Publications by authors named "Toby M Maher"

239 Publications

DNA Methylome Alterations are Associated with Airway Macrophage Differentiation and Phenotype During Lung Fibrosis.

Am J Respir Crit Care Med 2021 Jul 19. Epub 2021 Jul 19.

Imperial College London, London, United Kingdom of Great Britain and Northern Ireland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202101-0004OCDOI Listing
July 2021

Global incidence and prevalence of idiopathic pulmonary fibrosis.

Respir Res 2021 Jul 7;22(1):197. Epub 2021 Jul 7.

Center for Interstitial and Rare Lung Diseases, Department of Pneumology and Respiratory Critical Care Medicine, University of Heidelberg, Heidelberg, Germany.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease with considerable morbidity. Heterogeneity in epidemiologic studies means the full impact of the disease is unclear.

Methods: A targeted literature search for population-based, observational studies reporting incidence and/or prevalence of IPF from January 2009 to April 2020 was conducted. Identified studies were aggregated by country. For countries with multiple publications, a weighted average was determined. Incidence and prevalence data were adjusted for between-study differences where possible. The final model included adjusted estimates of incidence and prevalence per 10,000 of the population with 95% confidence intervals. As prevalence estimates vary depending on the definitions used, estimates were based on a specific case definition of IPF.

Results: Overall, 22 studies covering 12 countries met the inclusion criteria, with 15 reporting incidence and 18 reporting prevalence estimates. The adjusted incidence estimates (per 10,000 of the population) ranged from 0.35 to 1.30 in Asia-Pacific countries, 0.09 to 0.49 in Europe, and 0.75 to 0.93 in North America. Unadjusted and adjusted incidence estimates were consistent. The adjusted prevalence estimates ranged from 0.57 to 4.51 in Asia-Pacific countries, 0.33 to 2.51 in Europe, and 2.40 to 2.98 in North America. South Korea had the highest incidence and prevalence estimates. When prevalence estimates were compared to country-specific rare disease thresholds, IPF met the definition of a rare disease in all countries except South Korea. There were notable geographic gaps for IPF epidemiologic data.

Conclusions: Due to differences in study methodologies, there is worldwide variability in the reported incidence and prevalence of IPF. Based on the countries included in our analysis, we estimated the adjusted incidence and prevalence of IPF to be in the range of 0.09-1.30 and 0.33-4.51 per 10,000 persons, respectively. According to these prevalence estimates, IPF remains a rare disease. For consistency, future epidemiologic studies of IPF should take age, sex, smoking status, and the specificity of case definitions into consideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-021-01791-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261998PMC
July 2021

Enhanced IL-1β Release Following NLRP3 and AIM2 Inflammasome Stimulation Is Linked to mtROS in Airway Macrophages in Pulmonary Fibrosis.

Front Immunol 2021 15;12:661811. Epub 2021 Jun 15.

Laboratory of Molecular and Cellular Pneumonology, Respiratory Medicine Department, School of Medicine, University of Crete, Heraklion, Greece.

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 and 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.661811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248801PMC
June 2021

Effects of nintedanib by inclusion criteria for progression of interstitial lung disease.

Eur Respir J 2021 Jul 1. Epub 2021 Jul 1.

Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA.

The INBUILD trial investigated nintedanib 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 in the overall population (p=0.0002 for subgroup-by-time interaction) and -288.9, -156.2 and -100.1 mL·year 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.04587-2020DOI Listing
July 2021

50-gene risk profiles in peripheral blood predict COVID-19 outcomes: A retrospective, multicenter cohort study.

EBioMedicine 2021 Jun 19;69:103439. Epub 2021 Jun 19.

Divison of Pulmonary, Critical Care & Sleep Medicine. University of South Florida, Morsani College of Medicine, Tampa, FL 33602, USA. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214725PMC
June 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 2021 Jun 8. Epub 2021 Jun 8.

Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.

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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.41895DOI Listing
June 2021

Muscle stimulation in advanced idiopathic pulmonary fibrosis: a randomised placebo-controlled feasibility study.

BMJ Open 2021 06 2;11(6):e048808. Epub 2021 Jun 2.

Harefield Respiratory Research Group, Royal Brompton and Harefield Clinical Group, Guy's and St Thomas' Hospitals NHS Trust, London, UK.

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 about the credibility of placebo NMES.

Conclusions: Primarily owing to recruitment difficulties, a definitive trial using the current protocol to evaluate NMES in people with IPF is not feasible.

Trial Registration Number: NCT03499275.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2021-048808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174518PMC
June 2021

Identification of a missense variant in SPDL1 associated with idiopathic pulmonary fibrosis.

Commun Biol 2021 03 23;4(1):392. Epub 2021 Mar 23.

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

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, 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), 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-01910-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988141PMC
March 2021

Blood Transcriptomics Predicts Progression of Pulmonary Fibrosis and Associated Natural Killer Cells.

Am J Respir Crit Care Med 2021 Jul;204(2):197-208

Division of Pulmonary and Critical Care Medicine, The University of Virginia, Charlottesville, Virginia.

Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. To identify a predictor using short-term longitudinal changes in gene expression that forecasts future FVC decline and to characterize involved pathways and cell types. Seventy-four patients from COMET (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in IPF) 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-sequencing data from healthy control subjects were used as references to characterize cell type compositions from bulk peripheral blood mononuclear RNA-sequencing data that were associated with FVC decline. The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared with 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 downregulated and upregulated, respectively. Cellular deconvolution using single-cell RNA-sequencing data identified natural killer cells as significantly correlated with progression. Serial transcriptomic change predicts future FVC decline. An analysis of cell types involved in the progressor signature supports the novel involvement of natural killer cells in IPF progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202008-3093OCDOI Listing
July 2021

Assessment of recent evidence for the management of patients with systemic sclerosis-associated interstitial lung disease: a systematic review.

ERJ Open Res 2021 Jan 22;7(1). Epub 2021 Feb 22.

Dept of Rheumatology, University Hospital Zurich, Zurich, Switzerland.

This systematic review summarises current evidence to help guide treatment decisions for patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD). A systematic search of the literature (January 2012 to April 2018), including grey literature (searched between 1992 and 2011), was conducted using multiple electronic databases. Guidelines, meta-analyses, randomised controlled trials and observational studies reporting on risk stratification, screening, diagnosis, treatment and management outcomes for patients with SSc-ILD were included. A quality assessment of the included evidence was undertaken. In total, 2464 publications were identified and 280 included. Multiple independent risk factors for ILD in patients with SSc were identified, including older age, male sex and baseline pulmonary function. High-resolution computed tomography (HRCT) has been used for characterising ILD in patients with SSc, and pulmonary function tests are a key adjunctive component in the diagnostic and monitoring pathway. The clinical value of biomarkers relating to SSc-ILD diagnosis or assessment for disease progression is unknown at present. Immunosuppressive therapy (monotherapy or combined therapy) is the current standard of care for SSc-ILD; long-term evidence for effective and safe treatment of SSc-ILD is limited. Identification of patients at risk for SSc-ILD remains challenging. HRCT and pulmonary function tests are key to diagnosing and monitoring for disease progression. Although immunosuppressive therapy is considered current first-line treatment, it is partly associated with adverse effects and long-term follow-up evidence is limited. Novel therapies and biomarkers should be further explored in well-controlled clinical studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/23120541.00235-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897846PMC
January 2021

Monocyte Count as a Prognostic Biomarker in Patients with Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2021 Jul;204(1):74-81

Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom.

There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. We used pooled data from pirfenidone and IFNγ-1b trials to explore the association between monocyte count and prognosis in patients with IPF. This retrospective pooled analysis included patients (active and placebo arms) from the following four phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in FVC% predicted, ≥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. This analysis included 2,067 patients stratified by monocyte count (at baseline: <0.60 × 10 cells/L [ = 1,609], 0.60 to <0.95 × 10 cells/L [ = 408], and ≥0.95 × 10 cells/L [ = 50]). In adjusted analyses, a higher proportion of patients with monocyte counts of 0.60 to <0.95 × 10 cells/L or ≥0.95 × 10 cells/L versus <0.60 × 10 cells/L experienced IPF progression ( = 0.016 and  = 0.002, respectively), all-cause hospitalization ( = 0.030 and  = 0.003, respectively), and all-cause mortality ( = 0.005 and  < 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. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202003-0669OCDOI Listing
July 2021

Home spirometry in patients with idiopathic pulmonary fibrosis: data from the INMARK trial.

Eur Respir J 2021 Jul 8;58(1). Epub 2021 Jul 8.

Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.

Background: 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).

Methods: 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.

Results: 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=0.72-0.84), 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).

Conclusion: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01518-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264778PMC
July 2021

Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial.

Lancet Respir Med 2021 01;9(1):96-106

National Heart and Lung Institute, Imperial College London, London, UK; National Institute for Health Research Clinical Research Facility, Royal Brompton Hospital, London, UK; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address:

Background: In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline.

Methods: The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete.

Findings: Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug.

Interpretation: Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD.

Funding: Boehringer Ingelheim.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30330-1DOI Listing
January 2021

Idiopathic pulmonary fibrosis: Disease mechanisms and drug development.

Pharmacol Ther 2021 Jun 24;222:107798. Epub 2020 Dec 24.

Department of Medicine, University of British Columbia and Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, Canada.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2020.107798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142468PMC
June 2021

Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression.

Respirology 2021 May 17;26(5):461-468. Epub 2020 Dec 17.

Interstitial Lung Disease Unit, Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK.

Background And Objective: The 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.

Methods: Serum 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.

Results: In 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 DL 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 DL 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.

Conclusion: Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/resp.13988DOI Listing
May 2021

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 2020 12;324(22):2282-2291

MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.

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 1.2 ([95% CI, 0.9-1.6]; P = .32). There were no statistically significant differences in other event outcomes, lung function, or patient-reported outcomes. Patients in the co-trimoxazole group had 696 adverse events (nausea [n = 89], diarrhea [n = 52], vomiting [n = 28], and rash [n = 31]) and patients in the placebo group had 640 adverse events (nausea [n = 67], diarrhea [n = 84], vomiting [n = 20], and rash [n = 20]).

Conclusions And Relevance: Among patients with moderate or severe IPF, treatment with oral co-trimoxazole did not reduce a composite outcome of time to death, transplant, or nonelective hospitalization compared with placebo.

Trial Registration: ISRCTN Identifier: ISRCTN17464641.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.22960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724556PMC
December 2020

Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis.

Thorax 2021 01 19;76(1):73-82. Epub 2020 Nov 19.

Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK

Introduction: Fibroblastic foci represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling unmanipulated myofibroblasts within fibrotic foci in situ by laser capture microdissection.

Methods: The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as an -based approach to identify transcriptional signatures, which correlate with fibrillar collagen gene expression.

Results: WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collagen eigengene analysis revealed that transforming growth factor β1 (TGF-β1), RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene-edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-β1-induced mechanistic target of rapamycin complex 1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts.

Conclusion: These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesis in situ and further identify the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/thoraxjnl-2020-214902DOI Listing
January 2021

Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.

Eur Respir J 2021 05 27;57(5). Epub 2021 May 27.

National Institute for Health Research Respiratory Clinical Research Facility, Royal Brompton and Harefield NHS Foundation Trust, and Fibrosis Research Group, National Heart and Lung Institute, Imperial College London, London, UK.

Galectin (Gal)-3 is a profibrotic 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, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15-50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3-10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration ( ) values ranging from 0.6 to 3 h and a plasma half-life ( ) 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 and 10 mg dose groups compared with 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 (platelet-derived growth factor-BB, plasminogen activator inhibitor-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 bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02559-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156151PMC
May 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 2021 04 8;73(4):671-676. Epub 2021 Mar 8.

University of Washington, Seattle.

Objective: In the SENSCIS trial in subjects with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. This study was undertaken to investigate the effects of nintedanib on categorical changes in FVC and other measures of ILD progression.

Methods: In post hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC of ≥5% predicted or death and absolute decline in FVC of ≥10% predicted or death.

Results: A total of 288 subjects received nintedanib and 288 subjects received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had a decline in FVC of >5% to ≤10% predicted, and 3.5% and 5.2% had a decline in FVC of >10% to ≤15% predicted; 34.5% and 43.8% had a decrease in FVC of ≥3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC of ≥3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio (HR) for an absolute decline in FVC of ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% confidence interval [95% CI] 0.66-1.06) (P = 0.14), and the HR for an absolute decline in FVC of ≥10% predicted was 0.64 (95% CI 0.43-0.95) (P = 0.029).

Conclusion: These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc-ILD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.41576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048624PMC
April 2021

Itaconate controls the severity of pulmonary fibrosis.

Sci Immunol 2020 10;5(52)

National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression () is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciimmunol.abc1884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116646PMC
October 2020

Phase 2 trial to assess lebrikizumab in patients with idiopathic pulmonary fibrosis.

Eur Respir J 2021 02 4;57(2). Epub 2021 Feb 4.

National Jewish Health, Denver, CO, USA.

This phase 2, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of lebrikizumab, an interleukin (IL)-13 monoclonal antibody, alone or with background pirfenidone therapy, in patients with idiopathic pulmonary fibrosis (IPF).Patients with IPF aged ≥40 years with forced vital capacity (FVC) of 40%-100% predicted and diffusing capacity for carbon monoxide of 25%-90% predicted and who were treatment-naïve (cohort A) or receiving pirfenidone (2403 mg·day; cohort B) were randomised 1:1 to receive lebrikizumab 250 mg or placebo subcutaneously every 4 weeks. The primary endpoint was annualised rate of FVC % predicted decline over 52 weeks.In cohort A, 154 patients were randomised to receive lebrikizumab (n=78) or placebo (n=76). In cohort B, 351 patients receiving pirfenidone were randomised to receive lebrikizumab (n=174) or placebo (n=177). Baseline demographics were balanced across treatment arms in both cohorts. The primary endpoint (annualised rate of FVC % predicted decline) was not met in cohort A (lebrikizumab placebo, -5.2% -6.2%; p=0.456) or cohort B (lebrikizumab placebo, -5.5% -6.0%; p=0.557). In cohort B, a non-statistically significant imbalance in mortality favouring combination therapy was observed (hazard ratio 0.42 (95% CI 0.17-1.04)). Pharmacodynamic biomarkers indicated lebrikizumab activity. The safety profile was consistent with that in previous studies of lebrikizumab and pirfenidone as monotherapies.Lebrikizumab alone or with pirfenidone was not associated with reduced FVC % predicted decline over 52 weeks despite evidence of pharmacodynamic activity. Lebrikizumab was well tolerated with a favourable safety profile. These findings suggest that blocking IL-13 may not be sufficient to achieve a lung function benefit in patients with IPF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02442-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859504PMC
February 2021

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis.

Nat Commun 2020 09 16;11(1):4659. Epub 2020 Sep 16.

Nordic Bioscience A/S, Biomarkers and Research, Herlev Hovedgade 205-207, Herlev, Denmark.

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18397-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494911PMC
September 2020

Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from the SENSCIS trial.

Ann Rheum Dis 2020 11 5;79(11):1478-1484. Epub 2020 Aug 5.

Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.

Objectives: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

Methods: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks.

Results: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments.

Conclusions: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2020-217331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569371PMC
November 2020

The need for a holistic approach for SSc-ILD - achievements and ambiguity in a devastating disease.

Respir Res 2020 Jul 23;21(1):197. Epub 2020 Jul 23.

Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik, Heidelberg University Hospital and German Center for Lung Research, Heidelberg, Germany.

Systemic sclerosis (SSc) is a multi-organ autoimmune disease with complex interactions between immune-mediated inflammatory processes and vascular pathology leading to small vessel obliteration, promoting uncontrolled fibrosis of skin and internal organs. Interstitial lung disease (ILD) is a common but highly variable manifestation of SSc and is associated with high morbidity and mortality. Treatment approaches have focused on immunosuppressive therapies, which have shown some efficacy on lung function. Recently, a large phase 3 trial showed that treatment with nintedanib was associated with a reduction in lung function decline. None of the conducted randomized clinical trials have so far shown convincing efficacy on other outcome measures including quality of life determined by patient reported outcomes. Little evidence is available for non-pharmacological treatment and supportive care specifically for SSc-ILD patients, including pulmonary rehabilitation, supplemental oxygen, symptom relief and adequate information. Improved management of SSc-ILD patients based on a holistic approach is necessary to support patients in maintaining as much quality of life as possible throughout the disease course and to improve long-term outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-020-01459-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379834PMC
July 2020

The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2021 02;203(3):339-347

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization 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. To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects. We prospectively recruited individuals with a CHP diagnosis ( = 110), individuals with an IPF diagnosis ( = 45), and control subjects ( = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways. 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 subjects with IPF and subjects with CHP included , , , and . However, in IPF, dominated, whereas the percentage of reads assigned to in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the burden was increased in CHP, and and burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202002-0460OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874329PMC
February 2021