BACKGROUND:Patients with fibrosing interstitial lung disease (ILD) experience symptoms such as dyspnea, cough, and fatigue that impair quality of life. While palliative care can improve outcomes, timely referral to palliative care remains challenging due to prognostic uncertainty, variable practice, and the absence of standardized referral criteria. No consensus referral tool currently exists for fibrosing ILD. OBJECTIVES:To develop a pragmatic, needs-based tool to facilitate timely identification of ILD outpatients who may benefit from palliative care referral. METHODS:A multi-method study, guided by the Double Diamond framework and Experience-Based Co-Design principles, was conducted in three phases. In Phase 1, a targeted literature review identified 10 referral domains and 44 candidate indicators, which informed an international survey in which healthcare professionals ranked domains and rated indicators using a 5-point Likert scale. In Phase 2, semi-structured interviews with ILD experts explored referral practices, perceived utility of a referral tool, and implementation challenges. In Phase 3, co-design workshops with patients, caregivers, and clinicians, together with expert feedback meetings, prioritized referral triggers and refined the tool's language, layout, and usability. Findings from all phases informed iterative development of the Palliative Care referral Tool for ILD (PaCT-ILD). MEASUREMENTS AND MAIN RESULTS:The survey received 117 responses from 15 countries. Distressing symptoms, worsening quality of life, psychosocial distress, patient or caregiver request, recurrent hospitalizations, increasing care needs, and limited life expectancy were prioritized over co-morbidities and formal health-related quality-of-life instruments. Eleven ILD experts contributed interviews, generating eight themes on referral timing, clinical triggers, stigma, relational trust, and system-level barriers. Workshops confirmed the salience of symptom and needs-based triggers and led to refinements in wording and layout. The final PaCT-ILD is a one-page clinician-facing tool with five priority domains and three recommendation thresholds ("strongly recommend referral", "consider referral", "hold off referral"), including space to document reasons for non-referral and prompts to revisit palliative care at future visits. CONCLUSIONS:PaCT-ILD is a co-designed, needs-based referral aid that reflects real-world decision-making in ILD and offers a structured framework to support earlier, more consistent palliative care referral. Further evaluation is required to assess feasibility, acceptability, and impact on clinical outcomes.

The alternative reading frame (ARF) protein, encoded by the CDKN2A locus, is well-recognized for its role in tumor suppression. Emerging evidence has highlighted ARF as a critical regulator of innate immunity and inflammation, with links to increased susceptibility to cardiometabolic diseases. This study investigates the role of ARF in lung homeostasis and reveals that its deficiency in mice affects lipid metabolism and leads to pulmonary abnormalities resembling pulmonary alveolar proteinosis (PAP). ARF-deficient mice exhibited abnormal surfactant clearance, characterized by lipid and protein accumulation in the alveoli, foamy alveolar macrophages (AMs) with enlarged and vacuolated morphology, and increased bronchoalveolar lavage fluid turbidity. These changes were linked to disrupted surfactant homeostasis resulting from an imbalance between increased lipid uptake (via upregulation of scavenger receptors such as SR-A1 and CD36) and impaired lipid efflux, evidenced by reduced expression of the cholesterol transporter SR-BI. These mice also display reduced AM numbers, increased eosinophil and neutrophil infiltration, consistent with secondary PAP. Additionally, a distinctive chemokine and cytokine profile (elevated Ccl12, Ccl2, Cxcl1, and IL-10) was observed, which may be associated with type 2 immune responses and alternative AM polarization. Interestingly, ARF deficiency also appears to compromise AM maintenance through effects on self-renewal and survival. Pulmonary function tests revealed increased tissue elastance and damping, suggesting early-stage lung stiffness. Collectively, these findings highlight the essential role of ARF in lung homeostasis and lipid regulation, providing insights into its potential involvement in PAP pathogenesis.

Background: Sarcoidosis is a multi-organ granulomatous disease with a variable course. While several predictors of mortality have been described for pulmonary sarcoidosis, it is imperative to identify predictors of mortality in thoracic sarcoidosis (involving the lungs and/or lymph nodes) to guide its therapy and management effectively. This study aims to evaluate predictors of all-cause mortality at 5 years in patients with thoracic sarcoidosis from a Spanish cohort.Study design and methods: This retrospective analytical observational study focused on the Spanish cohort of thoracic sarcoidosis (SARCO-1), involving an analysis of 765 patients. The diagnosis was made according to the WASOG criteria of 1999. Various demographic, clinical, respiratory function, imaging, laboratory characteristics, and the composite physiologic index (CPI) at the time of diagnosis were assessed. Changes in respiratory function and imaging at one year, based on progressive pulmonary fibrosis (PPF) criteria, were also evaluated. These variables were analyzed as predictors of all-cause mortality at 5 years using univariate and multivariate analyses.Results: At 5 years from diagnosis, 43 (5.6%) deaths were reported. Upon multivariate analysis, age at diagnosis and baseline CPI emerged as independent predictors of mortality at 5 years. The age threshold of over 50 years (HR 21.16, CI 95% 2.75 – 162) and a CPI > 35 (HR 2.84, CI 95% 1.06 – 7.6) demonstrated the best discrimination of mortality. The presence of fibrosis at diagnosis, functional deterioration, and radiological progression within the first year did not emerge as predictors of mortality.Conclusions: The independent predictors of all-cause mortality at 5 years in thoracic sarcoidosis within a Spanish cohort were identified as age over 50 years and a CPI > 35.

BACKGROUND:Idiopathic inflammatory myopathies (IIM) are a diverse group of muscle diseases often complicated by interstitial lung disease (ILD), which significantly impacts morbidity and mortality. Krebs von den Lungen-6 (sKL-6) has been proposed as a biomarker for ILD severity. Nailfold videocapillaroscopy (NVC) detects microvascular changes, but its diagnostic and prognostic value in IIM remains unclear. OBJECTIVE:This study aimed to assess the relationship between NVC abnormalities, sKL-6 levels and pulmonary outcomes in IIM patients. METHODS:A retrospective analysis was conducted in IIM patients from a reference centre, comparing those with and without ILD. Data included epidemiological, clinical and immunological features, pulmonary function tests, sKL-6 levels and NVC findings. Statistical analyses included Spearman's rank correlation coefficient to assess the relationships between sKL-6 levels, pulmonary function tests and NVC parameters. Multiple logistic regression modelling to identify to identify predictors of IIM-ILD. RESULTS:Among 95 patients (34% male, median age 55.3 ± 24 years, disease duration 6.8 ± 7 years), ILD was associated with avascular zones (P = 0.004), capillary loss (P = 0.04) and microhaemorrhages (P = 0.04). Negative correlations were observed between capillary loss and enlarged capillaries with forced vital capacity (%FVC) (rs = -0.46, P = 0.001; rs = -0.57, P < 0.0001) and diffusing capacity of the lungs for carbon monoxide (%DLCO) (rs = -0.32, P = 0.04; rs = -0.23, P = 0.03). sKL-6 levels correlated positively with ILD (rs = 0.77, P = 0.0004), microhaemorrhages (rs = 0.21, P = 0.04) and avascular areas (rs = 0.64, P = 0.03), and negatively with %FVC (rs = -0.47, P = 0.001) and %DLCO (rs = -0.59, P = 0.005). Predictors of ILD included male sex, respiratory symptoms, %FVC, %DLCO, sKL-6, anti-Jo1 positivity and NVC abnormalities. CONCLUSIONS:NVC findings, sKL-6 levels, and autoantibodies are valuable in identifying and monitoring ILD in IIM, highlighting their role in early diagnosis and management.

Purpose of reviewThe intersection of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and interstitial lung disease (ILD) represents a complex and increasingly recognized clinical challenge. This review aims to summarize current understanding, highlight diagnostic and therapeutic approaches, and identify key gaps in the literature regarding ANCA-associated ILD.Recent findingsANCA positivity-particularly MPO-ANCA- is increasingly identified in patients with fibrotic ILD, even in the absence of systemic vasculitis. This overlap raises questions about disease classification and management, especially as radiologic patterns such as usual interstitial pneumonia (UIP) appear to predict prognosis. Immunosuppressive therapy remains the mainstay of treatment, though its role varies depending on the presence of systemic features and lung fibrosis. Emerging biomarkers, and the potential role of antifibrotic agents offer promising avenues for improved monitoring and therapy.SummaryANCA-ILD represents a heterogeneous and underexplored disease spectrum that challenges existing classification systems. A multidisciplinary approach is critical, and prospective studies are urgently needed to redefine diagnostic criteria and guide treatment strategies in order to improve clinical outcomes.

BACKGROUND:Patients with severe COVID-19 may develop lung fibrosis. Pirfenidone is an anti-fibrotic drug approved for idiopathic pulmonary fibrosis. The efficacy and safety of pirfenidone in patients with fibrotic interstitial lung changes after recovery from severe COVID-19 pneumonia were evaluated. METHODS:This was a phase 2, double-blind, placebo-controlled, Spanish multicentre clinical trial. Patients were randomised to receive pirfenidone or placebo (2:1) for 24 weeks. The primary end-point was the proportion of patients that improved, considered when percentage change in forced vital capacity (FVC) was ≥10% and/or any reduction in the fibrotic score on chest high-resolution computed tomography (HRCT). Secondary end-points included health-related quality of life (HRQoL), exercise capacity and drug safety profile. RESULTS:From 119 eligible patients, 113 were randomised and 103 were analysed (pirfenidone n=69 and placebo n=34). Most patients were male (73.5%) and were receiving low-dose prednisone; mean age was 63.7 years and mean body mass index was 29 kg·m-2. The percentage of patients that improved was similar in the pirfenidone and placebo groups (79.7% versus 82.3%, respectively). The mean predicted FVC increased by 12.74±20.6% with pirfenidone and 4.35±22.3% with placebo (p=0.071), and the HRCT (%) fibrotic score decreased by 5.44±3.69% with pirfenidone and 2.57±2.59% with placebo (p=0.52). Clinically meaningful improvement in HRQoL was not statistically different (55.2% in the pirfenidone group and 39.4% in the placebo group). Exercise capacity, adverse events and hospitalisations were similar between groups. No deaths were reported. CONCLUSIONS:The overall improvements in lung function and HRCT fibrotic score after 6 months with pirfenidone were not significantly different than with placebo.

Diffuse interstitial lung diseases (ILD) can have a significant impact on the health of affected patients. Questionnaires that adequately assess their health-related quality of life (HRQoL) are therefore essential. The King's Brief Interstitial Lung Disease (K-BILD) health status questionnaire is a specifically validated questionnaire to evaluate HRQoL in patients with diffuse ILD. Since it was only available in English, a study was conducted following the recommended methodology to develop a Spanish version of the questionnaire.

Resumen: Las enfermedades pulmonares intersticiales difusas (EPID) pueden impactar significativamente en la salud de aquellos pacientes que las padecen. Por ello, es preciso disponer de cuestionarios que permitan evaluar adecuadamente la calidad de vida relacionada con la salud (CVRS). El King's Brief Interstitial Lung Disease (K-BILD) health status questionnaire es un cuestionario validado específicamente para evaluar la CVRS en pacientes con EPID. Dado que solo estaba disponible en lengua inglesa, se desarrolló un estudio, siguiendo la metodología recomendada, para obtener una versión en lengua castellana de dicho cuestionario. Abstract: Diffuse interstitial lung diseases (ILD) can have a significant impact on the health of affected patients. Questionnaires that adequately assess their health-related quality of life (HRQoL) are therefore essential. The King's Brief Interstitial Lung Disease (K-BILD) health status questionnaire is a specifically validated questionnaire to evaluate HRQoL in patients with diffuse ILD. Since it was only available in English, a study was conducted following the recommended methodology to develop a Spanish version of the questionnaire.

BACKGROUND:Sarcoidosis is a multi-organ granulomatous disease with a variable course. To predict mortality in routine clinical practice is challenging, thus, it is imperative to identify predictors of mortality in pulmonary sarcoidosis to guide therapy and management effectively. This study aims to evaluate predictors of all-cause mortality at 5 years in patients with pulmonary sarcoidosis from a Spanish cohort. STUDY DESIGN:We developed a retrospective, multicentre analysis from the Spanish pulmonary sarcoidosis cohort (SARCO-I), which included 765 patients diagnosed according to 1999 WASOG criteria. Demographic, clinical, radiological, functional, and laboratory characteristics were analysed. Composite physiological index (CPI) at diagnosis and functional and imaging progression according to the progressive pulmonary fibrosis (PPF) criteria, were also assessed. Univariate and multivariate analyses were performed using Cox proportional hazards models to evaluate predictors of 5-year all-cause mortality. RESULTS:At 5 years from diagnosis, 43 (5.6 %) deaths were reported. Upon multivariate analysis, age at diagnosis and baseline CPI emerged as independent predictors of mortality at 5 years. The age threshold of over 50 years (HR 21.16, CI 95 % 2.75-162) and a CPI >35 (HR 2.84, CI 95 % 1.06-7.6) demonstrated the best discrimination of mortality. The presence of fibrosis at diagnosis, functional deterioration, and radiological progression within the first year did not emerge as predictors of mortality. CONCLUSION:Age over 50 years and a CPI greater than 35 were identified as independent predictors of 5-year all-cause mortality in our Spanish pulmonary sarcoidosis cohort.

Introduction: There are few studies investigating the clinical profile of older patients with interstitial lung disease (ILD), so this study investigated the characteristics of the older population diagnosed with ILD.Material and Methods: Retrospective study in a population of new referrals at an ILD clinic from January 2013 to September 2017. Patients over 64 years were selected. Data collection included diseases variables, diagnostic procedures and comorbidities. Gender-age-physiology (GAP) stage, composite physiologic index (CPI) and Charlson Index was calculated. Statistical analysis was performed to investigate risk factors associated with survival.Results: A total of 232 patients were included in this study. Mean age was 76.3 years (SD 6.5). As per protocol, 69.3% completed the initial assessment but this was lower in the elderly group (61.5%). The most frequent diagnosis was Unclassifiable ILD (24.1%), followed by ILD associated with connective tissue disease (21.6%), IPF (12.1%) and Hypersensitivity Pneumonitis (10.3%). During follow-up (36,7 months (SD 28.6)) a significant proportion of patients died (55 cases, 23.7% of the cohort), especially in the late older group (30.4%). Kaplan-Meier curves showed that those over 75 years have a worse survival even when adjusted by covariables (p< 0,001). CPI was the only score with statistical significance in a multivariate analysis (HR 1.06. p 0.006).Conclusions: Older adults with ILD featured a distinct clinical profile. Our findings highlight the need to develop non-invasive biomarkers and specific scores adapted to this age-group.

Introduction: Krebs von den Lungen 6 (KL-6) is a mucin-1 glycoprotein produced by type II pneumocytes. High levels of KL-6 in blood may be found in patients with lung fibrosis. In Asia this biomarker is used for diagnosis and prognosis in interstitial lung diseases (ILD). There is a lack of information regarding KL-6 cut-off point for diagnosis and prognosis in European population. The aim of this study was to establish the cut-off point for serum KL-6 associated with the presence of ILD in the Spanish population. Methods: Prospective study including subjects who underwent chest HRCT, PFTs and autoimmune blood analysis. Two groups were created: non-ILD subjects and ILD patients. Serum KL-6 concentrations were measured using a Lumipulse KL-6 reagent assay and the optimal cut-off value was evaluated by a ROC analysis. Data on demographics and smoking history was also collected. Results: One hundred seventy-nine patients were included, 102 with ILD. Median serum KL-6 values overall were 762 U/mL, 1080 (+/- 787) U/mL for the ILD group vs 340 (+/- 152) U/mL for the non-ILD group (p < 0.0001). The main radiological pattern was NSIP (43%). ROC analysis showed greater specificity (86%) and sensitivity (82%) for KL-6 465 U/mL for detecting ILD patients. The multivariate logistic regression model pointed to the male sex, higher KL-6 values, lower FVC and low DLCO values as independent factors associated with ILD. Conclusion: Serum KL-6 values greater than 465 U/mL have excellent sensitivity and specificity for detecting ILD in our Spanish cohort. Multicentre studies are needed to validate our results. (c) 2024 SEPAR. Published by Elsevier Espa na,S.L.U. All rights reserved.

Background/Aims Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired muscle diseases with distinct clinical, pathological and histological features. Interstitial lung disease (ILD) is a frequent pulmonary manifestation in IIM (IIM-ILD) and considerably influences morbidity and mortality. Krebs von den Lungen 6 (sKL-6) has been proposed as a potential biomarker reflecting the severity of ILD in connective tissue diseases. Raynaud's phenomenon is very frequent and the presence of microvascular changes in IIM have been described however, the role of nailfold videocapillaroscopy (NVC) in diagnosis and prognosis in IIM is not clearly established. We aim to determine if there is any association between NVC findings, sKL-6 levels and pulmonary involvement in patients with inflammatory myopathies. Methods We performed a retrospective study of IIM patients followed in a reference center and compared them according to the presence of ILD. Epidemiological, clinical and immunological data, pulmonary function tests (forced vital capacity and diffusing capacity for carbon monoxide), sKL-6 levels and NVC finding were retrieved. Statistical analysis was performed by T-test and Fisher's exact test to compare qualitative and/or quantitative variables and multiple logistic regression modelling to identify correlation between pulmonary function tests, NVC findings and sKL-6 levels. Results 95 patients were included, 47 patients (49%) with ILD. 34% were male with a median age at inclusion of 55.3 +/- 24 years. Avascular areas and capillary lossshowed a significant association with the presence of ILD (OR 2.43, 95% CI 1.3-5.7, p 0.004) and (OR 1.7, 95% CI 1.48-3.1, p 0.04). A negative correlation between capillary loss and enlarged capillaries was also found with FVC% (beta=-0.46, p 0.001 and beta=-0.57, p < 0.0001) and DLCO% (beta=-0.32, p 0.04 and beta=- 0.23, p 0.03), respectively. When we studied the correlation between sKL-6 levels, positive correlations with the presence of ILD (beta = 0.77, p 0.0004), the presence of hemorrhages (beta = 0.21, p 0.04) and avascular areas in NVC (beta = 0.64, p 0.03) and negative correlations with FVC% (beta=-0.47, p 0.001) and DLCO% (beta=-0.59, p, 0.005) were found. Male sex, respiratory symptoms, %FVC and %DLCO, sKL-6 levels, anti-Jo1 positivity and the presence of avascular areas and enlarged capillaries in NVC were identified as IIM-ILD predictors (R2=0.974, p = 0.006). Conclusion Capillary loss and avascular areas showed a significant association with the presence of ILD, worse FVC and DLCO values and sKL-6 levels. We identified nine predictors for developing ILD in IIM. NVC assessment and sKL-6 levels can have a predictive role for studying pulmonary function and assessing the prognosis of IIM-ILD. Disclosure C. Sieiro Santos: None. J. Tandaipan: None. D. Castillo: None. L. Mart & iacute;nez Mart & iacute;nez: None. H. Codes: None. L. Sainz: None. B. Magallares: None. P. Moya: None. H. Corominas: None. E. D & iacute;ez & Aacute;lvarez: None. I. Castellvi: None.

Interstitial lung diseases (ILDs) are characterized by inflammation or fibrosis of the pulmonary parenchyma. Despite the involvement of immune cells and soluble mediators in pulmonary fibrosis, the influence of antimicrobial peptides (AMPs) remains underexplored. These effector molecules display a range of activities, which include immunomodulation and wound repair. Here, we investigate the role of AMPs in the development of fibrosis in ILD. We compare the concentration of different AMPs and different cytokines in 46 fibrotic (F-ILD) and 17 non-fibrotic (NF-ILD) patients by ELISA and using peripheral blood mononuclear cells from in vitro stimulation in the presence of lysozyme or secretory leukocyte protease inhibitor (SLPI) from 10 healthy donors. We observed that bronchoalveolar lavage (BAL) levels of AMPs were decreased in F-ILD patients (lysozyme: p < 0.001; SLPI: p < 0.001; LL-37: p < 0.001; lactoferrin: p = 0.47) and were negatively correlated with levels of TGF-β (lysozyme: p = 0.02; SLPI: p < 0.001) and IL-17 (lysozyme: p < 0.001; SLPI: p < 0.001). We observed that lysozyme increased the percentage of CD86+ macrophages (p < 0.001) and the production of TNF-α (p < 0.001). We showed that lysozyme and SLPI were associated with clinical parameters (lysozyme: p < 0.001; SLPI: p < 0.001) and disease progression (lysozyme: p < 0.001; SLPI: p = 0.01). These results suggest that AMPs may play an important role in the anti-fibrotic response, regulating the effect of pro-fibrotic cytokines. In addition, levels of lysozyme in BAL may be a potential biomarker to predict the progression in F-ILD patients.

Abstract Background/Aims Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired muscle diseases with distinct clinical, pathological and histological features. Interstitial lung disease (ILD) is a frequent pulmonary manifestation in IIM (IIM-ILD) and considerably influences morbidity and mortality. Krebs von den Lungen 6 (sKL-6) has been proposed as a potential biomarker reflecting the severity of ILD in connective tissue diseases. Raynaud’s phenomenon is very frequent and the presence of microvascular changes in IIM have been described however, the role of nailfold videocapillaroscopy (NVC) in diagnosis and prognosis in IIM is not clearly established. We aim to determine if there is any association between NVC findings, sKL-6 levels and pulmonary involvement in patients with inflammatory myopathies. Methods We performed a retrospective study of IIM patients followed in a reference center and compared them according to the presence of ILD. Epidemiological, clinical and immunological data, pulmonary function tests (forced vital capacity and diffusing capacity for carbon monoxide), sKL-6 levels and NVC finding were retrieved. Statistical analysis was performed by T-test and Fisher’s exact test to compare qualitative and/or quantitative variables and multiple logistic regression modelling to identify correlation between pulmonary function tests, NVC findings and sKL-6 levels. Results 95 patients were included, 47 patients (49%) with ILD. 34% were male with a median age at inclusion of 55.3±24 years. Avascular areas and capillary lossshowed a significant association with the presence of ILD (OR 2.43, 95% CI 1.3-5.7, p 0.004) and (OR 1.7, 95% CI 1.48-3.1, p 0.04). A negative correlation between capillary loss and enlarged capillaries was also found with FVC% (β=-0.46, p 0.001 and β=-0.57, p < 0.0001) and DLCO% (β=-0.32, p 0.04 and β=- 0.23, p 0.03), respectively. When we studied the correlation between sKL-6 levels, positive correlations with the presence of ILD (β = 0.77, p 0.0004), the presence of hemorrhages (β = 0.21, p 0.04) and avascular areas in NVC (β = 0.64, p 0.03) and negative correlations with FVC% (β=-0.47, p 0.001) and DLCO% (β=-0.59, p, 0.005) were found. Male sex, respiratory symptoms, %FVC and %DLCO, sKL-6 levels, anti-Jo1 positivity and the presence of avascular areas and enlarged capillaries in NVC were identified as IIM-ILD predictors (R2=0.974, p = 0.006). Conclusion Capillary loss and avascular areas showed a significant association with the presence of ILD, worse FVC and DLCO values and sKL-6 levels. We identified nine predictors for developing ILD in IIM. NVC assessment and sKL-6 levels can have a predictive role for studying pulmonary function and assessing the prognosis of IIM-ILD. Disclosure C. Sieiro Santos: None. J. Tandaipan: None. D. Castillo: None. L. Martínez Martínez: None. H. Codes: None. L. Sainz: None. B. Magallares: None. P. Moya: None. H. Corominas: None. E. Díez Álvarez: None. I. Castellvi: None.