585 results found
Maher TM, 2021, Targeting Human Herpesviruses: An Effective Strategy for Treating Idiopathic Pulmonary Fibrosis?, ANNALS OF THE AMERICAN THORACIC SOCIETY, Vol: 18, Pages: 1285-1286, ISSN: 1546-3222
Stewart ID, Nanji H, Figueredo G, et al., 2021, Circulating fibrocytes are not disease-specific prognosticators in idiopathic pulmonary fibrosis, European Respiratory Journal, Vol: 58, ISSN: 0903-1936
OBJECTIVE: Circulating fibrocytes are elevated in idiopathic pulmonary fibrosis, but the relationship between fibrocyte level with lung function decline and outcomes is lacking replication in prospective clinical study. We aim to validate the utility of circulating fibrocyte levels as a prognostic biomarker in idiopathic pulmonary fibrosis. METHODS: We tested associations between circulating fibrocyte levels, mortality, disease progression and longitudinal lung function in a well-defined prospective observational study of pulmonary fibrosis (PROFILE; NCT01134822). A subset of recruited participants had blood samples processed for fibrocyte measurement, with flow cytometry based on CD45 and collagen-I gating. Associations were tested using univariable and multivariable generalised linear models. Mortality data were subsequently combined with an independent cohort in a mixed-effect multilevel analysis. RESULTS: In 102 participants with idiopathic pulmonary fibrosis, a previously defined mortality risk threshold of 5% circulating fibrocytes was not reproducible. An empirically defined cutpoint of 2.22% was associated with a greater risk of overall mortality in adjusted analysis (Hazard Ratio 2.24 95% CI 1.06-4.72). A 2.5 fold greater risk of mortality was supported in a pooled analysis with a historic cohort for a larger sample of 162 participants with idiopathic pulmonary fibrosis (Hazard Ratio 2.49 95% CI 2.41-2.56). We found no association of fibrocytes with lung function or disease progression. CONCLUSIONS: In a large sample of circulating fibrocytes from people with idiopathic pulmonary fibrosis, levels of 2.22% or above were associated with greater mortality, but not with disease related decline in lung function.
McErlean P, Bell CG, Hewitt RJ, et al., 2021, DNA Methylome Alterations are Associated with Airway Macrophage Differentiation and Phenotype During Lung Fibrosis., Am J Respir Crit Care Med
RATIONALE: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge of epigenetics of AMs in IPF are limited. METHODS: We undertook DNA methylation profiling using Illumina EPIC (850k) arrays in sorted AMs from Healthy (n=14) and IPF (n=30) donors. Cell-type deconvolution was performed using reference myeloid-cell DNA methylomes. MEASUREMENTS AND MAIN RESULTS: Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF-AMs. DNAm 'clock' analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKFB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. CONCLUSIONS: Collectively, our data identify that changes in the epigenome are associated with development and function of AMs in the IPF lung.
Aronson K, Danoff SK, Russell A-M, et al., 2021, Patient-centered Outcomes Research in Interstitial Lung Disease An Official American Thoracic Society Research Statement, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 204, Pages: E3-E23, ISSN: 1073-449X
Porter JC, Win T, Erlandsson K, et al., 2021, Measurement of hypoxia in the lung in IPF: an F-MISO PET CT study, European Respiratory Journal, ISSN: 0903-1936
Maher TM, Bendstrup E, Dron L, et al., 2021, Global incidence and prevalence of idiopathic pulmonary fibrosis, RESPIRATORY RESEARCH, Vol: 22
Maher TM, Brown KK, Kreuter M, et al., 2021, Effects of nintedanib by inclusion criteria for progression of interstitial lung disease, European Respiratory Journal, ISSN: 0903-1936
The INBUILD trial investigated nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs). We investigated decline in forced vital capacity (FVC) in subgroups based on the inclusion criteria for ILD progression.Subjects had a fibrosing ILD other than idiopathic pulmonary fibrosis and met these criteria for ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice: Group A, relative decline in FVC ≥10% predicted; Group B, relative decline in FVC ≥5-<10% predicted with worsened respiratory symptoms and/or increased extent of fibrosis on HRCT; Group C, worsened respiratory symptoms and increased extent of fibrosis on HRCT only.In the placebo group, the rates of FVC decline over 52 weeks in Groups A, B and C, respectively, were -241.9, -133.1 and -115.3 mL·year-1 in the overall population (p=0.0002 for subgroup-by-time interaction) and -288.9, -156.2 and -100.1 mL·year-1 among subjects with a usual interstitial pneumonia [UIP]-like fibrotic pattern on HRCT (p=0.0005 for subgroup-by-time interaction). Nintedanib had a greater absolute effect on reducing the rate of FVC decline in Group A than Group B or C. However, the relative effect of nintedanib versus placebo was consistent across the subgroups (p>0.05 for heterogeneity).In conclusion, the inclusion criteria used in the INBUILD trial, based on FVC decline or worsening of symptoms and extent of fibrosis on HRCT, were effective at identifying patients with progressive fibrosing ILDs. Nintedanib reduced the rate of decline in FVC across the subgroups based on the inclusion criteria related to ILD progression.
Juan Guardela BM, Sun J, Zhang T, et al., 2021, 50-gene risk profiles in peripheral blood predict COVID-19 outcomes: A retrospective, multicenter cohort study, EBioMedicine, Vol: 69, ISSN: 2352-3964
BACKGROUND: COVID-19 has been associated with Interstitial Lung Disease features. The immune transcriptomic overlap between Idiopathic Pulmonary Fibrosis (IPF) and COVID-19 has not been investigated. METHODS: we analyzed blood transcript levels of 50 genes known to predict IPF mortality in three COVID-19 and two IPF cohorts. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was applied to distinguish high versus low-risk profiles in all cohorts. SAMS cutoffs derived from the COVID-19 Discovery cohort were used to predict intensive care unit (ICU) status, need for mechanical ventilation, and in-hospital mortality in the COVID-19 Validation cohort. A COVID-19 Single-cell RNA-sequencing cohort was used to identify the cellular sources of the 50-gene risk profiles. The same COVID-19 SAMS cutoffs were used to predict mortality in the IPF cohorts. FINDINGS: 50-gene risk profiles discriminated severe from mild COVID-19 in the Discovery cohort (P = 0·015) and predicted ICU admission, need for mechanical ventilation, and in-hospital mortality (AUC: 0·77, 0·75, and 0·74, respectively, P < 0·001) in the COVID-19 Validation cohort. In COVID-19, 50-gene expressing cells with a high-risk profile included monocytes, dendritic cells, and neutrophils, while low-risk profile-expressing cells included CD4+, CD8+ T lymphocytes, IgG producing plasmablasts, B cells, NK, and gamma/delta T cells. Same COVID-19 SAMS cutoffs were also predictive of mortality in the University of Chicago (HR:5·26, 95%CI:1·81-15·27, P = 0·0013) and Imperial College of London (HR:4·31, 95%CI:1·81-10·23, P = 0·0016) IPF cohorts. INTERPRETATION: 50-gene risk profiles in peripheral blood predict COVID-19 and IPF outcomes. The cellular sources of these gene expression changes suggest common innate and adaptive immune responses in both diseases.
Kreuter M, Lee JS, Tzouvelekis A, et al., 2021, Monocyte count as a prognostic biomarker in patients with idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 74-81, ISSN: 1073-449X
Rationale: There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. Objectives: We used pooled data from pirfenidone and interferon gamma-1b trials to explore the association between monocyte count and prognosis in patients with IPF. Methods: This retrospective pooled analysis included patients (active and placebo arms) from four Phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in percent predicted forced vital capacity, ≥50 m decline in 6-minute walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models. Measurements and Main Results: This analysis included 2067 patients stratified by monocyte count (at baseline: <0.60 GI/L [n=1609], 0.60–<0.95 GI/L [n=408], and ≥0.95 GI/L [n=50]). In adjusted analyses, a higher proportion of patients with monocyte counts of 0.60–<0.95 GI/L or ≥0.95 GI/L versus <0.60 GI/L experienced IPF progression (p=0.016 and p=0.002, respectively), all-cause hospitalization (p=0.030 and p=0.003, respectively), and all cause mortality (p=0.005 and p<0.001, respectively) over 1 year. Change in monocyte count from baseline was not associated with any of the outcomes over 1 year and did not appear to be affected by study treatment. Conclusions: In patients with IPF, elevated monocyte count was associated with increased risks of IPF progression, hospitalization, and mortality. Monocyte count may provide a simple and inexpensive prognostic biomarker in IPF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (h
Wilson AM, Clark AB, Cahn A, et al., 2021, Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT, Efficacy and Mechanism Evaluation, Vol: 8, Pages: 1-110, ISSN: 2050-4365
<jats:sec id="abs1-1"> <jats:title>Background</jats:title> <jats:p>Idiopathic pulmonary fibrosis is an irreversible fibrosing lung disorder with a poor prognosis. Current treatments slow the rate of decline in lung function and may influence survival, but they have a significant side-effect profile and so additional therapeutic options are required. People with idiopathic pulmonary fibrosis have altered innate immunity and altered lung microbiota, with the bacterial burden relating to mortality. Two randomised controlled trials have demonstrated beneficial effects with co-trimoxazole (SEPTRIN<jats:sup>®</jats:sup>; Essential Generics Ltd, Egham, UK; Chemidex Generics Ltd, Egham, UK), with the suggestion of an improvement in rates of survival.</jats:p> </jats:sec> <jats:sec id="abs1-2"> <jats:title>Objectives</jats:title> <jats:p>To determine the clinical efficacy of co-trimoxazole in people with moderate to severe idiopathic pulmonary fibrosis.</jats:p> </jats:sec> <jats:sec id="abs1-3"> <jats:title>Design</jats:title> <jats:p>A Phase II, double-blind, placebo-controlled, parallel-group, randomised multicentre study.</jats:p> </jats:sec> <jats:sec id="abs1-4"> <jats:title>Setting</jats:title> <jats:p>UK specialist interstitial lung disease centres.</jats:p> </jats:sec> <jats:sec id="abs1-5"> <jats:title>Participants</jats:title> <jats:p>Patients who were randomised had idiopathic pulmonary fibrosis diagnosed by a multidisciplinary team. In addition, patients h
Trachalaki A, Tsitoura E, Mastrodimou S, et al., 2021, Enhanced IL-1β Release Following NLRP3 and AIM2 Inflammasome Stimulation Is Linked to mtROS in Airway Macrophages in Pulmonary Fibrosis, Frontiers in Immunology, Vol: 12, ISSN: 1664-3224
Fibrotic Interstitial lung diseases (ILDs) are complex disorders of variable clinical behaviour. The majority of them cause significant morbidity, whilst Idiopathic Pulmonary Fibrosis (IPF) is recognised as the most relentless. NLRP3, AIM2, and NLRC4 inflammasomes are multiprotein complexes driving IL-1β release; a proinflammatory and profibrotic cytokine. Several pathogenetic factors associated with IPF are identified as inflammasome activators, including increases in mtROS and bacterial burden. Mitochondrial oxidation and alterations in bacterial burden in IPF and other ILDs may lead to augmented inflammasome activity in airway macrophages (AMs). IPF (n=14), non-IPF-ILDs (n=12) patients and healthy subjects (n=12) were prospectively recruited and AMs were isolated from bronchoalveolar lavage. IL-1β release resulting from NLRP3, AIM2 and NLRC4 inflammasomes stimulation in AMs were determined and baseline levels of mitochondrial ROS and microbial burden were also measured. Our results showed that NLRP3 was more inducible in IPF and other ILDs compared to controls. Additionally, following AIM2 activation IL-1β release was significantly higher in IPF compared to controls, whereas similar trends were observed in Non-IPF-ILDs. NLRC4 activation was similar across groups. mtROS was significantly associated with heightened NLRP3 and AIM2 activation, and mitochondrial antioxidant treatment limited inflammasome activation. Importantly, microbial burden was linked to baseline IL-1β release and AIM2 and IL-18 relative expression independently of mtROS. In conclusion, the above findings suggested a link between the overactivation of NLRP3 and AIM2 inflammasomes, driven by mitochondrial oxidation, in the pathogenesis of lung fibrosis while changes in the microbiota may prime the inflammasome in the lungs.
Maher TM, Mayes MD, Stock C, et al., 2021, Effect of nintedanib on lung function in patients with systemic sclerosis-associated interstitial lung disease: further analyses of a randomized, double-blind, placebo-controlled trial., Arthritis Rheumatol
Following the publication of further analyses of the effects of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the SENSCIS trial (1), Dr Bredemeier queried whether the occurrence of gastrointestinal adverse events in subjects treated with nintedanib may have reduced the effectiveness of masking and so introduced bias (2).
Nolan CM, Patel S, Barker RE, et al., 2021, Muscle stimulation in advanced idiopathic pulmonary fibrosis: a randomised placebo-controlled feasibility study., BMJ Open, Vol: 11, Pages: 1-11, ISSN: 2044-6055
OBJECTIVES: To assess the acceptability of neuromuscular electrical stimulation (NMES) of the quadriceps muscles in people with idiopathic pulmonary fibrosis (IPF) and to identify whether a future definitive trial is feasible. DESIGN: A randomised, parallel, two-group, participant and assessor-blinded, placebo-controlled feasibility trial with embedded qualitative interviews. SETTING: Outpatient department, Royal Brompton and Harefield Hospitals. PARTICIPANTS: Twenty-two people with IPF: median (25th, 75th centiles) age 76 (74, 82) years, forced vital capacity 62 (50, 75) % predicted, 6 min walk test distance 289 (149, 360) m. INTERVENTIONS: Usual care (home-based exercise, weekly telephone support, breathlessness management leaflet) with either placebo or active NMES for 6 weeks, with follow-up at 6 and 12 weeks. PRIMARY OUTCOME MEASURES: Feasibility of recruitment and retention, treatment uptake and adherence, outcome assessments, participant and outcome assessor blinding and adverse events related to interventions. SECONDARY OUTCOME MEASURES: Outcome measures with potential to be primary or secondary outcomes in a definitive clinical trial. In addition, purposively sampled participants were interviewed to capture their experiences and acceptability of the trial. RESULTS: Out of 364 people screened, 23 were recruited: 11 were allocated to each group and one was withdrawn prior to randomisation. Compared with the control group, a greater proportion of the intervention group completed the intervention, remained in the trial blinded to group allocation and experienced intervention-related adverse events. Assessor blinding was maintained. The secondary outcome measures were feasible with most missing data associated with the accelerometer. Small participant numbers precluded identification of an outcome measure suitable for a definitive trial. Qualitative findings demonstrated that trial process and active NMES were acceptable but there were concerns abo
Spagnolo P, Kropski JA, Jones MG, et al., 2021, Idiopathic pulmonary fibrosis: Disease mechanisms and drug development, Pharmacology and Therapeutics, Vol: 222, Pages: 107798-107798, ISSN: 0163-7258
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown cause characterized by relentless scarring of the lung parenchyma leading to reduced quality of life and earlier mortality. IPF is an age-related disorder, and with the population aging worldwide, the economic burden of IPF is expected to steadily increase in the future. The mechanisms of fibrosis in IPF remain elusive, with favored concepts of disease pathogenesis involving recurrent microinjuries to a genetically predisposed alveolar epithelium, followed by an aberrant reparative response characterized by excessive collagen deposition. Pirfenidone and nintedanib are approved for treatment of IPF based on their ability to slow functional decline and disease progression; however, they do not offer a cure and are associated with tolerability issues. In this review, we critically discuss how cutting-edge research in disease pathogenesis may translate into identification of new therapeutic targets, thus facilitate drug discovery. There is a growing portfolio of treatment options for IPF. However, targeting the multitude of profibrotic cytokines and growth factors involved in disease pathogenesis may require a combination of therapeutic strategies with different mechanisms of action.
Denton C, Goh N, Humphries SM, et al., 2021, Associations Between Extent of Fibrotic Interstitial Lung Disease (ILD) and Forced Vital Capacity (FVC) at Baseline and Change in FVC in Subjects with Systemic Sclerosis-Associated ILD (SSc-ILD) in the SENSCIS Trial, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Stock CJW, Hoyles RK, Daccord C, et al., 2021, Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression, Respirology, Vol: 26, Pages: 461-468, ISSN: 1323-7799
Background and objectiveThe course of systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is highly variable, and accurate prognostic markers are needed. KL‐6 is a mucin‐like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21‐1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury.MethodsSerum KL‐6 and CYFRA 21‐1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed‐effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis.ResultsIn both cohorts, KL‐6 and CYFRA 21‐1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL‐6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc‐ILD, serum KL‐6, but not CYFRA 21‐1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL‐6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage.ConclusionOur results suggest serum KL‐6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc‐ILD.
Wiewrodt R, Goh N, Denton CP, et al., 2021, Effect of nintedanib in patients with limited and extensive systemic sclerosis-associated interstitial lung disease (SSc-ILD): data from the SENSCIS trial, Publisher: GEORG THIEME VERLAG KG, Pages: S29-S30, ISSN: 0934-8387
Dhindsa RS, Mattsson J, Nag A, et al., 2021, Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis, Communications Biology, Vol: 4, ISSN: 2399-3642
Idiopathic pulmonary fibrosis (IPF) is a fatal disorder characterised by progressive, destructive lung scarring. Despite substantial progress, the genetic determinants of this disease remain incompletely defined. Using whole genome and whole exome sequencing data from 752 individuals with sporadic IPF and 119,055 UK Biobank controls, we performed a variant-level exome-wide association study (ExWAS) and gene-level collapsing analyses. Our variant-level analysis revealed a novel association between a rare missense variant in SPDL1 and IPF (NM_017785.5:g.169588475 G > A p.Arg20Gln; p = 2.4 × 10−7, odds ratio = 2.87, 95% confidence interval: 2.03–4.07). This signal was independently replicated in the FinnGen cohort, which contains 1028 cases and 196,986 controls (combined p = 2.2 × 10−20), firmly associating this variant as an IPF risk allele. SPDL1 encodes Spindly, a protein involved in mitotic checkpoint signalling during cell division that has not been previously described in fibrosis. To the best of our knowledge, these results highlight a novel mechanism underlying IPF, providing the potential for new therapeutic discoveries in a disease of great unmet need.
Huang Y, Oldham JM, Ma S-F, et al., 2021, Blood transcriptomic predicts progression of pulmonary fibrosis and associates natural killer cells., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 197-208, ISSN: 1073-449X
Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objective: To identify a predictor using short-term longitudinal changes in gene-expression that forecasts future forced vital capacity (FVC) decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from Correlating Outcomes with biochemical Markers to Estimate Time-progression in IPF (COMET) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months, and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC-predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-seq (PBMC scRNA-seq) data from healthy controls were used as references to characterize cell type compositions from bulk PBMC RNA-seq data that were associated with FVC decline. Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared to a cross-sectional model. The FVC-predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were down- and up-regulated, respectively. Cellular deconvolution using scRNA-seq data identified natural killer (NK) cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. Analysis of cell types involved in the progressor signature supports the novel involvement of NK cells in IPF progression.
Maher TM, Mayes MD, Kreuter M, et al., 2021, Effect of Nintedanib on Lung Function in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease: Further Analyses of a Randomized, Double-Blind, Placebo-Controlled Trial, ARTHRITIS & RHEUMATOLOGY, Vol: 73, Pages: 671-676, ISSN: 2326-5191
Leeming DJ, Genovese F, Sand JMB, et al., 2021, Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis, Respiratory Research, Vol: 22, Pages: 1-7, ISSN: 1465-9921
Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.
Invernizzi R, Wu BG, Barnett J, et al., 2021, The respiratory microbiome in chronic hypersensitivity pneumonitis is distinct from that of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 339-347, ISSN: 1073-449X
RATIONALE: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises following repeated exposure and sensitisation to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease but to date, no study has investigated the composition of microbial communities in the lower airways in CHP. OBJECTIVE: To characterise and compare the airway microbiome in subjects with CHP, idiopathic pulmonary fibrosis (IPF) and controls. METHODS: We prospectively recruited individuals diagnosed with CHP (n=110), IPF (n=45) and controls (n=28). Subjects underwent bronchoalveolar lavage and bacterial DNA was isolated, quantified by qPCR and the 16S rRNA gene was sequenced to characterise the bacterial communities in the lower airways. MAIN MEASUREMENTS AND RESULTS: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both IPF and CHP subjects included Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. However, in IPF, Firmicutes dominated while the percentage of reads assigned to Proteobacteria in the same group was significantly lower compared to CHP subjects. At the genus level, Staphylococcus was increased in CHP and Actinomyces and Veillonella in IPF. The lower airway bacterial burden in CHP subjects was higher than controls but lower than those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. CONCLUSIONS: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF and, notably, bacterial burden in individuals with CHP fails to predict survival.
Maher TM, Costabel U, Glassberg MK, et al., 2021, Phase 2 trial to assess lebrikizumab in patients with idiopathic pulmonary fibrosis, EUROPEAN RESPIRATORY JOURNAL, Vol: 57, ISSN: 0903-1936
Noth I, Cottin V, Chaudhuri N, et al., 2021, Home spirometry in patients with idiopathic pulmonary fibrosis: data from the INMARK trial, European Respiratory Journal, Vol: 58, Pages: 1-10, ISSN: 0903-1936
Data from the INMARK trial were used to investigate the feasibility and validity of home spirometry as a measure of lung function decline in patients with idiopathic pulmonary fibrosis (IPF).Subjects with IPF and preserved forced vital capacity (FVC) were randomised to receive nintedanib or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Clinic spirometry was conducted at baseline and weeks 4, 8, 12, 16, 20, 24, 36 and 52. Subjects were asked to perform home spirometry at least once a week and ideally daily. Correlations between home- and clinic-measured FVC and rates of change in FVC were assessed using Pearson correlation coefficients.In total, 346 subjects were treated. Mean adherence to weekly home spirometry decreased over time but remained above 75% in every 4-week period. Over 52 weeks, mean adherence was 86%. Variability in change from baseline in FVC was greater when measured by home rather than clinic spirometry. Strong correlations were observed between home- and clinic-measured FVC at all time-points (r=0.72 to 0.84), but correlations between home- and clinic-measured rates of change in FVC were weak (r=0.26 for rate of decline in FVC over 52 weeks).Home spirometry was a feasible and valid measure of lung function in patients with IPF and preserved FVC, but estimates of the rate of FVC decline obtained using home spirometry were poorly correlated with those based on clinic spirometry.
Guillotin D, Taylor AR, Plate M, et al., 2021, Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis, THORAX, Vol: 76, Pages: 73-82, ISSN: 0040-6376
Hoffmann-Vold A-M, Maher TM, Philpot EE, et al., 2021, Assessment of recent evidence for the management of patients with systemic sclerosis-associated interstitial lung disease: a systematic review, ERJ OPEN RESEARCH, Vol: 7
Wilson AM, Clark AB, Cahn T, et al., 2020, Effect of co-trimoxazole (Trimethoprim-Sulfamethoxazole) vs placebo on death, lung transplant, or hospital admission in patients with moderate and severe idiopathic pulmonary fibrosis the EME-TIPAC randomized clinical trial, JAMA: Journal of the American Medical Association, Vol: 324, Pages: 2282-2291, ISSN: 0098-7484
Importance Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited treatment options. Patients with IPF have altered lung microbiota, with bacterial burden within the lungs associated with mortality; previous studies have suggested benefit with co-trimoxazole (trimethoprim-sulfamethoxazole).Objective To determine the efficacy of co-trimoxazole in patients with moderate and severe IPF.Design, Setting, and Participants Double-blind, placebo-controlled, parallel randomized trial of 342 patients with IPF, breathlessness (Medical Research Council dyspnea scale score >1), and impaired lung function (forced vital capacity ≤75% predicted) conducted in 39 UK specialist interstitial lung disease centers between April 2015 (first patient visit) and April 2019 (last patient follow-up).Interventions Study participants were randomized to receive 960 mg of oral co-trimoxazole twice daily (n = 170) or matched placebo (n = 172) for between 12 and 42 months. All patients received 5 mg of folic acid orally once daily.Main Outcomes and Measures The primary outcome was time to death (all causes), lung transplant, or first nonelective hospital admission. There were 15 secondary outcomes, including the individual components of the primary end point respiratory-related events, lung function (forced vital capacity and gas transfer), and patient-reported outcomes (Medical Research Council dyspnea scale, 5-level EuroQol 5-dimension questionnaire, cough severity, Leicester Cough Questionnaire, and King’s Brief Interstitial Lung Disease questionnaire scores).Results Among 342 individuals who were randomized (mean age, 71.3 years; 46 [13%] women), 283 (83%) completed the trial. The median (interquartile range) duration of follow-up was 1.02 (0.35-1.73) years. Events per person-year of follow-up among participants randomized to the co-trimoxazole and placebo groups were 0.45 (84/186) and 0.38 (80/209), respectively, with a hazard ratio of
Paynton ML, Allen RJ, Oldham J, et al., 2020, Human leukocyte antigen-wide association metaanalysis of idiopathic pulmonary fibrosis susceptibility, Publisher: SPRINGERNATURE, Pages: 718-719, ISSN: 1018-4813
Leavy OC, Ma S-F, Molyneaux PL, et al., 2020, Proportion of idiopathic pulmonary fibrosis risk explained by known Common genetic loci in European populations, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 775-778, ISSN: 1073-449X
Hirani N, MacKinnon AC, Nicol L, et al., 2020, Target-inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis., European Respiratory Journal, Vol: 57, Pages: 1-13, ISSN: 0903-1936
Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small molecule inhibitor of Gal-3.A randomised, double-blind, multi-centre, placebo-controlled, phase I/IIa study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF (NCT02257177). Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15 mg to 50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once daily doses of TD139 (0.3 mg to 10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side effects. TD139 was rapidly absorbed, with mean Tmax values ranging from 0.6 h to 3 h and a T½ of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 mg and 10 mg dose groups compared to placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (PDGF-BB, PAI-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on BAL macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.
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