European Respiratory Journal

RationaleHypersensitivity pneumonitis (HP) is an immunologically mediated form of lung disease resulting from inhalational exposure to various antigens. While there is growing understanding of the immune cells involved in HP, the relationship between clinical outcomes and circulating cell types in HP is not well established. MethodsSingle-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 40 patients with fibrotic hypersensitivity pneumonitis (fHP) in a clinical trial of pirfenidone (NCT02958917). After quality control, we compared data from 33 fHP patients with 36 sex-matched healthy controls (GSE196735). Using Seurat v5, we harmonized the data, formed clusters, and reduced dimensionality through UMAP. Cell type identities were assigned based on a published reference (GSE271789), with clusters annotated for predominant cell type(s) present in at least 30% of the cells. We compared cell type proportions between fHP and HC using the chi-squared test and performed differential expression analysis with DESeq2 on pseudobulk counts, adjusting for sex. Genes significantly upregulated in fHP versus HC at an FDR-adjusted p-value of 0.01 were used to create a multivariate predictive signature for clinical outcomes in fHP participants. Performance was assessed through leave-one-out cross-validation for prediction accuracy. ResultsCompared to HC, fHP has an increased proportion of non-classical CD16+ monocytes (4.2% fHP vs. 1.5% HC), C14+ monocytes with a myeloid-derived dendritic phenotype (2.1% fHP vs. 0.1% HC), platelets (1.0% fHP vs. 0.3% HC), plasmacytoid dendritic cells (0.5% fHP vs. 0.1% HC) and predominantly classical CD14+ monocytes (29.5% fHP vs. 3.4% HC, adjusted-p<0.001). In patients with fHP, cell clusters were associated with the presence of baseline chest CT honeycombing, increased extent of CT lung fibrosis, and worse progression-free survival. CD14+ monocytes consistently demonstrated a high prediction accuracy (>0.90) for these clinical metrics. ConclusionsPeripheral monocyte clusters may be valuable prognostic markers, potentially helping identify at-risk fHP patients.

BackgroundPulmonary hypertension (PH) involves progressive vascular remodeling and perivascular inflammation. Despite modest clinical improvements with current therapies, their limited ability to reverse remodeling or restore immune homeostasis highlights the need for novel agents. Liriodendrin (Lidd), derived from Sargentodoxae caulis, exhibits anti-inflammatory and antiproliferative activities, but its efficacy and molecular targets in PH are unknown. MethodsTwo well-established PH animal models - the SU5416/hypoxia (SuHx) mice model and monocrotaline (MCT)-induced rat model - were employed for in vivo assessment of Lidd conducted pharmacological effects. Primary human pulmonary artery smooth muscle cells (hPASMCs) were utilized for mechanistic investigations. RNA-sequencing (RNA-seq) analysis was conducted to identify potential signaling pathways modulated by Lidd treatment. The direct molecular target of Lidd was determined through integrated application of drug affinity responsive target stability (DARTS) assay coupled with western blot validation. To delineate histone lactylation-mediated transcriptional regulation, we combined Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing data analysis followed by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) verification. Genetic validation was achieved using PFKFB3-deficient murine models to verify the specificity of Lidd-mediated pharmacological actions. ResultsLidd administration attenuated pulmonary vascular remodeling, perivascular macrophage infiltration and PH progression in both SuHx and MCT models. Transcriptomic profiling of Lidd-treated hPASMCs revealed predominant enrichment of downregulated genes in inflammatory and cytokine-associated pathways. Mechanistically, Lidd directly bound PFKFB3 and enhanced its interaction with FZR1, promoting PFKFB3 ubiquitination and degradation, which reduced glycolysis-driven lactate and consequent histone lactylation. This, in turn, diminished transcriptional activation of proliferative and inflammatory mediators, including CCND1, TNC, and CCL2. Notably, exogenous lactate supplementation or endogenous lactate accumulation restored histone lactylation and paradoxically potentiated Lidds inhibitory effects on PASMC proliferation and migration, whereas p300 inhibition abrogated these lactate-mediated effects. Importantly, Lidd failed to confer additional protection in PFKFB3-deficient mice, confirming PFKFB3 as the primary target mediating its therapeutic action. ConclusionOur findings reveal that Lidd selectively targets the PFKFB3-mediated glycolytic-epigenetic axis to suppress PASMC phenotypic transformation and pulmonary vascular remodeling, positioning it as a promising therapeutic candidate for PH.

Background Elexacaftor-tezacaftor-ivacaftor (ETI) has been demonstrated to improve lung function in clinical trials; however, evidence describing effects on trajectories and whether long-term improvements are sustained (>1-year) is lacking. We estimated within-person lung clearance index (LCI) trajectories before and after ETI initiation, assessing changes in level and rate of change, alongside acute LCI change, up to three years after ETI initiation. Methods Prospective observational study of children at a tertiary hospital. Children aged 3-17 years with [&ge;]2 LCI testing occasions (i) before and (ii) after starting ETI were used to describe lung function trajectories. Children with [&ge;]1 pre-ETI and [&ge;]1 post-ETI LCI occasion(s) were used to describe acute LCI change after ETI initiation. Age-adjusted LCI trajectories for time periods (i) before and (ii) after ETI initiation were estimated using linear mixed-effects models, and pre- and post-ETI LCIs were compared using paired Wilcoxon tests. Results Mean pre-ETI and post-ETI longitudinal changes in LCI were -0.007 (95% CI: -0.28, 0.27; n=35) and 0.12 (95% CI: -0.17, 0.41; n=20) turnovers per year, respectively. Before ETI initiation, 57% (30/53) of patients had an LCI[&ge;]7.1 turnovers (indicating impaired lung function), compared to 26% (14/53) post-ETI, with a median LCI difference of -0.70 (95% CI -0.84, -0.46; p<0.001) turnovers. Within-individual variability in LCI decreased post-ETI. Conclusions Our real-world data within a unique longitudinal study provide a comprehensive picture of ETI benefit by outlining not only acute improvement in LCI but maintained stability in LCI trajectories and improved LCI stability sustained up to three years post-initiation.

BackgroundTBX4 variants are a recognised cause of paediatric pulmonary hypertension (PH), often associated with interstitial lung disease (ILD). Evidence for ILD-directed therapy in this group is lacking. MethodsWe conducted a retrospective study of children ([&le;]18 years) with TBX4-associated PH at a national centre (2001-2025). ILD was defined using ChILD-EU criteria. Patients treated with pulsed intravenous methylprednisolone were assessed for response using ChILD-EU categories. Secondary outcomes included respiratory severity score (RSS), functional class (FC), echocardiographic measures, and NT-proBNP. ResultsOf 21 children, 11 (52%) had ILD; 9 received corticosteroids. Median age at treatment was 0.8 years. A clear or best response occurred in 7/9 (78%). RSS improved in 6/9 (p=0.02), with all children on respiratory support showing partial or complete weaning. Functional class improved in all with FC III/IV at baseline (p=0.02). Right ventricular function improved (TAPSE z-score +1.65, p=0.04), and elevated NT-proBNP normalised. Key clinical milestones included ECMO weaning, transplant delisting, and discontinuation of prostacyclin therapy. No significant adverse effects were observed. Untreated children showed no early improvement. ConclusionsCorticosteroids were associated with meaningful improvements in respiratory and PH outcomes in TBX4-associated PH with ILD. Prospective evaluation is warranted.

ObjectiveCirculating fibrocytes are elevated in idiopathic pulmonary fibrosis, but the relationship between fibrocyte level with lung function decline and outcomes is lacking replication in prospective clinical study. We aim to validate the utility of circulating fibrocyte levels as a prognostic biomarker in idiopathic pulmonary fibrosis. MethodsWe tested associations between circulating fibrocyte levels, mortality, disease progression and longitudinal lung function in a well-defined prospective observational study of pulmonary fibrosis (PROFILE; NCT01134822). A subset of recruited participants had blood samples processed for fibrocyte measurement, with flow cytometry based on CD45 and collagen-I gating. Associations were tested using univariable and multivariable generalised linear models. Mortality data were subsequently combined with an independent cohort in a mixed-effect multilevel analysis. ResultsIn 102 participants with idiopathic pulmonary fibrosis, an empirically defined cutpoint of 2.22% was associated with a greater risk of overall mortality in adjusted analysis (Hazard Ratio 2.24 95% CI 1.06-4.72). A 2.5 fold greater risk of mortality was supported in a pooled analysis with a historic cohort for a larger sample of 162 participants of idiopathic pulmonary fibrosis, specifically (Hazard Ratio 2.49 95% CI 2.41-2.56). A previously defined mortality risk threshold of 5% circulating fibrocytes was not reproducible in this cohort, circulating fibrocytes were not significantly elevated above non-specific interstitial pneumonia or healthy controls.. We found no association of fibrocytes with lung function or disease progression. ConclusionsIn a prospective clinical cohort of idiopathic pulmonary fibrosis, circulating fibrocytes of 2.22% or above are associated with greater mortality, but do not associate with disease related decline in lung function. What is the key question?Can circulating fibrocytes provide reproducible prognostic biomarker value in fibrotic lung disease? What is the bottom line?Greater proportions of fibrocytes isolated from circulating leukocyte populations are associated with an increase risk of mortality in idiopathic pulmonary fibrosis, but no association was observed with disease related decline in lung function. Why read on?We present associations and limitations of circulating fibrocytes in the largest sample of individuals with pulmonary fibrosis, recruited into a prospective observational study, and replicate prognositic insights from a historic cohort.

BackgroundPulmonary fibrosis is of critical importance in childhood interstitial lung disease (chILD), yet fibrosis prevalence, impact on the clinical progression, and survival have not been systematically evaluated. MethodsData were extracted from the chILD-EU register, a European prospective multicenter cohort study with centralized peer-review on patient inclusion and systematic scoring of computed tomography (CT) scans and lung biopsies. Pulmonary fibrosis was determined based on predefined criteria (fibrosis register) or criteria used in clinical trials (fibrosis trial). We calculated fibrosis rates of chILD entities, evaluated fibrosis criteria and assessed longitudinal pulmonary function testing and survival rates of children with or without fibrosis. Results1,071 children diagnosed with chILD were included in the final analysis. The childhood prevalence of fibrosis was for 20.5% (220/1071) according to a single time point, register definition and 11.6% (62/534) according to the dual time point, trial definition. At the age when the children were able to perform pulmonary function tests, those with fibrosis had 15-20% worse predicted forced vital capacity (ppFVC), were older and diagnosed later. Throughout childhood, the disease trajectories assessed as decline in ppFVC and survival did not differ between children with or without pulmonary fibrosis or between the two fibrosis definitions. Overall, survival until the age of 20 years was about 70%. ConclusionsThis study assesses the prevalence, pulmonary function progression and survival of pulmonary fibrosis in chILD. The application of standardized criteria for pulmonary fibrosis enables identification of affected children among patients and may support early selection for anti-fibrotic therapies.

BackgroundInterstitial lung disease (ILD) is a known complication of rheumatoid arthritis (RA) with a lifetime risk in any individual of 7.7%. The TRAIL1 trial was a randomized, double-blinded, placebo-controlled, phase 2 study of safety, tolerability, and efficacy of pirfenidone for the treatment of patients with RA-ILD. MethodsThe TRAIL1 was a phase 2 trial intended to enroll 270 adult patients (18 to 85 years) with established RA-ILD at 33 sites in 4 countries. Patients were randomly assigned (1:1) to 2,403 mg oral pirfenidone or placebo daily. The primary endpoint was the incidence of the composite endpoint of decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or greater or death during the 52-week treatment period. Key secondary endpoints included change in absolute and FVC% over 52 weeks. FindingsThe trial was stopped early due to slow recruitment and soon after the shutdown of clinical trials as a consequence of the coronavirus disease 2019 (COVID-19) pandemic. Data from 123 patients enrolled were analyzed. The primary endpoint was met by 11.1% on pirfenidone vs. 15% on placebo [OR=0.67 (0.22, 2.03), p=0.48]. Subjects receiving pirfenidone had a slower rate of decline in lung function as measured by estimated annual change in FVC(ml) (-66 vs. -146, p=0.0082) and FVC(%) (-1.02 vs. -3.21, p=0.0028). This effect on decline was also seen when analyzed within participants with baseline usual interstitial pneumonia (UIP) pattern on HRCT (FVC(ml) (-43 vs. -169, p=0.0014) and FVC% (-0.2 vs. -3.81, p=0.0002)). There was no significant difference in the rate of treatment-emergent serious adverse events. InterpretationDue to early termination of the study, results should be interpreted with caution. Despite being underpowered to evaluate the primary endpoint, pirfenidone slowed the rate of decline of FVC over time in subjects with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials. FundingFunding for this investigator initiated trial was provided by Genentech, Inc. to Ivan O. Rosas, MD, on behalf of the TRAIL1 Investigators.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a disease with very poor prognosis and no curative therapies. The G protein-coupled, calcium/cation-sensing receptor (CaSR) is activated by environmental pollutants and by arginine-derived polyamines, which are thought to play a role in IPF. Whether the CaSR is involved in the pathogenesis of pulmonary fibrosis is unknown. ObjectiveTo investigate the CaSR as a novel drug target for the treatment of pulmonary fibrosis (PF). Methods and resultsCaSR protein expression is found in the airway epithelium in the neuroepithelial bodies of the healthy and IPF human lung. Expression of arginine pathway-linked polyamines is increased in PF patient saliva samples compared to non-PF patients. Arginine pathway metabolites, ornithine and spermine, activate the CaSR in primary normal human lung fibroblasts (NHLF), effects prevented by CaSR antagonism using the calcilytic NPS2143. In NHLF calcilytic also reversed the pro-fibrotic effects of exogenous TGF{beta}1 administration on Rho kinase and SMA expression, proliferation, collagen production and IL-8 secretion. Targeted CaSR ablation from fibroblasts and smooth muscle cells protects mice from spontaneously occurring, age-related lung fibrosis. ConclusionsSustained CaSR activation in the lung drives pro-fibrotic processes, which can be reversed by calcilytic. Pharmacological and genetic CaSR blockade reduce both TGF{beta}1-induced and naturally occurring pro-fibrotic changes. This work provides the scientific rationale for developing inhaled calcilytics as novel therapeutics for IPF. KEY MESSAGESO_ST_ABSKey questionC_ST_ABSHow does the calcium/cation-sensing receptor (CaSR) promote pulmonary fibrosis? Bottom lineThe CaSR is expressed in human IPF and experimental models of PF where receptor inhibition prevents pro-fibrotic changes and pulmonary remodeling. Why read onCaSR blockers, calcilytics, represent a novel treatment for IPF.

Background Idiopathic Pulmonary Fibrosis (IPF) is a fatal chronic lung disease with limited therapeutic options. While alveolar epithelial injury and fibroblast activation are well-studied, endothelial-mesenchymal transition (EndoMT) is emerging as a critical pathogenic mechanism. The regulatory role of exosomal miRNAs in pulmonary fibrosis remains unclear. This study investigates serum exosomal miRNAs, particularly let-7a-5p, in modulating EndoMT during the onset of pulmonary fibrosis. Methods Clinical cohorts of IPF patients and healthy controls were enrolled. Serum exosomal miRNAs were profiled, followed by differential expression and functional enrichment analyses. In vitro experiments involved human pulmonary artery endothelial cells (HPAECs) transfected with let-7a-5p mimic or inhibitor. Dual-luciferase reporter assays confirmed the binding between let-7a-5p and TGFBR1. HPAECs were co-cultured with lung epithelial cells to examine paracrine signaling. In vivo studies used a bleomycin-induced mouse model with let-7a-5p agomir administration. Assessments included histopathological staining, hydroxyproline content, Western blot, qPCR, micro-CT, and pulmonary function tests. Results Let-7a-5p was significantly downregulated in serum exosomes from IPF patients, correlating with clinical indicators. Mechanistically, let-7a-5p directly bound the TGFBR1 3'UTR to inhibit its expression. Inhibition of let-7a-5p upregulated -SMA, FN1, smad2/3 phosphorylation, and collagen I, while downregulating CD31 and VE-cadherin. Therapeutically, let-7a-5p mimic reversed bleomycin-induced EndoMT and suppressed epithelial-mesenchymal transition (EMT) via paracrine signaling. Mice administered agomir showed reduced fibrosis, improved lung function, and suppressed TGF-{beta}/Smad signaling. Conclusion Serum exosomal let-7a-5p suppresses pulmonary fibrosis by targeting TGFBR1 to inhibit EndoMT. Its downregulation in IPF patients correlates with disease progression, highlighting its biomarker potential.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease with a median survival of 3-5 years after diagnosis. Current antifibrotic therapies slow disease progression, but do not halt or reverse fibrosis, underscoring the need for new therapies. We identified a dysregulated oxysterol-GPR183 axis as a driver of IPF. Oxidized cholesterols were elevated in lungs from IPF patients, with myofibroblasts representing the dominant source of 7,25-hydroxycholesterol (7,25-OHC), the endogenous high affinity ligand for the oxysterol-sensing receptor GPR183. IPF patients had increased GPR183 expression in interstitial and monocyte-like macrophages compared to controls. In a bleomycin-induced model of pulmonary fibrosis genetic deletion of GPR183 reduced disease severity characterized by reduced fibrosis, inflammation, and accumulation of macrophages and myofibroblasts. Pharmacological inhibition of GPR183 with the antagonist NIBR189 attenuated fibrosis when administered preventatively from day 1-7 after bleomycin exposure. Notably, therapeutic treatment with the GPR183 antagonist after commencement of fibrosis development at day 10 post-bleomycin also significantly reduced fibrotic pathology, achieving efficacy comparable to the approved antifibrotic nintedanib. However, the GPR183 antagonist was more potent in reducing inflammation and myofibroblast activation compared to nintedanib. Together, these findings identify an oxysterol-GPR183 signaling axis that contributes to pulmonary fibrogenesis and provide a strong preclinical rationale for targeting GPR183 as a novel therapeutic strategy for IPF. One Sentence SummaryTargeting GPR183 reduced lung fibrosis and inflammation in a preclinical model, supporting GPR183 as a promising new therapy.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited treatment options. LTI-03 promotes alveolar epithelial cell survival and reduces profibrotic protein expression in experimental models of IPF. In this Phase 1b, placebo-controlled, dose-escalation study, 24 participants with IPF were randomized 3:1 into 2 sequential dose cohorts to LTI-03 (5 or 10 mg/day) or placebo for 14 days (ClinicalTrials.gov: NCT05954988). The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Exploratory analyses included pharmacokinetics and changes from baseline in expression of biomarkers related to fibrotic processes and epithelial integrity. Inhaled LTI-03 was well-tolerated, with no treatment-related discontinuations and only mild or moderate TEAEs; cough was the most common treatment-related TEAE. There was no evidence of airway obstruction by symptoms or spirometry. In bronchoscopy-derived deep bronchial brushing samples, both doses of LTI-03 significantly reduced interleukin-11 and thymic stromal lymphopoietin compared to placebo. Additionally, LTI-03 10 mg/day significantly reduced the expression of collagen type 1 alpha chain 1, CXC chemokine ligand 7 and galectin-7 compared to placebo. A trend in the reduction of plasma surfactant protein D was also observed in the LTI-03 10 mg/day group compared to placebo. The favorable safety and tolerability profile in addition to a reduction of disease-related biomarkers supports further evaluation of inhaled LTI-03 for IPF in a Phase 2 study (RENEW; ClinicalTrials.gov: NCT06968845).

IntroductionInterstitial lung abnormalities (ILAs) are subtle or mild parenchymal abnormalities observed in more than 5 % of the lungs on CT scans in patients in whom interstitial lung disease was not previously clinically suspected and is considered. ILA is considered to be partly undeveloped stages of idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). This study aims to clarify the frequency of subsequent IPF or PPF diagnosis, the natural course from the preclinical status of the diseases, and the course after commencing treatment. Methods and analysisThis is an ongoing, prospective, multicentre observational cohort study of patients with ILA referred from general health screening facilities with more than 70000 annual attendances. Up to 500 participants will be enrolled annually over 3 years, with 5-year assessments every six months. Treatment intervention including anti-fibrotic agents will be introduced in disease progression cases. The primary outcome is the frequency of subsequent IPF or PPF diagnoses. Additionally, secondary and further endpoints are associated with the efficacy of early therapeutic interventions in cases involving disease progression. Ethics and disseminationThis study protocol and informed consent documents have been approved by the Institutional Review Boards of Kumamoto University Hospital (approval number: 2368), Saiseikai Kumamoto Hospital (approval number: 809), and each participating institution. Additionally, written informed consent will be obtained from all participants. Patient recruitment commenced on 20 June 2022. The results will be disseminated through peer-reviewed publications and international conferences. Trial registration numberUMIN000045149 Strengths and limitations of this studyThis is the first prospective, multicentre, observational study to clarify the following points: O_LIthe aetiological data of patients with ILA from a large general health check-up population C_LIO_LIthe natural course of IPF or PPF from the asymptomatic stage C_LIO_LIthe effects and outcomes of early therapeutic intervention including anti-fibrotic agents for progressive cases of ILA. C_LI The limitations of the study: O_LIparticipants missing the regular 6-monthly visits after consenting to participate in the study because of their asymptomatic or the pandemic viral infection. C_LI

Rationale: Fibrosing interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF), have heterogeneous postdiagnosis courses. Existing prognostic tools often rely on pulmonary function testing, imaging, or laboratory data that may not be uniformly available and rarely provide individualized, time-updated forecasts of multiple clinically relevant trajectory events. Objectives: To determine whether longitudinal healthcare claims can generate test-free, time-updated forecasts of clinically actionable postdiagnosis trajectory events in patients with fibrosing ILD and IPF. Methods: Using de-identified longitudinal administrative claims from the Merative MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases, we constructed code-based digital twins (ZeBRA) encoding each patient's evolving diagnosis, pharmacy, and procedure history. Horizon-specific models forecast seven claims-observable events: supplemental oxygen escalation, pulmonary hypertension, acute respiratory failure/ARDS composite, nausea, diarrhea, liver injury, and gastrointestinal bleeding. The analytic cohort included 345,918 patients with fibrosing ILD, including 17,284 with IPF. Predictions were evaluated in a time-updated follow-up setting at 1-month, 6-month, and 1-year horizons. Results: Predictive discrimination was consistent across events and horizons. In fibrosing ILD, AUC ranged from 0.691 for liver injury at 1 year to 0.912 for oxygen dependence at 1 month, with PPV ranging from 0.189 to 0.714. At 1 month, oxygen dependence achieved an AUC of 0.912 +/- 0.005 with PPV of 0.473 +/- 0.005, and pulmonary hypertension achieved an AUC of 0.881 +/- 0.005 with PPV of 0.539 +/- 0.005. The IPF subcohort showed analogous horizon-dependent performance, with AUC ranging from 0.687 to 0.855 and PPV from 0.245 to 0.817. At 1 month in IPF, PPV was 0.753 +/- 0.015 for oxygen dependence and 0.817 +/- 0.011 for pulmonary hypertension. Conclusions: A test-free digital-twin framework derived from routine longitudinal claims can provide individualized, time-updated forecasts of actionable fibrosing ILD and IPF trajectory events without imaging, pulmonary function tests, laboratory data, clinical notes, or patient-facing data collection. These forecasts may support low-burden reassessment, anticipatory care planning, and earlier recognition of elevated near-term risk for respiratory deterioration or management-altering complications.

BackgroundNintedanib and pirfenidone are antifibrotic agents approved for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive fibrosing interstitial lung diseases. Despite their clinical significance, national trends in Medicare Part D spending and utilization for these therapies remain insufficiently characterized. ObjectiveTo evaluate national trends in Medicare Part D spending, claims, and cost-per-claim for nintedanib and pirfenidone from 2019 to 2023. MethodsMedicare Part D Drug Spending Dashboard data were analyzed for total spending, number of claims, and average spending per claim for nintedanib and pirfenidone. Trends over five years were assessed. ResultsTotal spending on nintedanib increased from 2019 to 2023, with a consistent rise in both claims and average cost per claim. In contrast, pirfenidones total spending declined sharply, primarily due to a reduction in claims. The average cost per claim for both drugs increased over the study period. ConclusionMedicare spending on antifibrotic therapies is increasingly dominated by nintedanib, reflecting evolving prescribing patterns and potential differences in tolerability or access. These findings have implications for cost-containment strategies and formulary management. Author SummaryIdiopathic pulmonary fibrosis (IPF) is a progressive lung disease treated with two antifibrotic medications: nintedanib and pirfenidone. These therapies are costly, and little is known about how Medicare has been spending on them in recent years. Using publicly available Medicare data from 2019 to 2023, we found that spending on nintedanib has increased significantly, while spending on pirfenidone has dropped. The average cost per prescription rose for both drugs. These findings may reflect changes in prescribing habits, patient access, and insurance coverage, and highlight the need to monitor drug costs and usage to ensure affordable treatment for patients.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive extracellular matrix deposition and irreversible architectural distortion of the lung. Fibrotic remodeling is driven by dynamic interactions among endothelial, fibroblast, epithelial and immune cells. Although pulmonary endothelial cells (ECs) are increasingly recognized as important contributors to IPF pathogenesis, the molecular and cellular events underlying endothelial dysfunction remains poorly understood. Using integrative multi-omics analyses of human IPF lungs combined with functional in vitro assays, we identify ACKR1-expressing venous endothelial cells (ACKR1+ VECs) as critical regulators of a pathogenic niche that promotes lung fibrosis. Single-cell RNA sequencing and spatial transcriptomics analyses reveal that ACKR1+ VECs exhibit a distinct pro-fibrotic and pro-inflammatory transcriptional program enriched for hypoxia responses, extracellular matrix remodeling, and immune cell recruitment. In both mouse and human fibrotic lungs, ACKR1+ VECs localize adjacent to fibroblastic foci and are surrounded by pro-fibrotic CD68+/CCR5+/SPP1+ macrophages-monocytes, suggesting a spatial organized cellular crosstalk supporting fibrotic remodeling. Consistent with these findings, in vitro co-culture assays using ACKR1+ VECs isolated from IPF lungs demonstrate that these cells drive myeloid recruitment and fibroblast activation through ACKR1 dependent mechanisms. Silencing of ACKR1 in IPF-derived VECs suppressed inflammatory and fibrotic transcriptional programs, and pharmacological inhibition of ACKR1 attenuated stromal and immune remodeling and reduced bleomycin-induced lung fibrosis in vivo. Together, these findings identify ACKR1+ VECs as key orchestrators of fibrosis progression and establish ACKR1 and the pathogenic vasculature as promising therapeutic targets for IPF. Clinical RelevanceIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. We identify ACKR1-expressing venous endothelial cells as key drivers of inflammatory and fibrotic remodeling and show that pharmacologic inhibition of ACKR1 attenuates experimental lung fibrosis. These findings establish endothelial ACKR1 as a promising therapeutic target and highlight the pulmonary vasculature as a novel avenue for disease-modifying therapies in IPF.

RationaleData on the prognostic value of peripheral blood mononuclear cell (PBMC) expression profiles, when used in fibrotic hypersensitivity pneumonitis (fHP) patients as an adjunct to traditional clinical assessment in predicting disease progression, remains limited. ObjectivesTo determine whether a baseline and time-course transcriptomic signature in PBMC from patients with fHP can enhance progression-free survival (PFS) prediction and complement clinical risk stratification. MethodsThe prospective multicenter study cohort included 133 participants with fHP. Lasso regression was employed to create a baseline and time-course (baseline to 12-month change) gene signature. We developed multivariable models incorporating clinical variables (age, sex, smoking status, exposure history, FVC% and quantitative measurements of lung fibrosis--derived from data-driven textural analysis, DTA) both with and without the baseline and time-course gene expression, and evaluated these models using receiver operating characteristic curves. Kaplan-Meier curves displaying high and low gene expression risk scores are presented. ResultsThe addition of a baseline gene expression profile to the logistic regression model of 24-month PFS using baseline clinical parameters markedly improved the predictive accuracy, increasing the area under the curve (AUC) from 0.77 to 0.93. Similarly, a logistic regression model of 12-month PFS using age, sex, smoking status, exposure history, and changes in FVC% and DTA over 12 months had an AUC of 0.81, which improved to 0.95 with the inclusion of changes in gene expression over the same period. A difference in PFS was noted when the cohort was divided based on whether their gene principal component analysis (PCA) scores were above or below the median. At baseline, patients with higher gene PCA scores had lower median survival than those with lower scores (267 days vs. not available; P = 0.008). Similarly, when assessing the change in gene expression from baseline to 12 months, patients with higher gene PCA scores had lower median survival than those with lower scores (203 days vs. 449 days; P = <0.001). ConclusionsIn fHP, a risk-indicative gene expression signature in peripheral blood at baseline, along with its changes over 12 months, predicts disease progression at 24 months and during the subsequent 12 months, respectively. Prognostic models based on gene expression and clinical factors strongly outperform models based solely on clinical factors.

ObjectiveIdiopathic pulmonary fibrosis (IPF) is a disease of high morbidity and mortality. We previously identified a novel subset of pathologic fibroblasts, characterized by CTHRC1 expression, uniquely present in fibrotic lung diseases. The aim of this study was to determine the association of serum CTHRC1 with clinical outcomes in IPF to assess its potential as a biologically relevant biomarker. MethodsA retrospective longitudinal cohort study was performed utilizing two cohorts including a discovery cohort of 352 IPF patients from University of California San Francisco (UCSF) and a validation cohort of 1,152 IPF patients from the Pulmonary Fibrosis Foundation (PFF) as well as 41 healthy controls. Serum CTHRC1 was measured by ELISA and patients were stratified by quartiles of CTHRC1 for analysis. For a subset of patients, serial serum and lung CTHRC1 expression were measured. Associations between CTHRC1 and clinical outcomes, including baseline lung function, lung function trajectory, and transplant-free survival were assessed. ResultsSerum CTHRC1 was elevated in IPF patients compared to healthy controls (UCSF 31661+11651 and PFF 33916+14547 vs. 24409+8630pg/ml, p<0.001). Elevated circulating CTRHC1 was associated with lower FVC% and DLCO% at baseline and a greater decline in FVC over one year. In both cohorts, higher CTHRC1 level was associated with worse transplant-free survival (p<0.03). ConclusionCirculating CTHRC1 levels are elevated in patients with IPF and associated with disease severity and overall survival. These findings further support the biological significance of CTHRC1 in IPF as a pathologic marker and potential biomarker reflecting the burden of pathologic fibroblasts in IPF. Key MessagesWhat is already known on this topic: IPF is a progressive fibrotic lung disease driven in part by activation and expansion of pathologic fibroblasts. CTHRC1+ fibroblasts have been identified in fibrotic lung tissue of IPF and are implicated in fibrogenesis. While CTHRC1+ expression in lung tissue has been established, its role as a potential circulating biomarker has yet to be studied. What this study adds: This study demonstrates serum CTHRC1 levels are significantly elevated in patients with IPF compared to healthy controls. Elevated serum CTHRC1 levels are associated with decreased baseline lung function, greater disease progression, and reduced 5-year transplant-free survival. How this study might affect research, practice or policy: These findings support CTHRC1 as a biologically relevant biomarker for prognostication in IPF.

BackgroundA significant proportion of patients experience prolonged pulmonary, cardiocirculatory or neuropsychiatric symptoms after Coronavirus disease 2019 (COVID-19), termed post-acute sequelae of COVID (PASC). Lung manifestations of PASC include cough, dyspnea on exertion and persistent radiologic abnormalities and have been linked to viral persistence, ongoing inflammation and immune dysregulation. So far, there is limited data on lung histopathology and tissue-based immune cell subtyping in PASC. Methods51 unvaccinated patients (median age, 40 years; 43% female) with a median of 17 weeks (range, 2-55 weeks) after mild SARS-CoV-2 infection (without hospitalization) underwent full clinical evaluation including high-resolution computed tomography (HR-CT) and transbronchial biopsy. We used RT-PCR/FISH and immunohistochemistry (nucleocapsid/spike/CD3/CD4/CD8) for residual SARS-CoV-2 detection and T lymphocyte subtyping, respectively. We assessed interstitial fibrosis and macrophage profiles by transmission electron microscopy (TEM) and immunofluorescence multiplex staining, while cytokine profiling in bronchoalveolar lavage (BAL) fluid was performed by legendplex immunoassay. ResultsDyspnea on exertion was the leading symptom of pulmonary PASC in our cohort. In 16% and 42.9% of patients, FEV1 and MEF50 were [&le;] 80% and 35.3% showed low attenuation volume (LAV) in >5% of lung area, in line with airflow obstruction. There was a significant correlation between oxygen pulse and time since COVID (p=0.009). Histopathologically, PASC manifested as organizing pneumonia (OP), fibrinous alveolitis and increased CD4+ T cell infiltrate predominantly around airways (bronchiolitis), while the residual virus components were detectable in only a single PASC patient (2%). T cell infiltrates around small airways were inversely correlated with time since COVID, however, this trend failed to reach statistical significance. We identified discrete interstitial fibrosis and a pro-fibrotic macrophage subtype (CD68/CD163/S100A9) as well as significantly elevated interleukin 1{beta} in BAL fluid from PASC patients (p=0.01), but H-scores for fibrotic macrophage population did not correlate with severity of clinical symptoms or T cell infiltration. InterpretationWe show decreased FEV1/MEF50 and increased LAV in line with obstructive lung disease due to CD4+ T cell-predominant bronchiolitis as well as evidence of pro-fibrotic signaling in a subset of unvaccinated PASC patients. Since our results point towards self-limiting inflammation of small airways without detectable viral reservoirs, it remains unclear whether pulmonary symptoms in PASC are SARS-CoV-2-specific or represent a general response to viral infection. Still, evidence of pro-fibrotic signaling should warrant clincal follow-up and further research into possible long-time fibrotic remodeling in PASC patients. Key pointsO_LIDyspnea on exertion is the leading clinical manifestation of PASC in the lung C_LIO_LIa minority of pts have significantly impaired lung function (FVC/TLC[&le;]80% or DLCO[&le;]70%) in spiroergometry and/or radiologic abnormalities, oxygen pulse seems to normalize over time O_LI16% and 42.9% of pts have FEV1 and MEF50[&le;]80% and 35.3% have LAV>5% of lung area, in line with airflow obstruction due to bronchiolitis C_LI C_LIO_LIResidual virus was not detectable in the lung tissue of all but one PASC patient (2%) C_LIO_LIHistologically, PASC may manifest as T cell-mediated bronchiolitis, OP and fibrinous alveolitis C_LIO_LIThere is evidence of fibrotic remodeling (ultrastructural interstitial fibrosis, pro-fibrotic macrophage subpopulation, pro-fibrotic cytokine IL-1{beta} in BAL) but this did not correlate with the degree of T cell infiltrate/bronchiolitis C_LI

Pulmonary fibrosis is an increasing and major cause of death worldwide. Understanding the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis may lead to urgently needed diagnostic and prognostic strategies for the disease. SOX9 is a core transcription factor that has been associated with fibrotic disease, however its role and regulation in acute lung injury and/or fibrosis have not been fully defined. In this study we apply a hypothesis based approach to uncover unique SOX9-protein signatures associated with both acute lung injury and fibrotic progression. Using in vivo models of lung injury in the presence or absence of SOX9, our study shows SOX9 is essential to the damage associated response of alveolar epithelial cells from an early time-point in lung injury. In parallel, as disease progresses, SOX9 is responsible for regulating tissue damaging ECM production from pro-fibrotic fibroblasts. In determining the in vivo role of SOX9 we identified secreted ECM components downstream of SOX9 as markers of acute lung injury and fibrosis. To underscore the translational potential of our SOX9-regulated markers, we analysed serum samples from acute COVID19, post COVID19 and idiopathic pulmonary fibrosis (IPF) patient cohorts. Our hypothesis driven SOX9-panels showed significant capability in all cohorts at identifying patients who had poor disease outcomes. This study shows that SOX9 is functionally critical to disease in acute lung injury and pulmonary fibrosis and its regulated pathways have diagnostic, prognostic and therapeutic potential in both COVID19 and IPF disease.

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive, incurable scarring disease of the lung. A common genetic variant near AKAP13, a multifunctional scaffold protein that integrates intracellular signalling through its interactions with RhoA and protein kinase A (PKA), has been associated with IPF susceptibility and elevated AKAP13 mRNA expression in lung tissue from patients. However, its contribution to the pathogenesis of IPF remains unclear. ObjectiveThis study investigates how an AKAP13 variant alters epithelial signalling and evaluates the therapeutic potential of targeting AKAP13. Findingsrs62025270-bearing iHBECs exhibited selective upregulation of AKAP13 isoforms, accompanied by increased cell adhesion and reduced proliferation. Transcriptomic profiling revealed upregulated fibrosis-related genes in rs62025270-bearing iHBECs, including SAA1, FGF2, MMP1, CTSB, COL4A1, and CDKN1A. rs62025270-bearing iHBECs also displayed increased RhoA activation and SMAD2 phosphorylation following LPA stimulation. Furthermore, cells harbouring the AKAP13 variant showed reduced intracellular cAMP levels. Pharmacological inhibition of AKAP13 with A13 reversed the pro-adhesive phenotype and reduced RhoA activation in iHBECs. Moreover, in IPF-derived PCLS, A13 suppressed SERPINE1, CCN2, and MMP7 expression, reduced SMAD2 nuclear translocation, and decreased hydroxyproline levels. ConclusionsPresence of an AKAP13 variant disrupts epithelial homeostasis and promotes pro-fibrotic signalling. Inhibition of AKAP13s RhoGEF domain with A13 restores epithelial function and attenuates fibrotic activation, supporting AKAP13 as a therapeutic target in IPF.