Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterised by relentless fibrotic progression resistant to standard therapy. Purinergic signalling is poorly defined in IPF and PPF, and in this study we performed gene and protein expression analysis of immune and epithelial cells to better characterize P2X and P2Y receptor subtypes in patients with progressive fibrotic interstitial lung diseases (ILD). Patients with ILD (n = 11), bronchoscopy patient controls (n = 6) or healthy control subjects (n = 11) were recruited. ILD nasal epithelial cells and bronchoalveolar lavage (BAL) immune cells showed significantly elevated protein expression levels of P2X7 (P = 0.0064) and P2Y4 receptors (P = 0.004 and P = 0.0145), with ILD monocytes additionally demonstrating increased P2X4 (P = 0.0022). Levels of the receptor agonist, extracellular ATP (eATP), were 13-fold higher in ILD compared to controls (P < 0.0001). eATP inversely correlated with lung function (P = 0.001), and associated with increased receptor expression in vitro (P = 0.0313). In addition, cytokines downstream of ATP purinergic receptor signalling including IL-β (P < 0.0001), TNFR1 (P = 0.0002), TGF-β (P = 0.002) and VEGF (P = 0.0048), were higher in BAL or plasma of ILD patient samples. These findings suggest eATP–P2 receptor signalling as a potential contributor to inflammation and fibrosis across IPF and PPF, highlighting this pathway as a promising therapeutic target.

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.

Fibrotic interstitial lung diseases (F-ILDs) are increasingly complicated by early-stage non-small cell lung cancer. For many of these patients, stereotactic ablative body radiotherapy (SABR) is the only feasible curative-intent option. However, pre-existing fibrosis markedly increases the risk of severe, sometimes fatal, post-treatment respiratory events. These episodes are usually labelled radiation pneumonitis (RP), yet their timing, distribution and lethality often resemble acute exacerbations (AEs) of the underlying interstitial lung disease (ILD) rather than classical, field-confined RP. In this narrative review, we synthesise observational data from the SABR series enriched for ILD, focusing on acute respiratory deterioration within weeks to months after treatment. We examine how inconsistent terminology and heterogeneous case definitions obscure the distinction between RP and radiation-triggered AE (RT-AE)-ILD, and we summarise clinical, radiological, physiological, dosimetric and biomarker risk factors. Mechanistic models suggest that radiation may amplify a primed fibrotic lung via convergent epithelial, endothelial and immune pathways, with potential modulation by antifibrotic therapy, corticosteroid exposure and infection. We argue that in patients with progressive F-ILD, at least a subset of post-SABR ‘pneumonitis’ episodes are better conceptualised as RT-AE, with implications for corticosteroid stewardship, infection prophylaxis and continuation of antifibrotics. Given the absence of trial-level evidence and the high baseline mortality of F-ILD, management must prioritise multidisciplinary evaluation, explicit shared decision-making and cautious individualisation rather than reflexive transplantation of RP algorithms. Prospective registries, standardised ILD phenotyping and translational studies are urgently needed to define risk boundaries and test whether antifibrotic-radiation strategies or particle therapies can safely deliver curative-intent treatment to this highly vulnerable population.

Total plasma N-glycans alter in disease states, with few studies focused on COVID-19. A discovery cohort of 310 COVID-19 patients, replicated with 97 COVID-19 patients and tested with 100 COVID-19 patients, was used to unearth the N-glycans capable of distinguishing infection, as well as prognosis of intensive care unit (ICU) admission and mortality. All significant bisected glycans were decreased in patients compared to controls, whilst fucosylated tri-antennary glycans and sialylated tetra-antennary glycans were increased in patients. For both those admitted to the ICU and those who died, Peak 61 (A4G4S4F) was elevated in the more severe disease course, while Peak 29 (FA2G2S2) was lowered. Pinpointing specific glycosylation changes has alluded to a potential story of glycoprotein pathways in response to SARS-CoV-2 infection. This study could be further explored through deriving the glycoproteins associated with the glycans of interest and the glycosylation changes experienced on these proteins.

Background: Human respiratory exposure to microplastics (MPs) has recently been demonstrated, but their distribution within thoracic tissues and association with lung malignancy remain poorly characterised. We investigated the presence, burden, morphology, and spectroscopic characteristics of MPs in thoracic tissue specimens and their relationship with lung malignancy. Methods: In this prospective observational study, 50 adults undergoing diagnostic thoracic surgical procedures for suspected lung malignancy were enrolled. Lung, pleural, and mediastinal lymph node specimens underwent contamination-controlled processing, microscopy, and representative particle analysis by confocal micro-Raman spectroscopy. Associations between MPs and clinicopathological variables were analysed. Results: Sixty-two morphologically identified microplastic particles were detected in 50 specimens, with MPs detected in 32 patients (64%). Fragments accounted for 97% of particles, with a median burden of one particle per specimen (IQR, 2). MP detection was significantly more frequent in patients with primary lung malignancy than in patients without primary lung malignancy, including those with metastatic malignancy and benign disease (81.8% vs. 50.0%, p = 0.020), who also exhibited a higher tissue MP burden (p = 0.024). Primary lung malignancy remained independently associated with MP detection after adjustment for age and smoking exposure (OR 4.09, 95% CI 1.06–15.79; p = 0.041). Particle morphology varied by biopsy site, with significantly smaller particles identified in mediastinal lymph nodes (p = 0.006). Synthetic anthropogenic spectral signatures were identified in 71% of particles. Conclusions: MPs are frequently present in human thoracic tissues and are associated with primary lung malignancy. Compartment-specific particle characteristics suggest distinct patterns of respiratory MP deposition and retention, supporting multicentre mechanistic studies.

A 42-year-old woman with a 25 pack-year smoking history, who quit 5 years prior to presentation, was referred to our outpatient clinic for reevaluation of multiple bilateral pulmonary nodules first identified 4 years earlier on chest computed tomography, performed following a self-limited flu-like illness with transient rash and nonproductive cough. Her symptoms resolved without intervention, and she remained clinically stable in the years that followed, with only occasional episodes of dry cough; however, the radiologic findings and her medical history prompted progressive diagnostic workup. Her medical history included non-Hodgkin lymphoma treated with chemotherapy 9 years before referral, with a documented relapse 5 years earlier and no evidence of active disease in the preceding 4 years. She had undergone total thyroidectomy for benign thyroid nodules 8 years before referral and partial nephrectomy for clear cell renal carcinoma 3 years earlier. At the time of referral, she was receiving thyroid hormone replacement therapy and a long-acting beta-agonist/long-acting muscarinic antagonist inhaler prescribed by her general practitioner for intermittent cough. She had no known TB exposure, no significant travel history, and no environmental or domestic risk factors, but reported occupational exposure from prior work in a charcoal grill restaurant. She had no history of aspiration episodes and reported no symptoms suggestive of chronic aspiration or dysphagia. Persistent abnormalities on serial imaging prompted extensive investigation over the years, including 2 surgical biopsies and multiple diagnostic studies, none of which yielded a definitive diagnosis. Despite the persistent radiographic findings, including nodules of varying size and semicalcified appearance, her clinical status remained stable, and no treatment had been initiated. She was ultimately referred to the department of respiratory medicine and admitted for further evaluation.

Background:Digital health technology enables collection of continuous physiological and behavioral data from participants in clinical trials. This supports hybrid trial designs, potentially reducing clinic visits and participant burden for patient monitoring. Interstitial lung disease (ILD) is characterized by an unpredictable clinical course, creating a need for new treatments and more sensitive approaches to assessing treatment effectiveness, disease progression, and clinically meaningful trial end points. Objective:This study aimed to explore the experiences of individuals with ILD using digital tools in a clinical study to inform digital health-enabled clinical research. Methods:This qualitative study was conducted within the PRODIGY-ILD (Predicting Outcomes using Digital Technology in Interstitial Lung Disease) cohort, a prospective observational study using wearable devices and electronic patient-reported outcome measures for a planned 3 years of longitudinal monitoring. Participants were recruited from a specialist outpatient ILD clinic. A topic guide was developed iteratively, and individual semistructured interviews were conducted remotely via Zoom (Zoom Video Communications, Inc) and/or telephone, audio-recorded, and transcribed. Data were analyzed using reflexive thematic analysis with NVivo software (Lumivero). Results:Fifteen of the final 20 participants recruited to the PRODIGY-ILD study consented and completed interviews. Four key themes were identified, highlighting how trust, digital literacy, participant-initiated engagement with data, and illness burden shape sustained participation in digital health-enabled clinical research: (1) trust and altruism override data concerns: confidence in researchers' data handling and a desire to contribute enabled data sharing; (2) navigating digital tools: friction and flexibility: digital literacy, usability, and device compatibility varied, but participants were able to use workarounds to maintain engagement; (3) participant-initiated engagement with wearable data: participants moved from passive to active engagement, in many cases integrating devices into daily routines; and (4) life-limiting illness as a constraint on digital trial participation: managing symptoms and severe comorbidities reduces motivation and engagement with study technology. Conclusions:Despite participants' motivations to contribute data to research, engagement was shaped by usability, participant-initiated engagement, and the constraints of living with chronic illness. There is a need for patient-centered design, tailored support, and flexible trial procedures to optimize adherence in digital health-enabled clinical research.

ACS-like presentations may rarely be the first sign of occult lung cancer. Interval changes on coronary angiography and atypical myocardial imaging should prompt consideration of metastatic cardiac involvement and a multidisciplinary diagnostic approach. https://bit.ly/48XvNLi.

BACKGROUND:Lymphangioleiomyomatosis (LAM) is a rare, slowly progressive neoplasm, predominantly affecting women, characterized by the presence of diffuse cystic lung disease. Its pathogenesis is driven by mutations in tuberous sclerosis complex (TSC) genes leading to mechanistic target of rapamycin (mTOR) pathway activation, with mTOR inhibitors licensed to slow disease progression. Emerging evidence implicates neutrophils in LAM pathogenesis through oestrogen signalling pathways. SUMMARY:Preclinical studies using TSC2 null mouse models demonstrate that oestrogen signalling promotes the expansion of neutrophils from bone marrow and recruitment to tumour sites. Immature myeloid-derived suppressor cells (MDSCs) create an immunosuppressive microenvironment that facilitates LAM tumour growth and metastasis. Neutrophil elastase (NE) is a key mediator, promoting tumour cell growth, migration, and invasion. Tumour burden is reduced in preclinical models on inhibition of NE or depletion of MDSCs. Clinical data validate these mechanisms, with elevation of neutrophil count and neutrophil-lymphocyte ratios (NLRs) correlating with accelerated lung function decline and increased incidence of pneumothorax. Both markers decrease following mTOR inhibitor therapy, suggesting pathway connections. KEY MESSAGES:The role of neutrophils in LAM pathogenesis appears to be mediated through oestrogen signalling pathways. Neutrophil counts and NLR are potential prognostic biomarkers for clinical practice. Potential neutrophil-directed therapies included NE inhibition and agents targeting oestrogen signalling. Further clinical investigation is warranted to translate these mechanistic insights into clinical practice.

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.

A 37-year-old man, who actively smoked with a 15 pack-year history, working in a greenhouse, was referred for evaluation of intermittent, nonpleuritic chest pain without specific characteristics. He reported no dyspnea, weight loss, hemoptysis, or fever. His medical history was unremarkable except for a left spontaneous pneumothorax 3 years earlier that failed to resolve with chest-tube drainage and required surgical bullectomy with apical and pleural biopsy, for which no diagnosis was established despite thorough evaluation. A chest radiograph during the patient's first hospitalization demonstrated a large, left-sided pneumothorax with partial lung collapse (Fig 1A), for which a chest tube was inserted; however, the lung could not be fully reexpanded (Fig 1B). A subsequent chest high-resolution CT scan (Fig 2) revealed bilateral apical pleural thickening and persistent left pneumothorax with subpleural parenchymal collapse. Because of the incomplete expansion, the patient underwent left apical bullectomy and pleurectomy through a limited thoracotomy. He recovered uneventfully and was discharged after a few days. Surgical specimens included an apical cap and visceral pleura. Histologic examination revealed dense pleural and subpleural fibrosis with an abrupt transition to relatively preserved underlying alveolar parenchyma (Fig 3). These findings were interpreted as nonspecific chronic pleuritis, and a definitive diagnosis could not be established at that time. He was not taking any medications, and no occupational exposure was mentioned. There was no family history of interstitial lung disease. The patient was referred to our hospital to investigate and manage his long-standing condition.

A European LAM Registry would enable standardised data collection, support clinical research and facilitate transnational collaboration, establishing an optimal platform for advancing care and developing a coordinated trial network https://bit.ly/4no2xlr.

Background: Pleuroparenchymal fibroelastosis (PPFE) is a rare fibroelastotic lung disease characterized histologically by dense pleural and subpleural fibrosis with upper-lobe predominance. In clinical practice, diagnosis often relies on characteristic radiologic findings, as surgical lung biopsy is rarely feasible. Unlike idiopathic pulmonary fibrosis, robust radiologic criteria validated against biopsy-proven cohorts remain limited, and the diagnostic performance of imaging alone is incompletely defined. Although initially described as idiopathic, PPFE is increasingly recognized in secondary settings, including connective tissue disease-associated interstitial lung disease (CTD-ILD), where it frequently overlaps with more common fibrotic patterns. Methods: We conducted a focused narrative review of the literature on PPFE in CTD-ILD, synthesizing evidence on morphology, epidemiology, clinical course, prognostic implications, and proposed pathobiological mechanisms, with emphasis on distinguishing true PPFE from PPFE-like lesions. Results: CTD-associated PPFE is associated with accelerated lung function decline, increased risk of pneumothorax, and poorer outcomes, particularly in systemic sclerosis and rheumatoid arthritis. However, distinguishing true PPFE from radiologic mimics remains challenging, and diagnostic approaches rely heavily on imaging without robust histopathologic validation. Proposed mechanisms include epithelial injury, immune dysregulation, and vascular or lymphatic abnormalities, although causal links remain unproven. Significant gaps persist regarding natural history and therapeutic responsiveness. Conclusions: Earlier identification of PPFE in CTD-ILD is important, as misclassification may delay risk stratification and management. Longitudinal imaging, multidisciplinary evaluation, and standardized diagnostic criteria are needed to improve clinical care and guide future research.

BACKGROUND:Autoimmune pulmonary alveolar proteinosis (aPAP) is characterised by abnormal alveolar surfactant accumulation and reduced pulmonary gas transfer. Disease severity and progression depend on pulmonary surfactant accumulation, the rate of which varies widely among patients. Currently, whole-lung lavage (WLL) is the most widely accepted therapy. This review addresses the burden of aPAP on patients, caregivers and society. METHODS:MEDLINE and Embase databases were systematically searched for reports on the manifestations, treatment burden, caregiver impact and healthcare costs of aPAP published after 2000. RESULTS:Out of 1023 publications identified, 50 reported relevant data (for 2855 aPAP patients), including 43 observational studies and seven phase 2/3 trials. Commonly reported symptoms included dyspnoea, cough and sputum production. Clinical manifestations included progressive hypoxaemia, reduced exercise capacity, reduced quality of life, and an increased rate of serious infections. Low prevalence and nonspecific signs and symptoms contributed to delayed diagnosis of aPAP, frequent misdiagnoses, use of multiple tests with nondiagnostic results, and therapies that were inappropriate or exacerbated the disease. WLL was the most frequently administered therapy, and many patients required repeat procedures. Medical care costs were higher for PAP patients than for non-PAP control patients. CONCLUSIONS:The results highlight the multifactorial and substantial burden of aPAP on patients. Significant unmet needs remain, particularly in achieving timely and accurate diagnosis and in providing effective, well-tolerated therapies that address the underlying pathophysiology of the disease.