS-CoV-2 and vaccine exposure with ASS-ILD, focusing on possible molecular mimicry between viral proteins and ARS molecules as a potential mechanism. Understanding the involvement of specific anti-ARS autoantibodies (PL-7 and PL-12) and the identification of genetic predispositions (HLA-B∗08:01 and HLA-DRB1∗03:01) in these patients may be key to underpinning these autoimmune manifestations. The study underscores the importance of a multidisciplinary approach and vigilant follow-up to optimize diagnosis and management. Further research is essential to elucidate the causal relationships and molecular mechanisms behind these observations.

PMID:39906838 | PMC:PMC11791273 | DOI:10.1016/j.heliyon.2024.e41311

Respirology. 2025 Feb 4. doi: 10.1111/resp.14892. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Fibrotic interstitial lung disease (ILD) is associated with high morbidity and mortality. Patients often exhibit impaired nutritional status and alterations in body composition, such as dynapenia and sarcopenia, which correlate with poor pulmonary function, reduced exercise tolerance and diminished quality of life. However, the impact of dynapenia and sarcopenia on prognosis has not been examined extensively in ILD patients. We assessed the impact of dynapenia and sarcopenia as risk factors for mortality and their prevalence in ILD.

METHODS: Prospective cohort study. ILD was classified into idiopathic pulmonary fibrosis (IPF), connective tissue disease-related ILD (CTD-ILD) and chronic hypersensitivity pneumonitis (CHP). Patients over 18 years old with a confirmed diagnosis of ILD were included, while those with diagnoses of cancer, human immunodeficiency virus and neurological disease were excluded. Dynapenia and sarcopenia were determined according to EWGSOP2 criteria.

RESULTS: Ninety-eight ILD patients were included; 33.66% had IPF, 47.96% had CTD-ILD, and 18.37% had CHP. The mean age was 63.89 ± 12.02 years; 37.76% were male. The risk factors associated with mortality included dynapenia (HR: 2.04, 95% CI: 1.10-3.77, p = 0.022), sarcopenia (HR: 1.88, 95% CI; 1.00-3.33, p = 0.049) and exercise tolerance (HR: 0.99, 95% CI; 0.99-0.99, p = 0.023), adjusted for confounding variables. The prevalence of dynapenia was 45% in ILD; 51% in IPF, 35% in CTD-ILD and 61% in CHP. The prevalence of sarcopenia was 29%; both IPF (39%) and CHP (50%) had a higher prevalence of sarcopenia than CTD-ILD (14%).

CONCLUSION: Sarcopenia and dynapenia are independent risk factors for mortality in ILD.

PMID:39905591 | DOI:10.1111/resp.14892

BMC Pulm Med. 2025 Feb 4;25(1):61. doi: 10.1186/s12890-025-03521-3.

ABSTRACT

BACKGROUND: Early identification of functional decline in fibrotic interstitial lung disease (F-ILD) is crucial for timely treatment and improved survival. While the 6-minute walk test (6MWT) is the standard for functional evaluation, it has practical limitations. The 1-minute sit-to-stand test (1MSTS) offers a simpler alternative; however, its correlation with the 6MWT in F-ILD patients remains unclear. This study aims to establish reference values for the 1MSTS in assessing functional capacity, evaluate its correlation with the 6MWT, and explore its utility in predicting 18-month mortality in F-ILD patients.

METHODS: This prospective study enrolled participants diagnosed with F-ILD based on multidisciplinary team discussions. Assessments included the 1MSTS, 6MWT, pulmonary function test (PFT), GAP score, mMRC scale, and Charlson Comorbidity Index (CCI). The association between 1MSTS repetitions and other variables was calculated using Spearman's rho. Bland-Altman plots assessed the agreement between 1MSTS repetitions and the 6MWT. Predictors of 18-month mortality were evaluated using ROC curve and Kaplan-Meier curve.

RESULTS: Of the 150 F-ILD patients, 37 (24.6%) had idiopathic pulmonary fibrosis (IPF), and 113 (75.4%) had connective tissue disease-related ILD (CTD-ILD). Using ≤ 23 repetitions as the cutoff for functional impairment in 1MSTS, 74 (47.3%) patients were classified as impaired. The 1MSTS significantly predicted 18-month mortality and demonstrated moderate correlations with GAP score (rs = -0.49), mMRC scale (rs = -0.47), and 6MWT distance (rs = 0.65). Bland-Altman analysis indicated agreement between 1MSTS repetitions and 6MWT distance. Using ≤ 23 repetitions as the cutoff value for the 1MSTS to predict 18-month mortality, the mortality rate was 76.4%, with an AUC of 0.81.

CONCLUSIONS: The findings suggest that ≤ 23 repetitions in the 1MSTS can serve as an indicator of functional impairment, demonstrate a good correlation with 6MWT distance, and effectively predict 18-month mortality in patients with F-ILD.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:39905346 | DOI:10.1186/s12890-025-03521-3

Radiology. 2025 Feb;314(2):e241001. doi: 10.1148/radiol.241001.

ABSTRACT

Background Prognostic value of radiologic features in interstitial lung disease (ILD) has been predominantly studied in idiopathic pulmonary fibrosis, but findings vary. The relative importance of features versus guideline-defined patterns in predicting outcomes is unknown. Purpose To identify radiologic features that are independently associated with transplant-free survival beyond clinical predictive factors across all ILD subtypes, and to identify whether individual features versus patterns are more important for prognostication. Materials and Methods This is a secondary analysis of the prospective Canadian Registry for Pulmonary Fibrosis. Consecutive patients with ILD were evaluated in standardized multidisciplinary discussions between January 2021 and March 2022. Radiologic features on thin-section CT images were quantified, and guideline-defined usual interstitial pneumonia (UIP) and fibrotic hypersensitivity pneumonitis (fHP) patterns were assigned. Multivariable Cox analysis was used to assess the associations of radiologic features with transplant-free survival, and nested models were used to test the relative importance of features compared with patterns. Results A total of 1593 patients (mean age, 66 years ± 12 [SD]; 800 male) were included. The following four features were associated with transplant-free survival: extent of honeycombing (hazard ratio, 1.20; 95% CI; 1.06, 1.36 per 10% increase in lung involvement; P = .005), extent of traction bronchiectasis (hazard ratio, 1.18; 95% CI: 1.10, 1.26 per 10% increase; P < .001), pulmonary artery diameter (hazard ratio, 1.03; 95% CI: 1.01; 1.04 per 1-mm increase; P = .002), and presence of subpleural sparing (hazard ratio, 0.76; 95% CI: 0.56, 0.96; P = .03). Guideline-defined patterns were not independently associated with survival in a model that included these four radiologic features, each of which retained its prognostic value. Conclusion The extent of fibrosis was predictive of worse outcomes across all ILD subtypes in a dose-dependent fashion and independent of well-recognized clinical prognostic factors. Guideline-defined UIP and fHP patterns each helped risk-stratify patients in isolation but lost prognostic value when accounting for the extent of fibrosis, suggesting that their previous association with mortality is based on these patterns acting as surrogates for a greater extent of fibrosis. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Wells in this issue.

PMID:39903073 | DOI:10.1148/radiol.241001