Immune mechanisms in fibrotic interstitial lung disease.

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Association of rare single nucleotide variant MUC5B rs35705950 with interstitial lung disease in Japanese rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is sometimes complicated by interstitial lung disease (ILD) with a poor prognosis. A single nucleotide variant (SNV) in MUC5B was associated with ILD in European RA patients. However, associations of this SNV were not found in Japanese RA patients, because its frequency in Japanese populations is very low. We investigated the associations of candidate SNVs including the MUC5B variant with ILD in Japanese RA. METHODS: Genotyping of MUC5B rs35705950, MUC2 rs7934606, MAD1L1 rs12699415, and PPFIBP2 rs6578890 in Japanese RA patients was conducted for association analyses. RESULTS: MUC5B rs35705950 was associated with usual interstitial pneumonia (UIP) (p = 0.0039, Pc = 0.0156, odds ratio [OR] 10.66, 95% confidence interval [CI] 2.05-55.37) or ILD (p = 0.0071, Pc = 0.0284, OR 7.33, 95%CI 1.52-35.44) in Japanese RA under the allele model. MUC2 rs7934606 was associated with UIP (p = 0.0072, Pc = 0.0288, OR 29.55, 95%CI 1.52-574.57) or ILD (p = 0.0037, Pc = 0.0148, OR 22.95, 95%CI 1.27-416.13) in RA. Haplotype analyses suggested the primary association of MUC5B rs35705950 with UIP in Japanese RA. No significant association of MAD1L1 rs12699415 or PPFIBP2 rs6578890 with UIP, nonspecific interstitial pneumonia, or ILD in RA was observed. CONCLUSIONS: MUC5B rs35705950 is associated with, and might be involved in the pathogenesis of ILD, especially UIP, in Japanese RA.

Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

BACKGROUND: The circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate with the presence of IPF, with the severity of IPF, or with the risk of clinically relevant outcomes among patients with IPF. METHODS: We analyzed enrollment plasma samples from 300 patients with IPF in the IPF-PRO Registry and 100 individuals without known lung disease using a set of targeted metabolomics and clinical analyte modules. Linear regression was used to compare metabolite and clinical analyte levels between patients with IPF and controls and to determine associations between metabolite levels and measures of disease severity in patients with IPF. Unadjusted and adjusted univariable Cox regression models were used to evaluate associations between circulating metabolites and the risk of mortality or disease progression among patients with IPF. RESULTS: Levels of 64 metabolites and 5 clinical analytes were significantly different between patients with IPF and controls. Among analytes with greatest differences were non-esterified fatty acids, multiple long-chain acylcarnitines, and select ceramides, levels of which were higher among patients with IPF versus controls. Levels of the branched-chain amino acids valine and leucine/isoleucine were inversely correlated with measures of disease severity. After adjusting for clinical factors known to influence outcomes, higher levels of the acylcarnitine C:16-OH/C:14-DC were associated with all-cause mortality, lower levels of the acylcarnitine C16:1-OH/C14:1DC were associated with all-cause mortality, respiratory death, and respiratory death or lung transplant, and higher levels of the sphingomyelin d43:2 were associated with the risk of respiratory death or lung transplantation. CONCLUSIONS: IPF has a distinct circulating metabolic profile characterized by increased levels of non-esterified fatty acids, long-chain acylcarnitines, and ceramides, which may suggest a more catabolic environment that enhances lipid mobilization and metabolism. We identified select metabolites that were highly correlated with measures of disease severity or the risk of disease progression and that may be developed further as biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov; No: NCT01915511; URL: www. CLINICALTRIALS: gov .

Identification of kynurenine and quinolinic acid as promising serum biomarkers for drug-induced interstitial lung diseases.

BACKGROUND: Drug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need. METHODS: Biomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls. RESULTS: Serum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients. CONCLUSIONS: The serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.

Utility of the 52-Gene Risk Score to Identify Patients with Idiopathic Pulmonary Fibrosis at Greater Risk of Mortality in the Era of Antifibrotic Therapy.

PURPOSE: We investigated whether a 52-gene signature was associated with transplant-free survival and other clinically meaningful outcomes in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry, which enrolled patients who were and were not taking antifibrotic therapy. METHODS: The 52-gene risk signature was implemented to classify patients as being at "high risk" or "low risk" of disease progression and mortality. Transplant-free survival and other outcomes were compared between patients with a low-risk versus high-risk signature. RESULTS: The 52-gene signature classified 159 patients as at low risk and 86 as at high risk; in these groups, respectively, 56.6% and 51.2% used antifibrotic therapy at enrollment. Among those taking antifibrotic therapy, patients with a low-risk versus high-risk signature were at decreased risk of death, a composite of lung transplant or death, and a composite of decline in DLco % predicted > 15%, lung transplant, or death. Similar results were observed in the overall cohort. CONCLUSIONS: These data suggest that the 52-gene signature can be used in patients with IPF treated with antifibrotic therapy to distinguish patients at higher risk of disease progression and mortality.

Progress in the Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease.

Pulmonary hypertension, frequently complicating the course of patients with fibrotic interstitial lung disease, is associated with significantly increased morbidity and mortality. The availability of multiple medications to treat pulmonary arterial hypertension has resulted in these agents being used beyond their original indication, including in patients with interstitial lung disease. Whether pulmonary hypertension in the context of interstitial lung disease is an adaptive response not to be treated or a maladaptive phenomenon amenable to therapy has been uncertain. Although some studies have suggested a benefit of treatment, there have been others demonstrating harm. This concise clinical review provides an overview of prior studies and the issues that have plagued drug development for a patient population in dire need of treatment options. More recently, there has been a paradigm shift, with the largest study to date demonstrating benefit, resulting in the first approved therapy in the United States for patients with interstitial lung disease complicated by pulmonary hypertension. A pragmatic management algorithm in the context of changing definitions, comorbid contributors, and an available treatment option is provided, as are considerations for future clinical trials.

Comprehensive Analysis of Fibroblast Activation Protein Expression in Interstitial Lung Diseases.

Rationale: Sustained activation of lung fibroblasts and the resulting oversynthesis of the extracellular matrix are detrimental events for patients with interstitial lung diseases (ILDs). Lung biopsy is a primary evaluation technique for the fibrotic status of ILDs, and is also a major risk factor for triggering acute deterioration. Fibroblast activation protein (FAP) is a long-known surface biomarker of activated fibroblasts, but its expression pattern and diagnostic implications in ILDs are poorly defined. Objectives: The present study aims to comprehensively investigate whether the expression intensity of FAP could be used as a potential readout to estimate or measure the amounts of activated fibroblasts in ILD lungs quantitatively. Methods: FAP expression in human primary lung fibroblasts as well as in clinical lung specimens was first tested using multiple experimental methods, including real-time quantitative PCR (qPCR), Western blot, immunofluorescence staining, deep learning measurement of whole slide immunohistochemistry, as well as single-cell sequencing. In addition, FAP-targeted positron emission tomography/computed tomography imaging PET/CT was applied to various types of patients with ILD, and the correlation between the uptake of FAP tracer and pulmonary function parameters was analyzed. Measurements and Main Results: Here, it was revealed, for the first time, FAP expression was upregulated significantly in the early phase of lung fibroblast activation event in response to a low dose of profibrotic cytokine. Single-cell sequencing data further indicate that nearly all FAP-positive cells in ILD lungs were collagen-producing fibroblasts. Immunohistochemical analysis validated that FAP expression level was closely correlated with the abundance of fibroblastic foci on human lung biopsy sections from patients with ILDs. We found that the total standard uptake value (SUV) of FAP inhibitor (FAPI) PET (SUVtotal) was significantly related to lung function decline in patients with ILD. Conclusions: Our results strongly support that in vitro and in vivo detection of FAP can assess the profibrotic activity of ILDs, which may aid in early diagnosis and the selection of an appropriate therapeutic window.

Evaluation of progressive pulmonary fibrosis in non-idiopathic pulmonary fibrosis-interstitial lung diseases: a cross-sectional study.

BACKGROUND: Progressive pulmonary fibrosis is the symptomatic, physiological, and radiological progression of interstitial lung diseases. The aim of this study was to examine the relationship between progressive pulmonary fibrosis and demographic characteristics and to evaluate the effect on clinical outcomes and mortality. METHODS: This cross-sectional study included 221 patients diagnosed with non-idiopathic pulmonary fibrosis interstitial lung diseases who were followed in the last 5 years. Patient symptoms, clinical, radiological, and demographic data were examined. Risk factors for the development of progressive pulmonary fibrosis and the relationship with clinical outcomes and mortality were examined. RESULTS: Of the patients, 33.0% (n = 73) had fibrotic idiopathic nonspecific interstitial pneumonia (iNSIP), 35.7% (n = 79) had fibrotic hypersensitivity pneumonia (HP), 18.1% (n = 40) had fibrotic connective tissue disease (CTD) interstitial lung diseases (ILD), and 13.1% (n = 29) had postinfectious fibrotic ILD. The progressive pulmonary fibrosis development rates of the subtypes were 46.5% iNSIP (n = 34), 86.0% fibrotic HP (n = 68), 42.5% fibrotic CTD-ILD (n = 17), and 20.7% postinfectious ILD (n = 6). The presence of progressive pulmonary fibrosis was associated with the development of respiratory failure and mortality (odds ratio [OR]: 2.70, 95% CI: 1.04-7.05 and OR: 2.13, 95% CI: 1.23-3.69). Progressive pulmonary fibrosis development was higher in hypersensitivity pneumonia patients with farmer's lung (OR: 5.06, 95% CI: 1.02-25.18). CONCLUSION: Progressive pulmonary fibrosis was more prevalent in older patients. Farming was an important risk factor in the development of hypersensitivity pneumonia-progressive pulmonary fibrosis. Respiratory failure and mortality were higher in those who developed progressive pulmonary fibrosis.

Value of bronchoalveolar lavage fluid metagenomic next-generation sequencing in acute exacerbation of fibrosing interstitial lung disease: an individualized treatment protocol based on microbiological evidence.

BACKGROUND: Acute exacerbation of fibrosing interstitial lung diseases (AE-ILD) is a serious life-threatening event per year. Methylprednisolone and/or immunosuppressive agents (ISA) are a mainstay in any regimen, under the premise that pulmonary infection has been promptly identified and controlled. We investigated the value of bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) on the treatment adjustment of AE-ILD. METHODS: We conducted a cross-sectional observational study. All data were collected prospectively and retrospectively analyzed. We included fifty-six patients with AE-ILD and nineteen stable ILD who underwent BALF mNGS at the beginning of admission. RESULTS: Patients with a variety of ILD classification were included. Connective-tissue disease related ILD (CTD-ILD) occupy the most common underlying non-idiopathic pulmonary fibrosis (non-IPF). The infection-triggered AE accounted for 39.29%, with the majority of cases being mixed infections. The microorganisms load in the AE-ILD group was significantly higher. After adjusted by mNGS, the therapy coverage number of pathogens was significantly higher compared to the initial treatment (p < 0.001). After treatment, the GGO score and the consolidation score were significantly lower during follow up in survivors (1.57 ± 0.53 vs. 2.38 ± 0.83 with p < 0.001, 1.11 ± 0.24 vs. 1.49 ± 0.47 with p < 0.001, respectively). Some detected microorganisms, such as Tropheryma whipplei, Mycobacterium, Aspergillus, and mixed infections were difficult to be fully covered by empirical medication. BALF mNGS was also very helpful for excluding infections and early administration of methylprednisolone and/or ISA. CONCLUSIONS: mNGS has been shown to be a useful tool to determine pathogens in patients with AE-ILD, the results should be fully analyzed. The comprehensive treatment protocol based on mNGS has been shown crucial in AE-ILD patients.

Integrating palliative care education in pulmonary rehabilitation: a randomized controlled study protocol.

BACKGROUND: Palliative care addresses multiple unmet needs of people with chronic obstructive pulmonary disease (COPD) or interstitial lung diseases (ILD) and their family and/or friend caregivers, but it remains highly underused. Pulmonary rehabilitation (PR) may provide a key opportunity to introduce palliative care. We aim to explore the effects of palliative care education as part of PR on knowledge about this field in people with COPD or ILD and their family and/or friend caregivers. METHODS: A randomized controlled study will compare PR with palliative care education (experimental) with traditional PR (control) in people with COPD or ILD and their family and/or friend caregivers. Family and/or friend caregivers will be invited to take part in education and psychosocial support sessions. In addition to the usual educational content, the experimental group will have a session on palliative care, a "Peer-to-peer session", two "Get-apart sessions" and online sessions. The "Peer-to-peer session" and the "Get-apart sessions" will be discussions about topics suggested by participants. The "Get-apart sessions" will be dedicated to people with COPD or ILD apart from their family and/or friend caregivers and vice versa. The online sessions will be zoom meetings to discuss any health-related issues raised by participants, at a flexible time. A mixed-methods approach will be used to evaluate the outcomes. The primary outcome will be knowledge about palliative care. Secondary outcomes will include attitude towards palliative care referral, symptoms, disease impact, health-related quality of life, needs, knowledge about the disease, burden of providing care, adherence, adverse events and referral to a specialist palliative care team. Quantitative and qualitative data will be collected at baseline and end of PR. At 6-months post-PR, only patient-reported outcomes will be collected. For the primary outcome, time*group interaction will be analyzed with mixed analysis of variance. DISCUSSION: This study aims to demonstrate the impact of integrating palliative care into the PR education program. TRIAL REGISTRATION: The trial was registered in the ClinicalTrials.gov U.S. National Library of Medicine, on 1st September, 2023 (NCT06046547).

Baricitinib and Pulse Steroids Combination Treatment in Hyperinflammatory COVID-19: A Rheumatological Approach in the Intensive Care Unit.

Hyperinflammatory Coronavirus disease 2019 (COVID-19) and rapidly-progressive interstitial lung diseases (RP-ILD) secondary to inflammatory myopathies (IIM) present important similarities. These data support the use of anti-rheumatic drugs for the treatment of COVID-19. The aim of this study was to compare the efficacy of combining baricitinib and pulse steroids with the Standard of Care (SoC) for the treatment of critically ill COVID-19 patients. We retrospectively enrolled consecutive patients admitted to the Intensive Care Unit (ICU) with COVID-19-pneumonia. Patients treated with SoC (dexamethasone plus remdesivir) were compared to patients treated with baricitinib plus 6-methylprednisolone pulses (Rheuma-group). We enrolled 246 patients: 104/246 in the SoC and 142/246 in the Rheuma-group. All patients presented laboratory findings suggestive of hyperinflammatory response. Sixty-four patients (26.1%) died during ICU hospitalization. The mortality rate in the Rheuma-group was significantly lower than in the SoC-group (15.5 vs. 40.4%, p < 0.001). Compared to the SoC-group, patients in the Rheuma-group presented significantly lower inflammatory biomarker levels after one week of treatment. Higher ferritin levels after one week of treatment were strongly associated with mortality (p < 0.001). In this large real-life COVID-19 cohort, baricitinib and pulse steroids led to a significant reduction in mortality, paralleled by a prompt reduction in inflammatory biomarkers. Our experience supports the similarities between hyperinflammatory COVID-19 and the IIM-associated RP-ILD.

[Idiopathic inflammatory myopathies : An interdisciplinary challenge]. / Idiopathische inflammatorische Myopathien : Eine interdisziplinäre Herausforderung.

Idiopathic inflammatory myopathies (IIM) are rare diseases (incidence 1:100,000) with a wide range of clinical symptoms and manifestations. Typical indicators of IIM are proximally emphasized muscle weakness and myalgias, which are usually accompanied by elevated creatine kinase levels and muscle atrophy. The autoantibody diagnostics separate IIM into different entities, which are each associated with a typical risk of organ manifestations and the occurrence of tumors. The IIM represents an interdisciplinary challenge and the diagnostics and treatment require the involvement of several disciplines including rheumatology, neurology, neuropathology, dermatology and pneumology. An accurate diagnosis and careful tumor screening are essential because of the association between certain subgroups of IIM and the occurrence of malignant tumors.

Clinical implications of frailty assessed in hospitalized patients with acute-exacerbation of interstitial lung disease.

BACKGROUND: Approximately 50% of patients with interstitial lung disease (ILD) experience frailty, which remains unexplored in acute exacerbations of ILD (AE-ILD). A better understanding may help with prognostication and resource planning. We evaluated the association of frailty with clinical characteristics, physical function, hospital outcomes, and post-AE-ILD recovery. METHODS: Retrospective cohort study of AE-ILD patients (01/2015-10/2019) with frailty (proportion ≥0.25) on a 30-item cumulative-deficits index. Frail and non-frail patients were compared for pre- and post-hospitalization clinical characteristics, adjusted for age, sex, and ILD diagnosis. One-year mortality, considering transplantation as a competing risk, was analysed adjusting for age, frailty, and Charlson Comorbidity Index (CCI). RESULTS: 89 AE-ILD patients were admitted (median: 67 years, 63% idiopathic pulmonary fibrosis). 31 were frail, which was associated with older age, greater CCI, lower 6-min walk distance, and decreased independence pre-hospitalization. Frail patients had more major complications (32% vs 10%, p = .01) and required more multidisciplinary support during hospitalization. Frailty was not associated with 1-year mortality (HR: 0.97, 95%CI: [0.45-2.10]) factoring transplantation as a competing risk. CONCLUSIONS: Frailty was associated with reduced exercise capacity, increased comorbidities and hospital complications. Identifying frailty may highlight those requiring additional multidisciplinary support, but further study is needed to explore whether frailty is modifiable with AE-ILD.

[Pulmonary fibrosis after a new coronavirus infection - versions and controversies: A review].

Fibrosis is a dynamic process characterized by a typical cascade of events as a result of overexpressed repair of connective tissue in response to injury, and manifested by excessive accumulation of extracellular matrix. The development of fibrosis is a determining factor in the pathogenesis, clinical course and prognosis of many diseases, among which interstitial lung diseases occupy a special place. According to a large Russian registry (ClinicalTrials.gov: NCT04492384), in a third of patients with COVID-19, the volume of lung parenchyma involvement exceeds 50% (CT 3-4). The rapid growth in the number of patients who have had a coronavirus infection with lung damage has raised the issues of its long-term consequences to the number of the most relevant in internal medicine of the current time. Often, in the outcome of a coronavirus infection, patients retain clinical and functional changes that are similar to interstitial lung diseases of a different origin, the prognosis of which is determined by the development of interstitial fibrosis and the rate of its progression. This article is an attempt to consider topical issues of fibrogenesis in patients who have undergone a new coronavirus infection through the prism of polar data on immunobiology, clinical course and prognosis.

Investigating the role of platelets and platelet-derived transforming growth factor-ß in idiopathic pulmonary fibrosis.

Transforming growth factor-ß1 (TGFß1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFß1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFß1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGFß1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFß1 in megakaryocytes and platelets (TGFß1fl/fl.PF4-Cre) were used in the well-characterized bleomycin-induced pulmonary fibrosis (PF) animal model. In a discovery cohort, we found significantly higher mortality in patients with IPF who had elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGFß1, and CCL5, a chemokine produced by inflammatory cells, in the blood, lung, and bronchoalveolar lavage (BAL) of patients with IPF. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation nor fibrosis was significantly different between TGFß1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first time that platelet-derived TGFß1 does not significantly mediate inflammation or fibrosis in a PF animal model. Furthermore, our human studies revealed blood platelet counts do not consistently predict mortality in IPF but other platelet-derived mediators, such as C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.NEW & NOTEWORTHY Platelets are a rich source of profibrotic TGFß; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFß in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFß does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.

Respiratory Comorbidities Associated with Bronchiectasis in Patients with Common Variable Immunodeficiency in the USIDNET Registry.

BACKGROUND: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development. OBJECTIVE: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID. METHODS: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis. RESULTS: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population. CONCLUSION: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication.

Walking the path of treatable traits in interstitial lung diseases.

Interstitial lung diseases (ILDs) are complex and heterogeneous diseases. The use of traditional diagnostic classification in ILD can lead to suboptimal management, which is worsened by not considering the molecular pathways, biological complexity, and disease phenotypes. The identification of specific "treatable traits" in ILDs, which are clinically relevant and modifiable disease characteristics, may improve patient's outcomes. Treatable traits in ILDs may be classified into four different domains (pulmonary, aetiological, comorbidities, and lifestyle), which will facilitate identification of related assessment tools, treatment options, and expected benefits. A multidisciplinary care team model is a potential way to implement a "treatable traits" strategy into clinical practice with the aim of improving patients' outcomes. Multidisciplinary models of care, international registries, and the use of artificial intelligence may facilitate the implementation of the "treatable traits" approach into clinical practice. Prospective studies are needed to test potential therapies for a variety of treatable traits to further advance care of patients with ILD.

Differentiating interstitial lung diseases from other respiratory diseases using electronic nose technology.

INTRODUCTION: Interstitial lung disease (ILD) may be difficult to distinguish from other respiratory diseases due to overlapping clinical presentation. Recognition of ILD is often late, causing delay which has been associated with worse clinical outcome. Electronic nose (eNose) sensor technology profiles volatile organic compounds in exhaled breath and has potential to detect ILD non-invasively. We assessed the accuracy of differentiating breath profiles of patients with ILD from patients with asthma, chronic obstructive pulmonary disease (COPD), and lung cancer using eNose technology. METHODS: Patients with ILD, asthma, COPD, and lung cancer, regardless of stage or treatment, were included in a cross-sectional study in two hospitals. Exhaled breath was analysed using an eNose (SpiroNose) and clinical data were collected. Datasets were split in training and test sets for independent validation of the model. Data were analyzed with partial least squares discriminant and receiver operating characteristic analyses. RESULTS: 161 patients with ILD and 161 patients with asthma (n = 65), COPD (n = 50) or lung cancer (n = 46) were included. Breath profiles of patients with ILD differed from all other diseases with an area under the curve (AUC) of 0.99 (95% CI 0.97-1.00) in the test set. Moreover, breath profiles of patients with ILD could be accurately distinguished from the individual diseases with an AUC of 1.00 (95% CI 1.00-1.00) for asthma, AUC of 0.96 (95% CI 0.90-1.00) for COPD, and AUC of 0.98 (95% CI 0.94-1.00) for lung cancer in test sets. Results were similar after excluding patients who never smoked. CONCLUSIONS: Exhaled breath of patients with ILD can be distinguished accurately from patients with other respiratory diseases using eNose technology. eNose has high potential as an easily accessible point-of-care medical test for identification of ILD amongst patients with respiratory symptoms, and could possibly facilitate earlier referral and diagnosis of patients suspected of ILD.

Pulmonary fibrosis treatment in children - What have we learnt from studies in adults?

Pulmonary fibrosis (PF) in children is a rare complication of specific forms of childhood interstitial lung diseases (chILD) with extremely limited scientific evidence to guide optimal management. Whilst there continues to be significant progress in PF management for adult populations, paediatric guidelines have stagnated. New anti-fibrotic medications (nintedanib and pirfenidone) are finding regular use amongst adult PF patients but remain largely unstudied and untested in children. Although there are major differences between the two age-group populations, it is useful to learn from the evolution of adult PF management, especially in the absence of dedicated paediatric studies. Whilst there have been recent trials aimed at assessing the safety and efficacy of drugs such as nintedanib and hydroxychloroquine, there is still a dire need for more research aimed at further assessing current treatment practices and evaluating the safety and efficacy of new emerging treatments in the paediatric population.