Background:We investigated the prognostic potential of circulating biomarkers at baseline and the effects of nintedanib on changes in these biomarkers in subjects with progressive pulmonary fibrosis (PPF). Methods:In the INBUILD trial, subjects with PPF received nintedanib (n=332) or placebo (n=331). Associations between biomarker levels at baseline and the rate of forced vital capacity (FVC) decline (mL·year-1) over 52 weeks, time to interstitial lung disease (ILD) progression (absolute decline in FVC % predicted ≥10%) or death over 52 weeks, time to first acute exacerbation or death over the whole trial, and time to death over the whole trial were assessed in the placebo group. Changes in adjusted mean levels of biomarkers in the nintedanib and placebo groups were assessed using linear mixed models for repeated measures. Biomarker data were log2 transformed prior to analysis. Analyses were corrected for multiplicity. Results:Baseline level of s-ICAM was significantly associated with rate of FVC decline and time to ILD progression or death over 52 weeks in the placebo group. No biomarker was significantly associated with time to first acute exacerbation or death or time to death. Decreases in Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), CA-125 and CA19-9 were observed in subjects who received nintedanib versus placebo over 52 weeks. The largest decrease was in CA-125. In a mediation analysis, 16.4% of the effect of nintedanib on change in FVC at week 52 was attributed to the treatment-related decrease in CA-125 at week 12. Conclusions:In subjects with PPF, nintedanib reduced circulating CA-125 and, to a lesser extent, other markers of epithelial dysfunction.

BACKGROUND:Pulmonary alveolar proteinosis (PAP) is a rare disease. Only a small number of case reports describing lung transplantation (LTx) as a treatment option for PAP have been published. Due to this limited evidence, current guidelines on LTx for PAP remain vague. To address this gap, we collected cases of LTx for PAP worldwide. METHODS:214 centres were approached to contribute any cases of LTx performed for PAP. Re-transplantations and multi-organ transplantations were excluded. Patients were divided into two groups based on the presence of PAP recurrence after LTx. Time-to-event analyses were performed using Kaplan-Meier curves and Cox proportional-hazards modelling was performed with PAP recurrence as a time-dependent covariate. RESULTS:At a response rate of 64%, 31 centres contributed 63 patients. Most had primary PAP (n=20; 39.2%). Six patients with secondary PAP were identified (11.8%), while seven (13.7%) had congenital and 18 (35.3%) unclassified PAP. Aetiology was not specified in 12. Patients underwent transplantation at a median (interquartile range) 11 (3-17) years after initial diagnosis. Nine (15%) patients developed PAP recurrence after LTx. No significant difference was found regarding patient characteristics between the patients with versus without recurrence. Freedom from recurrence was 96.2% (1 year), 83.5% (5 years) and 70.1% (10 years) post-LTx. PAP recurrence as time-dependent covariate was not significantly associated with graft loss (hazard ratio 1.88, 95% CI 0.51-6.91; p=0.342) in a Cox proportional-hazards model. CONCLUSION:LTx provides excellent peri-operative and long-term outcomes for patients with end-stage PAP and should be recommended in treatment guidelines. Although recurrence of PAP occurs in ∼15% of cases, overall survival appeared unaffected in our limited dataset.

Abstract:Bronchoalveolar lavage (BAL) is a minimally invasive procedure frequently used in the evaluation of pulmonary diseases. The primary indications for its use include the diagnosis of inflammation, infection, and interstitial lung diseases. Additionally, BAL plays a role in tumor diagnostics, detection of rejection following lung transplantation, and the diagnosis of occupational lung diseases (e.g., berylliosis, asbestosis).Although BAL alone mostly does not enable a definitive diagnosis, analysis of the BAL fluid provides important findings that are essential when interpreted in the clinical context. Successful analysis and interpretation require careful sample collection and rapid processing. Sample preparation is technically straightforward, and routine staining (Giemsa) is uncomplicated. BAL is widely available, cost-effective, and an indispensable tool in the diagnostic workup of pulmonary diseases.

INTRODUCTION:Sex-related differences in interstitial lung disease (ILD) phenotypes are well recognized, but it remains unclear whether sex itself independently influences outcomes in non-idiopathic pulmonary fibrosis (non-IPF) ILD once comorbidities, lung function, and treatment are considered. METHODS:In the prospective INSIGHTS-ILD registry (data cut 17 September 2025), we compared men and women with non-IPF ILD using descriptive analyses and Cox models with prespecified adjustment steps: model A (age, comorbidity count, and smoking), model B (A + forced vital capacity [FVC] and diffusing capacity of the lung for carbon monoxide [DLCO]), and model C (B + antifibrotic therapy). Prespecified subgroup analyses included age strata (≤55 and >55 years) and ILD entities. Longitudinal FVC and DLCO trajectories were assessed over 24 months. RESULTS:Among 883 patients (483 men and 400 women), exposures and disease entities differed significantly by sex: men reported more occupational/environmental exposures and had higher rates of fibrotic idiopathic interstitial pneumonia, whereas women more frequently had autoimmune-related ILD and a family history of ILD. Men had a higher comorbidity burden and more often received antifibrotic therapy at baseline. Survival was shorter in men (HR: 1.51; 95% CI: 1.03-2.21), but this association disappeared after adjustment in model A (HR: 1.04; 95% CI: 0.65-1.68), model B (HR: 1.03; 95% CI: 0.61-1.74), and model C (HR: 1.04; 95% CI: 0.62-1.77). Progression-free survival and transplant-free survival showed no consistent sex-related differences. Longitudinal FVC and DLCO declines were modest and largely parallel in both sexes, with no significant between-group differences. Findings were similar across age groups and ILD entities. CONCLUSION:Men and women with non-IPF ILD differ in exposures, phenotypes, and comorbidities, but after accounting for these factors, sex is not an independent predictor of survival or functional progression. Risk assessment should therefore primarily be based on objective disease characteristics rather than sex alone.

Background:Current treatments for idiopathic pulmonary fibrosis (IPF) slow but do not stop/reverse disease progression. The lysophosphatidic acid (LPA) axis is identified as a therapeutic target for IPF. Objective:This study aims to assess BI 1819479, an LPA pathway inhibitor, in patients with IPF (ClinicalTrials.gov Identifier: NCT06335303). Methods:In this placebo-controlled, phase II trial, patients will be randomised (2:1:1:1) to receive one of three oral doses of BI 1819479 or placebo, stratified by nintedanib/pirfenidone use. Patients aged ≥40 years with IPF, forced vital capacity (FVC) ≥45% of predicted normal and haemoglobin-corrected diffusing capacity for carbon monoxide ≥25% of predicted normal at screening will be included. Patients with relevant airway obstruction (pre-bronchodilator forced expiratory volume in 1 s/FVC <0.7), acute IPF exacerbation ≤12 weeks prior to screening, treatment with immunosuppressive medications (other than oral corticosteroids) or prednisone >15 mg·day-1 or equivalent, will be excluded. Treatment with approved IPF treatments (nintedanib/pirfenidone) is allowed if at a stable dose for ≥12 weeks prior to trial entry. Patients will be treated until completing 52 weeks, or 24 weeks after the last patient is randomised, whichever occurs first. The primary end-point is the annual rate of FVC decline (mL·year-1) assessed up to 52 weeks; the secondary end-point is absolute change from baseline in FVC at week 24. Safety will be assessed throughout. Conclusion:This trial evaluates the efficacy, safety and dose range of BI 1819479 in patients with IPF, offering a potential additional treatment option, and will establish appropriate dosing for phase III trials.

Background Single nucleotide polymorphisms (SNPs) within Toll interacting protein (TOLLIP) coding gene have been associated with progression, prognosis and treatment response in idiopathic pulmonary fibrosis (IPF). These SNPs seem to influence mRNA expression and serum levels of TOLLIP. The aim of this study was to investigate TOLLIP serum concentrations in a previously genotyped cohort of patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD).Patients and methods 106 consecutive patients with SSc (77 female) with (n=53) and without ILD (n=53) and 60 healthy controls (HCs) were included. TOLLIP concentrations were measured using a commercially available ELISA kit (Cloud-Clone, USA) in serum samples from patients and HC previously genotyped for two SNPs within TOLLIP (rs3750920, rs5743890).Results Patients with SSc had tendentially lower TOLLIP serum concentrations than HC (0.111 (95% CI 0.101 to 0.123) vs 0.141 (95% CI 0.104 to 0.191) ng/µL, p=0.076). Patients with SSc-ILD showed significantly higher TOLLIP levels than patients with SSc without ILD (0.126 (95% CI 0.106 to 0.151) vs 0.098 (95% CI 0.091 to 0.105) ng/µL, p=0.010). At a cut-off value of ≥0.1135 ng/µL serum TOLLIP yielded a 71% sensitivity and 74% specificity for identifying ILD (AUC=0.74, 95% CI 0.593 to 0.889, p=0.007). Serum TOLLIP concentrations did not differ significantly across rs3750920 or rs5743890 genotypes. TOLLIP concentration inversely correlated with age (r=−0.256, p<0.001), whereas no significant associations with gender, body mass index, C-reactive protein, forced vital capacity or diffusing capacity of the lung for carbon monoxide at time of sampling were observed.Conclusion Patients with SSc show lower TOLLIP serum concentrations than HC, while patients with SSc-ILD exhibit higher TOLLIP levels than those without. TOLLIP might serve as a biomarker of ILD in patients with SSc.

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogenous clinical manifestations, including interstitial lung disease (ILD). Respiratory manifestations are the leading causes of mortality in patients with ASMD type B and type A/B. In ILD, the percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO) is a common clinical endpoint; however, its clinical relevance in patients with ASMD remains unclear. This post hoc analysis explored the relationship between DLCO and mortality risk in patients with ASMD type B and type A/B. Data from a prospective natural history study (NCT02004704) and a retrospective cohort study conducted in the United States were pooled based on the eligibility criteria. Percent predicted DLCO was imputed for 10 records (9/68 patients), assuming an annual 1

RATIONALE:Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES:To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS:We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS:We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS:We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.

Background:Idiopathic pulmonary fibrosis (IPF) and other progressive pulmonary fibrosis (PPF) forms are associated with significant morbidity and mortality. Pirfenidone and nintedanib are the currently approved antifibrotic drugs in Germany. Based on the positive results of both Phase-3 trials FIBRONEER-IPF and FIBRONEER-ILD, the phosphodiesterase-4B inhibitor nerandomilast was approved in 2025 for the treatment of IPF in USA, but not yet in Germany. Materials and methods:We performed a comparative analysis of the results of phase 3 randomized clinical trials of pirfenidone, nintedanib and nerandomilast regarding patient characteristics, efficacy and safety. Results:Eight phase 3 trials were included: 3 with pirfenidone, 3 with nintedanib, und 2 with nerandomilast. The characteristics of the trials' populations showed substantial differences. In terms of the primary endpoint reduction of FVC decline over one year, all the three compounds demonstrated similar efficacy. Secondary endpoints across the trials were heterogeneous, and no positive efficacy for patient-reported outcomes was observed for any of the three drugs. The best tolerability and safety profile was demonstrated for nerandomilast. Conclusion:In the near future, nerandomilast could become the third available antifibrotic drug in Germany for the treatment of IPF and PPF, showing a similar efficacy profile to pirfenidone and nintedanib, with a better tolerability. The different trials populations should be considered when comparing the clinical trials results. New guidelines are mandatory to unravel the role of nerandomilast in the treatment algorithm of IPF and PPF.

Background Idiopathic pulmonary fibrosis (IPF) and other progressive pulmonary fibrosis (PPF) forms are associated with significant morbidity and mortality. Pirfenidone and nintedanib are the currently approved antifibrotic drugs in Germany. Based on the positive results of both Phase-3 trials FIBRONEER-IPF and FIBRONEER-ILD, the phosphodiesterase-4B inhibitor nerandomilast was approved in 2025 for the treatment of IPF in USA, but not yet in Germany. Materials and methods We performed a comparative analysis of the results of phase 3 randomized clinical trials of pirfenidone, nintedanib and nerandomilast regarding patient characteristics, efficacy and safety. Results Eight phase 3 trials were included: 3 with pirfenidone, 3 with nintedanib, und 2 with nerandomilast. The characteristics of the trials' populations showed substantial differences. In terms of the primary endpoint reduction of FVC decline over one year, all the three compounds demonstrated similar efficacy. Secondary endpoints across the trials were heterogeneous, and no positive efficacy for patient-reported outcomes was observed for any of the three drugs. The best tolerability and safety profile was demonstrated for nerandomilast. Conclusion In the near future, nerandomilast could become the third available antifibrotic drug in Germany for the treatment of IPF and PPF, showing a similar efficacy profile to pirfenidone and nintedanib, with a better tolerability. The different trials populations should be considered when comparing the clinical trials results. New guidelines are mandatory to unravel the role of nerandomilast in the treatment algorithm of IPF and PPF.

Zusammenfassung Die idiopathische Lungenfibrose (IPF) und auch andere progredient pulmonale Fibrosen (PPF) sind mit einer hohen Morbidität und Mortalität verbunden. Pirfenidon und Nintedanib sind aktuell die zwei zugelassenen und nach Leitlinien empfohlenen antifibrotisch wirksamen Substanzen. Die Zulassung des Phosphodiesterase-4B-Inhibitors Nerandomilast wird aufgrund der positiven Ergebnisse der beiden Phase-3-Studien FIBRONEER-IPF und FIBRONEER-ILD 2026 in Deutschland erwartet. Es erfolgte eine vergleichende Analyse von Phase-3 Studienergebnissen der Wirkstoffe Pirfenidon, Nintedanib und Nerandomilast bezüglich Patientencharakteristika, Studienendpunkte und Sicherheitsdaten. Acht Phase-3-Studien wurden identifiziert, drei zu Pirfenidon, drei zu Nintedanib und zwei zu Nerandomilast. Es zeigen sich z.T. deutlich unterschiedliche Studienpopulationen, bzw. Patientencharakteristika. Für alle drei Substanzen konnte bezüglich des primären Endpunktes, der Reduktion des FVC-Abfalls über ein Jahr, eine ähnlich gute Wirksamkeit belegt werden. Bezüglich sekundärer Endpunkte sind die Daten heterogen, positive Effekte auf Patienten-bezogene Endpunkte fehlen bei allen drei Wirkstoffen. Die beste Verträglichkeit liegt bei Nerandomilast. Mit Nerandomilast wird bald ein drittes antifibrotisches Medikament zur Behandlung fibrotischer Lungenerkrankungen zur Verfügung stehen, welches einen ähnlich positiven Effekt auf die Krankheitsprogression hat wie Pirfenidon und Nintedanib, aber besser verträglich ist. Unterschiedliche Studienkohorten müssen bei Vergleichen allerdings berücksichtigt werden. Für die klinische Einordnung sind letztlich Leitlinien-Empfehlungen zeitnah erforderlich.

Sarcoidosis is a systemic granulomatous disease influenced by genetic and environmental factors, resulting in a wide range of phenotypic variation. Accordingly, it often represents a diagnostic and therapeutic challenge. In recent years, evidence has notably accelerated across both diagnostic and therapeutic domains. EBUS-guided cryobiopsy has shown promising diagnostic improvement supported by randomized controlled trial data, while quantitative FDG-PET/CT biomarkers, novel radiotracers targeting somatostatin receptors and vascular adhesion protein 1, and multiparametric cardiac MRI have expanded the precision and prognostic value of imaging. Preclinical proteomic signatures and electronic nose technology suggest a future of earlier, less invasive detection. The 2025 WASOG Position Paper marked a paradigm shift in corticosteroid use, arguing against the traditional corticosteroid-centered model of sarcoidosis treatment. The PREDMETH trial supports methotrexate as a first-line alternative to prednisone in pulmonary sarcoidosis. Emerging targeted therapies-JAK inhibitors, PDE-4 inhibitors, and SGLT-2 inhibitors in sarcoid cardiomyopathy-provide preliminary but promising evidence of efficacy. Collectively, these advances outline a trajectory toward more precise, less toxic, and increasingly personalized management of sarcoidosis.

Objectives: To identify clinical features distinguishing anti-synthetase syndrome (ASyS)-related ILD (ASyS-ILD) from non-ASyS ILD and to compare outcomes across ILD subgroups.Methods: We utilized an international, real-world physician-reported database to compare ASyS-ILD and ILD related to other causes. Comparative analysis was performed against the overall control group, and the five main control ILD disease subgroups. Logistic regression assessed associations with supplemental oxygen use and ILD-hospitalization, and Cox proportional hazards models evaluated associations with all-cause mortality. Results: Among 1,557 ASyS-ILD and 828 controls, ASyS-ILD patients were younger, had more acute onset, and had worse restrictive physiology. Nonspecific interstitial pneumonia (NSIP) was the most common radiological pattern across all groups. In ASyS-ILD, NSIP (55%) was followed by organizing pneumonia (OP, 19%), similar to ILD in dermatomyositis (DM) with and without MDA5 antibodies (NSIP 53% and 64%, OP 32% and 11%, respectively). NSIP remained common in rheumatoid arthritis (RA) and systemic sclerosis (SSc) ILD (39% and 59%) but was followed by usual interstitial pneumonia (36% and 14%). Compared with controls, ASyS-ILD had higher odds of hospitalization (OR 1.81, 95%CI 1.38-2.37). Mortality in ASyS-ILD was primarily pulmonary then cardiovascular, Five-year survival in ASyS-ILD was 94.7% which was comparable or higher than most control subgroups, except anti-MDA5-associated ILD (90.3%). ASyS-ILD had higher all-cause mortality (HR 1.66, 95%CI 1.03–2.66) than controls. Conclusions: ASyS-ILD is characterized by a younger, more acute, and symptomatic onset compared with other ILDs, and is associated with higher hospitalization rates and worse mortality, underscoring its overall more severe clinical course.

Sarcoidosis is a complex systemic granulomatous disease that can affect multiple organs, with pulmonary involvement being the most common. Its pathogenesis involves genetic predisposition and chronic immune dysregulation, which increase susceptibility to environmental or endogenous triggers, leading to an aberrant immune response. Imaging plays a central role in diagnosis and has evolved from traditional chest radiography Scadding staging to a computed tomography-based classification and radiomics that improves disease phenotyping. Due to its variable presentation, diagnosing sarcoidosis and attributing symptoms to the disease can be challenging; therefore, awareness and consideration of alternative diagnoses remain essential. The clinical course of sarcoidosis is unpredictable; many patients do not require therapy. Treatment decisions must be individualised, balancing disease severity, risk of organ damage, quality of life and potential toxicity of medication. However, the lack of both reliable prognostic tools and clear criteria for high-risk cases contributes to substantial heterogeneity in disease management. While the guidelines still recommend corticosteroids as first-line treatment, recent data show that methotrexate and prednisone have comparable effects on pulmonary function, although differ in side-effect profiles and time to efficacy. For refractory cases, second-line therapy involves combining or switching drugs, with anti-tumour necrosis factor agents representing third-line options, ideally in expert hands. Novel therapies targeting pathways involved in disease pathogenesis are under investigation. There is growing consensus on the need to revise current treatment algorithms to minimise corticosteroid use and adopt more evidence-based approaches. Future priorities include identifying prognostic biomarkers, refining trial design and establishing meaningful end-points to improve individualised care for the heterogeneous population of patients with sarcoidosis.

Background/Objectives: Krebs von den Lungen-6 (KL-6) is a mucin-like glycoprotein that is elevated in a variety of lung diseases and used as a diagnostic and prognostic biomarker in people with cystic fibrosis (pwCF). Single nucleotide polymorphisms (SNPs) in mucin-1 (MUC1) influence KL-6 serum concentration. This study investigated the relationship between serum KL-6 concentrations in pwCF and a MUC1 SNP and its longitudinal dynamics. Methods: The study included pwCF (n = 174) and healthy controls (n = 30). In pwCF, 365 samples were collected for longitudinal analyses; KL-6 levels were measured and the MUC1 SNP rs4072037 was genotyped in pwCF and controls. Cross-sectional and longitudinal associations between KL-6, genotype, and clinical parameters, such as infectious exacerbation, body mass index, inflammatory values and lung function, were analyzed using linear mixed-effects models. Results: Serum KL-6 was significantly elevated in pwCF compared with controls (458 ± 357 vs. 283 ± 103 U/mL; p < 0.001). Homozygous G/G carriers exhibited higher baseline KL-6 than A/A carriers (627 ± 673 vs. 397 ± 148 U/mL; p < 0.001), while heterozygous individuals showed intermediate levels. Longitudinally, the MUC1 SNP and interindividual differences in vital capacity (ppFVC) primarily determined baseline KL-6 levels, explaining 52.5% of variance. Short-term intraindividual fluctuations were largely driven by infectious exacerbations independent of genotype, accounting for ~10% of within-subject variance. Conclusions: PwCF generally showed elevated serum KL-6 levels and reflected both stable interindividual differences, mainly driven by the MUC1 SNP and ppFVC. Dynamic intraindividualchanges were associated with infectious exacerbations. Given the influence of MUC1 polymorphisms (e.g., rs4072037) on KL-6 concentration, personalized interpretation based on the genotype status may be informative in pwCF.