Imperial College London

DrPhilipMolyneaux

Faculty of MedicineNational Heart & Lung Institute

Reader in Interstitial Lung Disease
 
 
 
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p.molyneaux

 
 
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Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

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118 results found

Macaluso C, Boccabella C, Kokosi M, Sivarasan N, Kouranos V, George PM, Margaritopoulos G, Molyneaux PL, Chua F, Maher TM, Jenkins GR, Nicholson AG, Desai SR, Devaraj A, Wells AU, Renzoni EA, Stock CJWet al., 2022, Short-term lung function changes predict mortality in patients with fibrotic hypersensitivity pneumonitis, RESPIROLOGY, ISSN: 1323-7799

Journal article

Furusawa H, Peljto AL, Walts AD, Cardwell J, Molyneaux PL, Lee JS, Fernández Pérez ER, Wolters PJ, Yang IV, Schwartz DAet al., 2022, Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis, Thorax, ISSN: 0040-6376

A subset of patients with hypersensitivity pneumonitis (HP) develop lung fibrosis that is clinically similar to idiopathic pulmonary fibrosis (IPF). To address the aetiological determinants of fibrotic HP, we investigated whether the common IPF genetic risk variants were also relevant in study subjects with fibrotic HP. Our findings indicate that common genetic variants in TERC, DSP, MUC5B and IVD were significantly associated with fibrotic HP. These findings provide support for a shared etiology and pathogenesis between fibrotic HP and IPF.

Journal article

McElroy AN, Invernizzi R, Laskowska JW, O'Neill A, Doroudian M, Moghoofei M, Mostafaei S, Li F, Przybylski AA, O'Dwyer DN, Bowie AG, Fallon PG, Maher TM, Hogaboam CM, Molyneaux PL, Hirani N, Armstrong ME, Donnelly SCet al., 2022, Candidate role for toll-like receptor 3 L412F polymorphism and infection in acute exacerbation of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Rationale: The Toll-like receptor 3 Leu412Phe (TLR3 L412F) polymorphism attenuates cellular anti-viral responses and is associated with accelerated disease progression in IPF. The role of TLR3 L412F in bacterial infection in IPF or in acute exacerbations (AE) has not been reported. Objective: To characterize the association between TLR3 L412F and AE-related death in IPF. To determine the effect of TLR3 L412F on the lung microbiome and on anti-bacterial TLR-responses of primary lung fibroblasts from IPF patients. Methods: TLR-mediated anti-bacterial and anti-viral responses were quantitated in L412F-wild-type and 412F-heterozygous primary lung fibroblasts from IPF patients using ELISA, western blot analysis and qPCR. Hierarchical heatmap analysis was employed to establish bacterial and viral clustering in nasopharyngeal lavage (NPL) samples from AE-IPF patients. 16S rRNA qPCR and pyrosequencing were used to determine the effect of TLR3 L412F on the IPF lung microbiome. Measurements and Main Results: A significant increase in AE-related death in 412F-variant IPF patients was reported. We established that 412F-heterozygous IPF lung fibroblasts have reduced anti-bacterial TLR responses to LPS (TLR4), Pam3CYSK4 (TLR1/2), flagellin (TLR5) and FSL-1 (TLR6/1) and have reduced responses to live Pseudomonas aeruginosa infection. Using 16S rRNA sequencing, we demonstrated that 412F-heterozygous IPF patients have a dysregulated lung microbiome with increased frequencies of Streptococcus and Staphylococcus spp. Conclusions: This study reveals that TLR3 L412F dysregulates the IPF lung microbiome and reduces the responses of IPF lung fibroblasts to bacterial TLR-agonists and live bacterial infection. These findings identify a candidate role for TLR3 L412F in viral- and bacterial-mediated AE-death.

Journal article

Torrisi SE, Kahn N, Wälscher J, Polke M, Lee JS, Molyneaux PL, Sambataro FM, Heussel CP, Vancheri C, Kreuter Met al., 2021, Outcomes and incidence of PF-ILD according to different definitions in a real-world setting, Frontiers in Pharmacology, Vol: 12, ISSN: 1663-9812

Background: Almost one-third of fibrosing ILD (fILDs) have a clinical disease behavior similar to IPF, demonstrating a progressive phenotype (PF-ILD). However, there are no globally accepted criteria on the definition of a progressive phenotype in non-IPF fILD yet. Four different definitions have been used; however, no internationally accepted definition currently exists.Research Question: To compare the clinical and functional characteristics of progressive fILD according to the currently available definitions.Study design and methods: Cases of fILD were identified retrospectively from the database of the tertiary referral center for ILD in Heidelberg. Lung function, clinical signs of progression, and radiological changes were evaluated. Patients with fILD were considered to have progression according to each of the four available definitions: Cottin (CO), RELIEF (RE), INBUILD (IN), and UILD study. Lung function changes, expressed as mean absolute decline of FVC%, were reported every 3 months following diagnosis and analyzed in the context of each definition. Survival was also analyzed.Results: A total of 566 patients with non-IPF fILD were included in the analysis. Applying CO-, RE-, IN-, and UILD-definitions, 232 (41%), 183 (32%), 274 (48%), and 174 (31%) patients were defined as PF-ILD, respectively. RE- and UILD-criteria were the most stringent, with only 32 and 31% patients defined as progressive, while IN- was the most broad, with almost 50% of patients defined as progressive. CO- definition was in-between, classifying 41% as progressive. PF ILD patients with a UILD definition had worse prognosis.Interpretation: Depending on the definition used, the existing criteria identify different groups of patients with progressive fILD, and this may have important prognostic and therapeutic implications.

Journal article

Wu Z, Molyneaux PL, 2021, Choosing pharmacotherapy for ILD in patients with connective tissue disease, Breathe, Vol: 17, ISSN: 1810-6838

Interstitial lung disease (ILD) is a well-recognised complication of connective tissue diseases (CTD), leading to significant mortality and morbidity. The pathogenesis is thought to be driven by immune-mediated inflammation and subsequent architectural damage [1]. Current pharmacotherapy options predominantly focus on the use of immune suppression, although recently antifibrotic therapy has shown some promise. This article will highlight the best available evidence for treatment options in the most common forms of CTD-ILD.

Journal article

Boustani K, Ghai P, Invernizzi R, Hewitt R, Maher T, Li Q-Z, Molyneaux P, Harker Jet al., 2021, Autoantibodies are present in the bronchoalveolar lavage but not circulation in patients with fibrotic interstitial lung disease, ERJ Open Research, ISSN: 2312-0541

Fibrotic interstitial lung disease (fILD) has previously been associated with the presence of autoantibody. While studies have focused on systemic autoimmunity, the role of local autoantibodies in the airways remains unknown. We therefore extensively characterised the airway and peripheral autoantibody profiles in patients with fILD and assessed association with disease severity and outcome.Bronchoalveolar lavage (BAL) was collected from a cohort of fILD patients and total BAL antibody concentrations were quantified. An autoantigen microarray was used to measure IgG and IgA autoantibodies against 122 autoantigens in BAL from 40 idiopathic pulmonary fibrosis (IPF), 20 chronic hypersensitivity pneumonitis (CHP), 20 connective tissue disease-associated ILD (CTD-ILD) patients and 20 controls.A subset of patients with fILD but not healthy controls had a local autoimmune signature in their BAL that was not present systemically, regardless of disease. The proportion of patients with IPF with a local autoantibody signature was comparable to that of CTD-ILD, which has a known autoimmune pathology, identifying a potentially novel subset of patients. The presence of an airway autoimmune signature was not associated with reduced survival probability or changes in lung function

Journal article

Oldham JM, Lee CT, Wu Z, Bowman WS, Pugashetti JV, Dao N, Tonkin J, Seede H, Echt G, Adegunsoye A, Chua F, Maher TM, Garcia CK, Strek ME, Newton CA, Molyneaux Pet al., 2021, Lung function trajectory in progressive fibrosing interstitial lung disease, European Respiratory Journal, ISSN: 0903-1936

Proposed criteria for progressive fibrosing interstitial lung disease (PF-ILD) have been linked to increased mortality risk, but lung function trajectory after satisfying individual criterion remains unknown. Because survival is rarely employed as the primary endpoint in therapeutic trials, identifying PF-ILD criteria that best predict subsequent change in forced vital capacity (FVC) could improve clinical trial design. A retrospective, multi-center longitudinal cohort analysis was performed in consecutive patients with fibrotic connective tissue disease-associated ILD (CTD-ILD), chronic hypersensitivity pneumonitis and idiopathic interstitial pneumonia at three US centers (test cohort) and one UK center (validation cohort). One-year change in FVC after satisfying proposed PF-ILD criteria was estimated using joint modeling. Subgroup analyses were performed to determine whether results varied across key subgroups. One thousand two hundred twenty-seven patients were included, with CTD-ILD predominating. Six of nine PF-ILD criteria were associated with differential one-year change in FVC, with radiologic progression of fibrosis, alone and in combination with other features, associated with the largest subsequent decline in FVC. Findings varied significantly by ILD subtype, with CTD-ILD demonstrating little change in FVC after satisfying most PF-ILD criteria, while other ILDs showed significantly larger changes. Findings did not vary after stratification by radiologic pattern or exposure to immunosuppressant therapy. Near-term change in FVC after satisfying proposed PF-ILD criteria was heterogeneous depending on the criterion assessed and was strongly influenced by ILD subtype. These findings may inform future clinical trial design and suggest ILD subtype should be taken into consideration when applying PF-ILD criteria.

Journal article

Hindocha S, Campbell D, Ahmed M, Giorgakoudi K, Sharma B, Yosaf N, Molyneaux P, Hunter B, Kalsi H, Cui W, Davidson M, Bhosle J, Minchom A, Locke I, McDonald F, O'Brien M, Popat S, Lee R, Hindocha Set al., 2021, Immune checkpoint inhibitor and radiotherapy-related pneumonitis: an informatics approach to determine real-world incidence, severity, management & resource implications, Frontiers in Medicine, Vol: 8, Pages: 1-10, ISSN: 2296-858X

Pneumonitis is a well-described, potentially life-threatening adverse effect of immune checkpoint inhibitors (ICI) and thoracic radiotherapy. It can require additional investigations, treatment, and interruption of cancer therapy. It is important for clinicians to have an awareness of its incidence and severity, however real-world data are lacking and do not always correlate with findings from clinical trials. Similarly, there is a dearth of information on cost impact of symptomatic pneumonitis. Informatics approaches are increasingly being applied to healthcare data for their ability to identify specific patient cohorts efficiently, at scale. We developed a Structured Query Language (SQL)-based informatics algorithm which we applied to CT report text to identify cases of ICI and radiotherapy pneumonitis between 1/1/2015 and 31/12/2020. Further data on severity, investigations, medical management were also acquired from the electronic health record. We identified 248 cases of pneumonitis attributable to ICI and/or radiotherapy, of which 139 were symptomatic with CTCAE severity grade 2 or more. The grade ≥2 ICI pneumonitis incidence in our cohort is 5.43%, greater than the all-grade 1.3–2.7% incidence reported in the literature. Time to onset of ICI pneumonitis was also longer in our cohort (mean 4.5 months, range 4 days-21 months), compared to the median 2.7 months (range 9 days−19.2 months) described in the literature. The estimated average healthcare cost of symptomatic pneumonitis is £3932.33 per patient. In this study we use an informatics approach to present new real-world data on the incidence, severity, management, and resource burden of ICI and radiotherapy pneumonitis. To our knowledge, this is the first study to look at real-world incidence and healthcare resource utilisation at the per-patient level in a UK cancer hospital. Improved management of pneumonitis may facilitate prompt continuation of cancer therapy, and improved outcomes f

Journal article

Nolan CM, Polgar O, Schofield SJ, Patel S, Barker RE, Walsh JA, Ingram KA, George PM, Molyneaux PL, Maher TM, Man WD-Cet al., 2021, Pulmonary rehabilitation in idiopathic pulmonary fibrosis and COPD: a propensity matched real-world study, Chest, ISSN: 0012-3692

BACKGROUND: The adherence to and clinical efficacy of pulmonary rehabilitation in idiopathic pulmonary fibrosis (IPF), particularly in comparison to people with chronic obstructive pulmonary disease (COPD), remains uncertain. The objectives of this real-world study were to compare the responses of patients with IPF with a matched group of patients with COPD undergoing the same supervised, outpatient pulmonary rehabilitation program, and to determine whether pulmonary rehabilitation is associated with survival in IPF. RESEARCH QUESTION: Do people with IPF improve to the same extent with pulmonary rehabilitation as a matched group of individuals with COPD, and are non-completion of and/or non-response to pulmonary rehabilitation associated with one-year all-cause mortality in IPF? STUDY DESIGN AND METHODS: Using propensity score matching, 163 patients with IPF were matched 1:1 with a control group of 163 patients with COPD referred to pulmonary rehabilitation. We compared between-group pulmonary rehabilitation completion rates and response. Survival status in the IPF cohort was recorded over one-year following pulmonary rehabilitation discharge. Cox proportional-hazards regression explored the association between pulmonary rehabilitation status and all-cause mortality. RESULTS: Similar pulmonary rehabilitation completion rates (IPF: 69%; COPD: 63%; p=0.24) and improvements in exercise response were observed in both groups with no significant mean (95% confidence interval (CI)) between-group differences in incremental shuttle walk (ISW) change (2 (-18 to 22) meters). Pulmonary rehabilitation non-completion (hazard ratio (HR) (95%CI) 5.62 (2.24 to 14.08)) and non-response (HR (95%CI) 3.91 (1.54 to 9.93)) were independently associated with increased one-year all-cause mortality in IPF. INTERPRETATION: Compared with a matched group of patients with COPD, this real-word study demonstrates that patients with IPF have similar completion rates and magnitude of response to pul

Journal article

McErlean P, Bell CG, Hewitt RJ, Busharat Z, Ogger PP, Ghai P, Albers GJ, Calamita E, Kingston S, Molyneaux PL, Beck S, Lloyd CM, Maher TM, Byrne AJet al., 2021, DNA methylome alterations are associated with airway macrophage differentiation and phenotype during lung fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 954-966, ISSN: 1073-449X

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 about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.

Journal article

Wild JM, Porter JC, Molyneaux PL, George PM, Stewart I, Allen RJ, Aul R, Baillie JK, Barratt SL, Beirne P, Bianchi SM, Blaikley JF, Brooke J, Chaudhuri N, Collier G, Denneny EK, Docherty A, Fabbri L, Gibbons MA, Gleeson F, Gooptu B, Hall IP, Hanley NA, Heightman M, Hillman TE, Johnson SR, Jones MG, Khan F, Lawson R, Mehta P, Mitchell JA, Plate M, Poinasamy K, Quint JK, Rivera-Ortega P, Semple M, Simpson AJ, Smith DJF, Spears M, Spencer LG, Stanel SC, Thickett DR, Thompson AAR, Walsh SLF, Weatherley ND, Weeks ME, Wootton DG, Brightling CE, Chambers RC, Ho L-P, Jacob J, Piper Hanley K, Wain L, Jenkins RGet al., 2021, Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID), BMJ Open Respiratory Research, Vol: 8, Pages: 1-10, ISSN: 2052-4439

Introduction The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD).Methods and analysis The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment.Ethics and dissemination All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals.Conclusion This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD.

Journal article

Juan Guardela BM, Sun J, Zhang T, Xu B, Balnis J, Huang Y, Ma S-F, Molyneaux PL, Maher TM, Noth I, Michaud G, Jaitovich A, Herazo-Maya JDet 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.

Journal article

Kreuter M, Lee JS, Tzouvelekis A, Oldham JM, Molyneaux PL, Weycker D, Atwood M, Kirchgaessler K-U, Maher TMet 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

Journal article

Trachalaki A, Tsitoura E, Mastrodimou S, Invernizzi R, Vasarmidi E, Bibaki E, Tzanakis N, Molyneaux PL, Maher TM, Antoniou Ket 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.

Journal article

Nolan CM, Patel S, Barker RE, Walsh JA, Polgar O, Maddocks M, George PM, Renzoni EA, Wells AU, Molyneaux PL, Kouranos V, Chua F, Maher TM, Man WD-Cet 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

Journal article

Myall KJ, Molyneaux PL, West AG, authorset al., 2021, Reply: A role for steroids in COVID-19 associated pneumonitis at six-week follow-up?, Annals of the American Thoracic Society, Vol: 18, Pages: 1083-1084, ISSN: 1546-3222

Journal article

Myall KJ, Mukherjee B, Castanheira AM, Lam JL, Benedetti G, Mak SM, Preston R, Thillai M, Dewar A, Molyneaux PL, West AGet al., 2021, Persistent post-COVID-19 interstitial lung disease: an observational study of corticosteroid treatment, Annals of the American Thoracic Society, Vol: 18, Pages: 799-806, ISSN: 2329-6933

RATIONALE: The natural history of recovery from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) remains unknown. Since fibrosis with persistent physiological deficit is a previously-described feature of patients recovering from similar coronaviruses, treatment represents an early opportunity to modify the disease course, potentially preventing irreversible impairment. OBJECTIVES: Determine the incidence of and describe the progression of persistent inflammatory interstitial lung disease (ILD) following SARS-CoV2 when treated with prednisolone. METHODS: A structured assessment protocol screened for sequelae of SARS-CoV2 pneumonitis. 837 patients were assessed by telephone four weeks after discharge. Those with ongoing symptoms had outpatient assessment at six weeks. Thirty patients diagnosed with persistent interstitial lung changes at multi-disciplinary team meeting were reviewed in the interstitial lung disease service and offered treatment. These patients had persistent, non-improving symptoms. RESULTS: At four weeks post-discharge, 39% of patients reported ongoing symptoms (325/837), and were assessed. Interstitial lung disease, predominantly organising pneumonia, with significant functional deficit was observed in 35/837 survivors (4.8%). Thirty of these patients received steroid treatment, resulting in a mean relative increase in transfer factor following treatment of 31.6% (standard deviation ± 27.64, p <0.001), and FVC of 9.6% (standard deviation ± 13.01, p = 0.014), with significant symptomatic and radiological improvement. CONCLUSION: Following SARS-CoV-2 pneumonitis, a cohort of patients are left with both radiological inflammatory lung disease and persistent physiological and functional deficit. Early treatment with corticosteroids was well tolerated and associated with rapid and significant improvement. This preliminary data should inform further study into the natural history and potential treatment for patients with persist

Journal article

Stock CJW, Hoyles RK, Daccord C, Kokosi M, Visca D, De Lauretis A, Alfieri V, Kouranos V, Margaritopoulos G, George PM, Molyneaux PL, Chua F, Maher TM, Abraham DJ, Ong V, Donovan J, Sestini P, Denton CP, Wells AU, Renzoni EAet 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.

Journal article

Dhindsa RS, Mattsson J, Nag A, Wang Q, Wain L, Allen R, Wigmore EM, Ibanez K, Vitsios D, Deevi SVV, Wasilewski S, Karlsson M, Lassi G, Olsson H, Muthas D, Monkley S, Mackay A, Murray L, Young S, Haefliger C, Maher TM, Belvisi MG, Jenkins G, Molyneaux PL, Platt A, Petrovski Set 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.

Journal article

Chua F, Vancheeswaran R, Draper A, Vaghela T, Knight M, Mogal R, Singh J, Spencer LG, Thwaite E, Mitchell H, Calmonson S, Mahdi N, Assadullah S, Leung M, O'Neill A, Popat C, Kumar R, Humphries T, Talbutt R, Raghunath S, Molyneaux PL, Schechter M, Lowe J, Barlow Aet al., 2021, Early prognostication of COVID-19 to guide hospitalisation versus outpatient monitoring using a point-of-test risk prediction score, Thorax, Vol: 76, Pages: 696-703, ISSN: 0040-6376

INTRODUCTION: Risk factors of adverse outcomes in COVID-19 are defined but stratification of mortality using non-laboratory measured scores, particularly at the time of prehospital SARS-CoV-2 testing, is lacking. METHODS: Multivariate regression with bootstrapping was used to identify independent mortality predictors in patients admitted to an acute hospital with a confirmed diagnosis of COVID-19. Predictions were externally validated in a large random sample of the ISARIC cohort (N=14 231) and a smaller cohort from Aintree (N=290). RESULTS: 983 patients (median age 70, IQR 53-83; in-hospital mortality 29.9%) were recruited over an 11-week study period. Through sequential modelling, a five-predictor score termed SOARS (SpO2, Obesity, Age, Respiratory rate, Stroke history) was developed to correlate COVID-19 severity across low, moderate and high strata of mortality risk. The score discriminated well for in-hospital death, with area under the receiver operating characteristic values of 0.82, 0.80 and 0.74 in the derivation, Aintree and ISARIC validation cohorts, respectively. Its predictive accuracy (calibration) in both external cohorts was consistently higher in patients with milder disease (SOARS 0-1), the same individuals who could be identified for safe outpatient monitoring. Prediction of a non-fatal outcome in this group was accompanied by high score sensitivity (99.2%) and negative predictive value (95.9%). CONCLUSION: The SOARS score uses constitutive and readily assessed individual characteristics to predict the risk of COVID-19 death. Deployment of the score could potentially inform clinical triage in preadmission settings where expedient and reliable decision-making is key. The resurgence of SARS-CoV-2 transmission provides an opportunity to further validate and update its performance.

Journal article

Huang Y, Oldham JM, Ma S-F, Unterman A, Liao S-Y, Barros AJ, Bonham CA, Kim JS, Vij R, Adegunsoye A, Strek ME, Molyneaux PL, Maher TM, Herazo-Maya JD, Kaminski N, Moore BB, Martinez FJ, Noth Iet 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.

Journal article

Simpson T, Barratt SL, Beirne P, Chaudhuri N, Crawshaw A, Crowley LE, Fletcher S, Gibbons MA, Hallchurch P, Horgan L, Jakaityte I, Lewis T, McLellan T, Myall KJ, Miller R, Smith DJF, Stanel S, Thillai M, Thompson F, Wallis T, Wu Z, Molyneaux PL, West AGet al., 2021, The burden of Progressive Fibrotic Interstitial lung disease across the UK., European Respiratory Journal, Vol: 58, Pages: 1-4, ISSN: 0903-1936

Journal article

Molyneaux PL, 2021, The microbiome in IPF: tissue is not the issue., Thorax, Vol: 76, Pages: 218-218, ISSN: 0040-6376

Journal article

Invernizzi R, Wu BG, Barnett J, Ghai P, Kingston S, Hewitt RJ, Feary J, Li Y, Chua F, Wu Z, Wells AU, George PM, Renzoni EA, Nicholson AG, Rice A, Devaraj A, Segal LN, Byrne AJ, Maher TM, Lloyd CM, Molyneaux PLet al., 2021, The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis., Am J Respir Crit Care Med, Vol: 203, Pages: 339-347

Rationale: 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.Objectives: To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects.Methods: We prospectively recruited individuals with a CHP diagnosis (n = 110), individuals with an IPF diagnosis (n = 45), and control subjects (n = 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.Measurements and Main 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 subjects with IPF and subjects with CHP included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. However, in IPF, Firmicutes dominated, whereas the percentage of reads assigned to Proteobacteria in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the Staphylococcus burden was increased in CHP, and Actinomyces and Veillonella 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.Conclusions: 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.

Journal article

Leavy OC, Ma S-F, Molyneaux PL, Maher TM, Oldham JM, Flores C, Noth I, Jenkins RG, Dudbridge F, Wain LV, Allen RJet 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

Journal article

Hirani N, MacKinnon AC, Nicol L, Ford P, Schambye H, Pedersen A, Nilsson UJ, Leffler H, Sethi T, Tantawi S, Gavelle L, Slack RJ, Mills R, Karmakar U, Humphries D, Zetterberg F, Keeling L, Paul L, Molyneaux PL, Li F, Funston W, Forrest IA, Simpson AJ, Gibbons MA, Maher TMet 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.

Journal article

Ogger PP, Albers GJ, Hewitt RJ, O'Sullivan BJ, Powell JE, Calamita E, Ghai P, Walker SA, McErlean P, Saunders P, Kingston S, Molyneaux PL, Halket JM, Gray R, Chambers DC, Maher TM, Lloyd CM, Byrne AJet al., 2020, Itaconate controls the severity of pulmonary fibrosis, Science Immunology, Vol: 5, Pages: 1-13, ISSN: 2470-9468

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 (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- 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.

Journal article

Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali H, Agnew S, Babu S, Barber CM, Barratt S, Bendstrup E, Bianchi S, Castillo Villegas D, Chaudhuri N, Chua F, Coker R, Chang W, Crawshaw A, Crowley LE, Dosanjh D, Fiddler CA, Forrest IA, George PM, Gibbons MA, Groom K, Haney S, Hart SP, Heiden E, Henry M, Ho L-P, Hoyles RK, Hutchinson J, Hurley K, Jones MG, Jones S, Kokosi M, Kreuter M, Mackay LS, Mahendran S, Margaritopoulos G, Molina-Molina M, Molyneaux PL, O'Brien A, O'Reilly K, Packham A, Parfrey H, Poletti V, Porter JC, Renzoni E, Rivera-Ortega P, Russell A-M, Saini G, Spencer LG, Stella GM, Stone H, Sturney S, Thickett D, Thillai M, Wallis T, Ward K, Wells AU, West A, Wickremasinghe M, Woodhead F, Hearson G, Howard L, Baillie JK, Openshaw PJM, Semple MG, Stewart I, Jenkins RG, ISARIC4C Investigatorset al., 2020, Outcome of hospitalization for COVID-19 in patients with interstitial lung disease: an international multicenter study., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 1656-1665, ISSN: 1073-449X

RATIONALE: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. OBJECTIVES: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age, sex and comorbidity matched population. METHODS: An international multicenter audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. MEASUREMENTS AND MAIN RESULTS: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 2.27, 1.39-3.71). CONCLUSIONS: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal article

Stock CJ, Conti C, Montero-Fernandez Á, Caramori G, Molyneaux PL, George PM, Kokosi M, Kouranos V, Maher TM, Chua F, Rice A, Denton CP, Nicholson AG, Wells A, Sestini P, Renzoni EAet al., 2020, Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype?, Thorax, Vol: 75, Pages: 901-903, ISSN: 0040-6376

The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.

Journal article

Zhang YZ, Brambilla C, Molyneaux PL, Rice A, Robertus JL, Jordan S, Lim E, Lang-Lazdunski L, Begum S, Dusmet M, Anikin V, Beddow E, Finch J, Asadi N, Popat S, Le Quesne J, Husain AN, Cookson WO, Moffatt MF, Nicholson AGet al., 2020, Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade, Histopathology, Vol: 77, Pages: 423-436, ISSN: 0309-0167

AIMS: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (1) externally validate the prognostic role of pleomorphic features in E-MPM and (2) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. METHODS AND RESULTS: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared those without (5.4 months vs 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 months vs. 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. CONCLUSIONS: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.

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