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.

Abstract Background: Liquid biopsy enables minimally invasive tumor genomic assessment. We evaluated serial circulating tumor DNA (ctDNA) monitoring for KRAS and EGFR in metastatic lung cancer to characterize mutational dynamics, correlate changes with clinical events, and assess plasma testing for early resistance detection. Aims: Describe longitudinal KRAS and EGFR plasma patterns during systemic therapy and relate ctDNA kinetics to treatment changes and outcomes. Methods: Thirty-five metastatic lung cancer patients were prospectively enrolled (31.4% female; median age 70, IQR 41-84). Plasma was collected at baseline and, for 20 patients, at weeks 4, 8, 12 and 24 and thereafter until progression or death. KRAS and EGFR status was assessed with targeted ctDNA assays using the Idylla platform. Results: Tissue-plasma concordance was fair to moderate for KRAS and EGFR (Cohen’s kappa 0.35 and 0.43). Serial monitoring showed marked interpatient heterogeneity and dynamic shifts in mutant allele fractions. Two patients had early KRAS increases at week 4; one died and the other progressed to second-line therapy and developed a second KRAS codon 12 mutation (G12R alongside baseline G12C) at week 8, consistent with clonal diversification. Another patient showed oscillating KRAS detection—present at baseline and week 8 but absent at weeks 4 and 12—suggesting transient clonal suppression and re-expansion related to treatment scheduling. One patient’s EGFR levels tracked therapy: high at baseline and week 4, cleared at week 8 after switching to Amivantamab, then reappeared at week 12 after treatment discontinuation for toxicity. EGFR mutations were observed in one patient only (8.3%); others remained EGFR wild type throughout follow-up. Conclusions: Longitudinal plasma KRAS and EGFR testing captured evolving mutational landscapes that anticipated progression and reflected treatment effects, including emergence of secondary clones and transient suppression of mutant fractions. Serial ctDNA profiling is a pragmatic adjunct to tissue genotyping for early resistance detection and therapeutic guidance. Larger cohorts are needed to quantify predictive performance and integrate ctDNA kinetics into clinical decision algorithms. Citation Format: Valentina Buzzi, Greta Berti, Michele Santillo, Arianna Belli, Giulia Favarato, Mauro Iannopollo, Elisabetta Rosi, Federico Lavorini, Sara Tomassetti, Annarosa Arcangeli, Elena Lastraioli. Dynamic plasma KRAS and EGFR ctDNA profiling identifies treatment response and nascent resistance in metastatic lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7845.

Lung biopsy has traditionally played a fundamental role in addressing diagnostic uncertainty and guiding management of fibrotic interstitial lung disease (fILD). Multiple lung biopsy procedures are available for evaluating fILD, including bronchoscopic techniques such as transbronchial biopsy and transbronchial lung cryobiopsy, as well as surgical lung biopsy, which is now almost exclusively conducted using minimally invasive video-assisted thoracoscopic surgery. The various evolving -considerations for and against lung biopsy have led to substantial ambiguity regarding the optimal timing and choice of biopsy method. The rationale for performing a lung biopsy in fILD is multifaceted, shaped by its potential to enhance diagnostic confidence and inform therapeutic decisions, weighed against procedural risks, and further nuanced by patient values and preferences. The objective of this state-of-the-art document from a multidisciplinary group of experts and patient representatives is to summarize the rationale for and against lung biopsy in the evaluation and management of fILD. Amid ongoing technological innovations, we further emphasize that future research should prioritize the development and validation of minimally invasive and noninvasive modalities that may serve as either alternatives or adjuncts to biopsy in the diagnostic evaluation of fILD.

Acute exacerbations (AEs) occur both in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung disease (fILD). These events confer high morbidity and mortality, with a lack of proven effective therapeutic interventions. The objective of this state-of-the-art document is to summarize latest evidence since the 2016 international working group report on AE-IPF, expanding it across the spectrum of all fILDs. A comprehensive literature review on the epidemiology, associated and risk factors, prognosis, and management of AE-fILD is summarized. In addition to revising the AE definition and diagnostic criteria for broad application across different fILDs, a conceptual framework for acute respiratory worsening (ARW) has been proposed to encompass a variety of acute respiratory deteriorations, both related and unrelated to AE. This allows structured evaluation in both clinical and research settings. The proposed revised definition for AE-fILD is an acute respiratory event characterized by increased respiratory symptoms or signs and associated with radiologic or histologic features consistent with diffuse alveolar damage (with or without superimposed organizing pneumonia) in a patient with known or newly diagnosed fILD. On the other hand, ARW refers to a heterogeneous group of clinical events with acute symptom worsening not attributable to DAD in patients with fILD, such as pulmonary edema, bronchitis, and pneumonia, although severe pneumonia can trigger AE-fILD. Additionally, we discuss considerations for inclusion of AE as a clinical trial endpoint, as well as research priorities for advancing knowledge on the pathogenic mechanisms, event prediction, risk stratification, and development of drugs and supportive treatments.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which the earliest cellular events driving fibrosis remain poorly defined. Here, we analyzed lung samples from three independent and unique cohorts of patients with early disease and preserved lung function (Florence, NIH, Forli), applying an integrated multi-modal approach combining single-nucleus RNA sequencing, bulk transcriptomics, immunostaining, and spatial transcriptomics. Single nuclear RNA sequencing of samples obtained by diagnostic bronchoscopic cryobiopsy (Florence, n= 22) revealed that early IPF is characterized by a marked shift in alveolar epithelial composition, with loss of AT1 and AT2 cells and the emergence of aberrant basaloid cells and alveolar epithelial intermediate cells. These populations exhibited transcriptional programs associated with epithelial plasticity and profibrotic signaling and closely resembled those observed in end-stage IPF. Higher proportions of aberrant basaloid and alveolar epithelial intermediate cells were associated with subsequent disease progression, whereas AT2 cell abundance correlated with preserved lung function. Fibrotic CTHRC1+ fibroblasts are largely restricted to advanced disease, while endothelial remodeling and inflammatory fibroblast states are already evident in early IPF. Spatial transcriptomic analyses confirmed early disruption of the alveolar niche, with replacement of normal epithelial-capillary interactions by aberrant epithelial and venous endothelial cells (Forli, n= 24); the findings were replicated through single cell RNA sequencing of samples obtained by video assisted thoracoscopy two decades earlier (NIH n=9). Together, these findings identify that alveolar niche remodeling with loss of its normal components, and emergence of aberrant basaloid cells are features of early IPF, highlighting epithelial dysfunction as a key potential target for therapeutic interventions in early disease.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive respiratory rare disease characterized by an irreversible loss of lung function, with unknown etiology and poor prognosis. A population registry-based study was conducted to provide estimates of prevalence, incidence and survival of IPF. The study included all cases diagnosed with IPF in the years 2000–2022 and residing in Tuscany, Italy. Prevalence as of December 31, 2022, was calculated by sex and age class. Incidence was calculated across the period 2018–2022. Survival at 1, 5 and 10 years from diagnosis with 95

Transbronchial lung cryobiopsy (TBLC) has rapidly established itself as a promising, less invasive alternative to surgical lung biopsy for the evaluation of interstitial lung diseases (ILDs). While its diagnostic accuracy and safety are increasingly recognized in clinically overt forms, its role within the more subtle spectrum of interstitial lung abnormalities (ILAs) and early ILDs remains insufficiently defined and therefore largely debated. In this expert narrative review, we explore the current state of evidence surrounding TBLC and its potential applicability in these emerging clinical entities, addressing technical variability, diagnostic performance, safety profile, and integration within multidisciplinary frameworks. We further examine the ethical and clinical tension arising from the use of invasive diagnostics to largely asymptomatic or minimally symptomatic individuals, where the balance between potential benefit and harm remains undefined. Beyond these pragmatic considerations, TBLC offers a unique vantage point into the onset of fibrotic remodeling: its broader application may unveil the earliest histopathologic and biological substrates of chronic and acute tissue injury in ILDs, including aberrant basaloid cells, potential indicators of maladaptive repair that may orchestrate the fibrotic cascade. By enabling recognition of usual interstitial pneumonia (UIP) at its inception, TBLC holds the promise not merely of refining risk stratification, but of opening new therapeutic horizons in which antifibrotic strategies may be deployed at a stage when disease is still modifiable. We contend that rigorously designed prospective studies are urgently needed to determine whether early tissue sampling with TBLC can transform ILAs from incidental findings into a window of therapeutic opportunity, thereby altering the otherwise progressive trajectory of fibrosing lung diseases.

Aspiration pneumonia (AP) is common in patients with pneumonia evaluated in Emergency Department (ED). The therapeutic management of these patients often involves secretion suctioning through two main techniques: laryngotracheal aspiration (LTA) and fibrobronchoscopic aspiration (FBA). Despite both techniques being employed, there are no studies comparing the clinical outcomes. This prospective single-center observational case control study was conducted in the ED of Careggi University Hospital in Italy. Adult patients with radiological evidence of pneumonia, clinical diagnosis of AP and need for oxygen therapy were included from the 12th December 2023 to the 31st December 2024. The primary endpoints were 30 day-mortality and the length of hospital stay. Secondary endpoints included admission setting, changes in Horowitz index and O2 delivery device, and procedure-related complications. Statistical analysis was conducted on the entire sample and subsequently on a selected population using propensity score matching (PSM). 257 patients with a mean age of 78.0 ± 15.2 years were included in the study. There were no significant differences between LTA and FAB groups regarding 30-day mortality (37.7

Unilateral pulmonary fibrosis (UPF) is an uncommon manifestation of interstitial lung disease that may arise from various causes. Among those, cardiovascular etiology is often overlooked because affected patients do not present history of exposure of any kind, are frequently asymptomatic or present only mild, subtle and nonspecific symptoms. As a result, these cases are usually identified incidentally on imaging performed for unrelated reasons, contributing to under recognition of their true prevalence. We report 3 patients with incidentally detected UPF on high-resolution computed tomography (HRCT), each associated with a distinct vascular abnormality, both congenital and acquired conditions: unilateral absence of the pulmonary artery, chronic pulmonary thromboembolism, and pulmonary artery branch hypoplasia. Our aim with this case series is to highlights the diverse radiologic patterns of vascular UPF, underscoring the importance of considering vascular causes in the differential diagnosis of unilateral fibrotic lung disease.

This narrative review explores the complementary roles of indwelling pleural catheters (IPCs) and medical thoracoscopy (MT) in the evaluation and management of unexplained exudative pleural effusions, including malignant pleural effusion. IPCs offer a minimally invasive strategy for long-term outpatient management, which is particularly advantageous for patients with non-expandable lungs or limited functional status. Conversely, MT remains the gold standard for diagnostic accuracy and facilitates therapeutic procedures such as pleurodesis under direct visualisation. Recent evidence supports the integration of IPCs and MT as a hybrid approach, offering synergistic benefits including enhanced symptom control, reduced hospital admissions and improved patient-centred outcomes. This review synthesises current literature to provide a practical and evidence-based overview of these techniques and their evolving role in pleural disease management.

Pneumonia remains a major cause of morbidity and mortality worldwide. Rapid diagnostic testing with molecular syndromic panels (MSP) has proved useful for the management of antimicrobial treatment of hospital-acquired pneumonia (HAP). In this study, we evaluated the impact of early use of MSP testing in the Emergency Department (ED) for the management of antibiotic therapy in patients with moderate to severe CAP with risk factors for multi-drug-resistant pathogens (CAP-MDR). Patients presenting at the ED with diagnosis of moderate to severe CAP-MDR underwent microbiological analysis of lower respiratory tract specimens by culture and MSP testing (bioMérieux, FilmArray® Pneumonia Plus Panel). The primary outcome was the percentage of cases in which MSP testing modified the empiric antimicrobial therapy started according to local protocols. Among the secondary outcomes we included the time elapsed from ED admission to antibiotic change or confirmation upon receipt of the MSP results. Between June 2024 and May 2025, 93 patients were enrolled (age, 72.9 ± 13.9 years; 62.4

RATIONALE Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic disease characterized by exertional dyspnea and non-productive chronic cough. Although the pathogenesis of IPF is unknown, genetic and environmental factors could be implicated in the development of the fibrotic process. Currently, early and/or minimally invasive biomarkers are not available for this disease. In this context, liquid biopsy techniques are gaining an increasingly important role in the evaluation of such biomarkers. Particularly, circulating microRNAs (miRNAs) can provide valuable insights into theunderlying pathogenetic mechanisms of complex and multifactorial diseases. In this study, we aimed at investigating the profile of circulating miRNAs in patients with IPF.METHODS We analised the profile of circulating miRNAs through small RNA sequencing (RNASeq) in the plasma of 14 patients with IPF and 7 healthy subjects. All patients aged between 59 and 88 years, and had high-resolution CT features suggestive for definite or probable usual interstitial pneumonia (UIP).RESULTS Thirty differentially expressed miRNAs were identified, including 21 up-regulated and 9 down-regulated. This profile was found to be unique for this type of pathology, showing no overlap with circulating miRNAs identified in other fibrotic diseases such as liver cirrhosis and autoinflammatory diseases such as Systemic Lupus Erythematosus and vasculitis like Behçet's syndrome. Functional analysis using Gene Ontology (GO) revealed several terms related to fibrosis, particularly signaling mechanisms mediated by GTPases and cell adhesion molecules. Analysis conducted through the KEGG ontology showed significant enrichment for the term Non-Small Cell Lung Cancer (NSCLC).Specifically, among the target genes and miRNAs deregulated in patients with IPF, we identified genes relevant to the pathophysiology of this type of tumor (ALK, EGFR numerous kinases, genes related to apoptosis, etc.).CONCLUSIONS Overall, the results of the present study, albeit preliminary, open up interesting views for studying pathophysiological mechanisms and lay the groundwork for the use of miRNAs as early biomarkers of IPF and its progression

Introduction Hemophagocytic Lymphohistiocytosis (HLH) is a rare, aggressive, and life-threatening disorder characterized by sustained but ineffective immune system activation that leads to severe and systemic hyperinflammation. It may occur as a genetic or sporadic condition, often triggered by an infection. The multifaceted pathogenesis results in a wide range of non-specific symptoms, signs, and laboratory findings that challenge its recognition. The pulmonary involvement is underdiagnosed and may manifest as pneumonia, which can lead to respiratory failure. Despite the great improvement achieved in terms of survival, a considerable proportion of patients with HLH still die from progressive disease. Case Presentation We discuss the case of a unique form of respiratory distress and multiorgan failure with inconclusive radiological and lung biopsy investigations. The patient was finally diagnosed, by genetic analysis, with HLH, and promptly treated as per HLH-94 treatment protocol. Conclusion This case report aims to emphasize that clinical, laboratory, instrumental, and even pathological findings in HLH might not be unequivocal; nonetheless, a rapid diagnosis and treatment are mandatory, given the high mortality of the disease.