Imperial College London

DrPeterGeorge

Faculty of MedicineNational Heart & Lung Institute

Honorary Clinical Senior Lecturer
 
 
 
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p.george

 
 
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Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
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71 results found

Hewitt RJ, Bartlett EC, Ganatra R, Butt H, Kouranos V, Chua F, Kokosi M, Molyneaux PL, Desai SR, Wells AU, Jenkins RG, Renzoni EA, Kemp SV, Devaraj A, George PMet al., 2022, Lung cancer screening provides an opportunity for early diagnosis and treatment of interstitial lung disease., Thorax

Interstitial lung abnormalities (ILA) can be incidentally detected in patients undergoing low-dose CT screening for lung cancer. In this retrospective study, we explore the downstream impact of ILA detection on interstitial lung disease (ILD) diagnosis and treatment. Using a targeted approach in a lung cancer screening programme, the rate of de novo ILD diagnosis was 1.5%. The extent of abnormality on CT and severity of lung function impairment, but not symptoms were the most important factors in differentiating ILA from ILD. Disease modifying therapies were commenced in 39% of ILD cases, the majority being antifibrotic therapy for idiopathic pulmonary fibrosis.

Journal article

Gerovasili V, Shah A, Singanayagam A, George PM, Njafuh R, Prendecki M, Carby M, Willicombe M, Kelleher P, Reed Aet al., 2022, Impaired Humoral and Cellular Responses to COVID-19 Vaccine in Heart and Lung Transplant Recipients, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 1476-1479, ISSN: 1073-449X

Journal article

Koteci A, Morgan A, Portas L, Whittaker H, Kallis C, George P, Quint Jet al., 2022, Left-sided heart failure burden and mortality in idiopathic pulmonary fibrosis: a population-based study, BMC Pulmonary Medicine, Vol: 22, Pages: 1-11, ISSN: 1471-2466

BackgroundCardiovascular disease is prevalent in idiopathic pulmonary fibrosis (IPF), yet the extent of left-sided heart failure (HF) burden, whether this has changed with time and whether HF impacts mortality risk in these patients are unknown. The aims of this study were therefore to determine the temporal trends in incidence and prevalence of left-sided HF in patients with IPF in England and compare these to published estimates in the general population and those with comparable chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD), as well as determine the risk of all-cause and cause-specific mortality in patients with comorbid left-sided HF and IPF at population-level using electronic healthcare data.MethodsClinical Practice Research Datalink (CPRD) Aurum primary-care data linked to mortality and secondary-care data was used to identify IPF patients in England. Left-sided HF prevalence and incidence rates were calculated for each calendar year between 2010 and 2019, stratified by age and sex. Risk of all-cause, cardiovascular and IPF-specific mortality was calculated using multivariate Cox regression.ResultsFrom 40,577patients with an IPF code in CPRD Aurum, 25, 341 IPF patients met inclusion criteria. Left-sided HF prevalence decreased from 33.4% (95% CI 32.2–34.6) in 2010 to 20.9% (20.0–21.7) in 2019. Left-sided HF incidence rate per 100 person-years (95% CI) remained stable between 2010 and 2017 but decreased from 4.3 (3.9–4.8) in 2017 to 3.4 (3.0–3.9) in 2019. Throughout follow-up, prevalence and incidence were higher in men and with increasing age. Comorbid HF was associated with poorer survival (adjusted HR (95%CI) 1.08 (1.03–1.14) for all-cause mortality; 1.32 (1.09–1.59) for cardiovascular mortality).ConclusionLeft-sided HF burden in IPF patients in England remains high, with incidence almost 4 times higher than in COPD, a comparable lung disease with similar cardiovascular risk factors.

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., 2022, Pulmonary rehabilitation in idiopathic pulmonary fibrosis and COPD: a propensity matched real-world study, Chest, Vol: 161, Pages: 728-737, 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

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, Vol: 27, Pages: 202-208, ISSN: 1323-7799

Background and objectiveA proportion of patients with fibrotic hypersensitivity pneumonitis (fHP) follow a progressive disease course despite immunosuppressive treatment. Little is known about predictors of mortality in fHP. We aimed to investigate the impact of short-term lung function changes in fHP on mortality.MethodsBaseline demographics for 145 consecutive patients with a multi-disciplinary team diagnosis of fHP, as well as baseline and 1-year follow-up of lung function, baseline echocardiographic findings, bronchoalveolar lavage (BAL) cellularity and all-cause mortality were recorded. Changes in forced vital capacity (FVC) ≥ 5% and ≥10%, and diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 10% and ≥15% at 1 year were calculated. Cox proportional hazards analysis was performed to test for associations with mortality.ResultsBaseline lung function severity, age, presence of honeycombing on computed tomography (CT) and echocardiographic pulmonary arterial systolic pressure (PASP) ≥ 40 mm Hg were associated with early mortality, while BAL lymphocytosis was associated with improved survival. A decline in FVC ≥ 5% (hazard ratio [HR]: 3.10, 95% CI: 2.00–4.81, p < 0.001), FVC ≥ 10% (HR: 3.11, 95% CI: 1.94–4.99, p < 0.001), DLCO ≥ 10% (HR: 2.80, 95% CI: 1.78–4.42, p < 0.001) and DLCO ≥ 15% (HR: 2.92, 95% CI: 1.18–4.72, p < 0.001) at 1 year was associated with markedly reduced survival on univariable and multivariable analyses after correcting for demographic variables, disease severity, honeycombing on CT and treatment, as well as BAL lymphocytosis and PASP ≥ 40 mm Hg on echocardiography, in separate models.ConclusionWorsening in FVC and DLCO at 1 year, including a marginal decline in FVC ≥ 5% and DLCO&th

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

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

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

Chaudhuri N, George PM, Kreuter M, Molina-Molina M, Rivera-Ortega P, Stella GM, Stewart I, Spencer LG, Wells AU, Jenkins RGet al., 2021, Hospitalization outcomes for COVID-19 in patients with interstitial lung disease: a potential role for aerodigestive pathophysiology? reply, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 522-524, ISSN: 1073-449X

Journal article

Invernizzi R, Wu BG, Barnett J, Ghai P, Kingston S, Hewitt RJ, Feary J, Li Y, Chua F, Wu Z, Wells AU, 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, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 339-347, ISSN: 1073-449X

RATIONALE: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises following repeated exposure and sensitisation to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease but to date, no study has investigated the composition of microbial communities in the lower airways in CHP. OBJECTIVE: To characterise and compare the airway microbiome in subjects with CHP, idiopathic pulmonary fibrosis (IPF) and controls. METHODS: We prospectively recruited individuals diagnosed with CHP (n=110), IPF (n=45) and controls (n=28). Subjects underwent bronchoalveolar lavage and bacterial DNA was isolated, quantified by qPCR and the 16S rRNA gene was sequenced to characterise the bacterial communities in the lower airways. MAIN MEASUREMENTS AND RESULTS: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both IPF and CHP subjects included Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. However, in IPF, Firmicutes dominated while the percentage of reads assigned to Proteobacteria in the same group was significantly lower compared to CHP subjects. At the genus level, Staphylococcus was increased in CHP and Actinomyces and Veillonella in IPF. The lower airway bacterial burden in CHP subjects was higher than controls but lower than those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. CONCLUSIONS: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF and, notably, bacterial burden in individuals with CHP fails to predict survival.

Journal article

George PM, Hida T, Putman RK, Hino T, Desai SR, Devaraj A, Kumar S, Mackintosh JA, Gudnason V, Hatabu H, Gudmundsson G, Hunninghake GMet al., 2020, Hiatus hernia and interstitial lung abnormalities, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936

Journal article

Ahmetaj-Shala B, Ricky V, Santosh A, Peter G, Nicholas K, Jane Met al., 2020, Cardiorenal tissues express SARS-CoV-2 entry genes and basigin (BSG/CD147) increases with age in endothelial cells, JACC: Basic to Translational Science, Vol: 5, Pages: 1111-1123, ISSN: 2452-302X

Objectives: To obtain mechanistic insight into COVID-19 within a cardiovascular setting.Background: Thrombosis and vascular dysfunction are part of the complex pathology seen in severe COVID-19 and advancing age is the most significant risk factor. Little is known about age and expression of pathways utilised by the COVID-19 virus, SARS-CoV-2, in cardiovascular tissues.Methods: We used publicly available databases (GTEx, GEO and Array Express) to investigate gene expression levels, in adult tissues, of the two putative SARS-CoV-2 receptors, ACE2 and BSG along with a selected range of genes thought to be involved in virus binding/processing. Our analysis included; vessels (aorta and coronary artery), heart (atrial appendage and left ventricle), kidney (cortex), whole blood, lung, colon and spleen along with endothelial cells, nasal and bronchial epithelium and peripheral blood mononuclear cells. Gene expression levels were then analysed for age associations.Results: We found: (i) cardiovascular tissues/endothelial cells express the required genes for SARS-CoV-2 infection, (ii) SARS-CoV-2 receptor pathways, ACE2/TMPRSS2 and BSG/PPIB(A) polarise to lung/epithelium and vessel/endothelium respectively, (iii) expression of host genes are relatively stable with age and (iv) notable exceptions are ACE2 which decreases with age in some tissues and BSG which increases with age in endothelial cells.Conclusion: Our data identifies a positive correlation of BSG with age in endothelial cells. Since BSG is utilised by other pathogens and is implicated in a range of cardiovascular disease, our observations may have relevance to our understanding of mechanisms associated with other pathogens and in the diseases associated with aging respectively.

Journal article

George PM, Barratt SL, Condliffe R, Desai SR, Devaraj A, Forrest I, Gibbons MA, Hart N, Jenkins RG, McAuley DF, Patel BV, Thwaite E, Spencer LGet al., 2020, Respiratory follow-up of patients with COVID-19 pneumonia, Thorax, Vol: 75, Pages: 1009-1016, ISSN: 0040-6376

The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.

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

George PM, Spagnolo P, Kreuter M, Altinisik G, Bonifazi M, Martinez FJ, Molyneaux PL, Renzoni EA, Richeldi L, Tomassetti S, Valenzuela C, Vancheri C, Varone F, Cottin V, Costabel U, Erice ILD working groupet al., 2020, Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities., The Lancet Respiratory Medicine, Vol: 8, Pages: 925-934, ISSN: 2213-2600

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.

Journal article

George PM, Wells AU, Jenkins RG, 2020, Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy, The Lancet Respiratory Medicine, Vol: 8, Pages: 807-815, ISSN: 2213-2600

In December, 2019, reports emerged from Wuhan, China, of a severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the end of April, 2020, over 3 million people had been confirmed infected, with over 1 million in the USA alone, and over 215 000 deaths. The symptoms associated with COVID-19 are diverse, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome. The major risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male sex, and comorbidities such as hypertension and diabetes. However, the role of antifibrotic therapy in patients with IPF who contract SARS-CoV-2 infection, and the scientific rationale for their continuation or cessation, is poorly defined. Furthermore, several licensed and potential antifibrotic compounds have been assessed in models of acute lung injury and viral pneumonia. Data from previous coronavirus infections such as severe acute respiratory syndrome and Middle East respiratory syndrome, as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection. Antifibrotic therapies that are available or in development could have value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and might have a role in preventing fibrosis after SARS-CoV-2 infection.

Journal article

Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali H, Agnew S, Babu S, Barber CM, Barratt S, Bendstrup E, Bianchi S, Villegas DC, Chaudhuri N, Chua F, Coker R, Chang W, Crawshaw A, Crowley LE, Dosanjh D, Fiddler CA, Forrest IA, George P, Gibbons MA, Groom K, Haney S, Hart SP, Heiden E, Henry M, Ho L-P, Hoyles RK, Hutchinson J, Hurley K, Jones M, Jones S, Kokosi M, Kreuter M, MacKay L, Mahendran S, Margaritopoulos G, Molina-Molina M, Molyneaux PL, OBrien A, OReilly K, Packham A, Parfrey H, Poletti V, Porter J, 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, ISARIC4C Investigators, Jenkins RGet al., 2020, Outcome of hospitalisation for COVID-19 in patients with interstitial lung disease: an international multicentre study., Publisher: bioRxiv

Rationale: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. Objectives: To assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population. Methods: An international multicentre 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 1.98, 1.13−3.46). 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.

Working paper

Stock CJW, De Lauretis A, Visca D, Daccord C, Kokosi M, Kouranos V, Margaritopoulos G, George PM, Molyneaux PL, Nihtyanova S, Chua F, Maher TM, Ong V, Abraham DJ, Denton CP, Wells AU, Wain LV, Renzoni EAet al., 2020, Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease, Clinical Rheumatology, Vol: 39, Pages: 1173-1179, ISSN: 0770-3198

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr = 6.6 × 10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.&b

Journal article

George PM, Wells AU, 2020, Contemporary Concise Review 2019: Interstitial lung disease, RESPIROLOGY, Vol: 25, Pages: 756-763, ISSN: 1323-7799

Journal article

Hoffmann-Vold A-M, Maher TM, Philpot EE, Ashrafzadeh A, Barake R, Barsotti S, Bruni C, Carducci P, Carreira PE, Castellví I, Del Galdo F, Distler JHW, Foeldvari I, Fraticelli P, George PM, Griffiths B, Guillén-Del-Castillo A, Hamid AM, Horváth R, Hughes M, Kreuter M, Moazedi-Fuerst F, Olas J, Paul S, Rotondo C, Rubio-Rivas M, Seferian A, Tomčík M, Uzunhan Y, Walker UA, Więsik-Szewczyk E, Distler Oet al., 2020, The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements, The Lancet Rheumatology, Vol: 2, Pages: e71-e83, ISSN: 2665-9913

BackgroundSystemic sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods.MethodsEvidence-based consensus statements for systemic sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in systemic sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement.FindingsBetween July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with systemic sclerosis should be screened for systemic sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in systemic sclerosis; pulmonary function tests support screening and diagnosis; systemic sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to e

Journal article

Bax S, Jacob J, Ahmed R, Bredy C, Dimopoulos K, Kempny A, Kokosi M, Kier G, Renzoni E, Molyneaux PL, Chua F, Kouranos V, George P, McCabe C, Wilde M, Devaraj A, Wells A, Wort SJ, Price LCet al., 2020, Right ventricle to left ventricle ratio at CTPA predicts mortality in interstitial lung disease, Chest, Vol: 157, Pages: 89-98, ISSN: 0012-3692

INTRODUCTION: Patients with interstitial lung disease (ILD) may develop pulmonary hypertension (PH), often disproportionate to ILD severity. Right ventricle to left ventricle diameter ratio (RV:LV) measured at CT pulmonary angiography (CTPA), has been shown to provide valuable information in pulmonary arterial hypertension patients and to predict death or deterioration in acute pulmonary embolism. METHODS: Demographics, ILD subtype, echocardiography and detailed CTPA measurements were collected in consecutive patients undergoing both CTPA and right heart catheterisation (RHC) at the Royal Brompton Hospital between 2005 and 2015. Fibrosis severity was formally scored using CT criteria. RV:LV ratio at CTPA was evaluated by three different methods. Cox-proportional hazard analysis was used to assess the relation of CTPA-derived parameters to predict death or lung transplantation. RESULTS: 92 patients were included: 64% male, mean age 65±11 years, with FVC 57±20% (predicted), TLCOc 22±8% (predicted) and KCOc 51±17% (predicted). PH was confirmed at RHC in 78%. Of all CTPA-derived measures, an RV:LV ratio ≥1.0 strongly predicted mortality or transplantation at univariate analysis (HR 3.26, 95%CI:1.49-7.13, p=0.003), whereas invasive haemodynamic data did not. The RV:LV ratio remained an independent predictor at multivariate analysis (HR: 3.19, CI:1.44-7.10, p=0.004), adjusting for an ILD diagnosis of IPF and CT derived ILD severity. CONCLUSION: An increased RV:LV ratio measured at CTPA provides a simple, non-invasive method of risk stratification in patients with suspected ILD-PH. This should prompt closer follow up, more aggressive treatment and consideration of lung transplantation.

Journal article

Alfieri V, Crisafulli E, Visca D, Chong WH, Stock C, Mori L, de Lauretis A, Tsipouri V, Chua F, Kouranos V, Kokosi M, Hogben C, Molyneaux PL, George PM, Maher TM, Chetta AA, Sestini P, Wells AU, Renzoni EAet al., 2019, Physiological predictors of exertional oxygen desaturation in patients with fibrotic interstitial lung disease, European Respiratory Journal, Vol: 55, Pages: 1-4, ISSN: 0903-1936

Journal article

Nolan CM, Birring SS, Maddocks M, Maher TM, Patel S, Barker RE, Jones SE, Walsh JA, Wynne SC, George PM, Man WD-Cet al., 2019, King's Brief Interstitial Lung Disease questionnaire: responsiveness and minimum clinically important difference, European Respiratory Journal, Vol: 54, ISSN: 0903-1936

Health status is increasingly used in clinical practice to quantify symptom burden and as a clinical trial endpoint in patients with interstitial lung disease (ILD). The Kings Brief Interstitial Lung Disease (KBILD) questionnaire is a brief validated 15-item, disease-specific, health-related quality of life questionnaire that is increasingly used in clinical trials, but little data exist regarding the minimum clinically important difference (MCID). Using pulmonary rehabilitation as a model, we aimed to determine responsiveness of the KBILD and provide estimates of the MCID.KBILD, Chronic Respiratory Questionnaire (CRQ), Medical Research Council dyspnoea scale (MRC) and incremental shuttle walk test (ISW) were measured in 209 patients with ILD (105 with idiopathic pulmonary fibrosis (IPF)) before and after an outpatient pulmonary rehabilitation programme. Changes with intervention and Cohen's effect size were calculated. Anchor- (linear regression and Receiver Operating Characteristic plots) or distribution-based approaches (0.5 * standard deviation, standard error of measurement) were used to estimate the MCID of KBILD domain and total scores.KBILD, CRQ, MRC and ISW improved with intervention and the effect sizes of KBILD domain and total scores ranged from 0.28 to 0.38. Using anchor-based estimates, the MCID estimate for KBILD-Psychological, KBILD-Breathlessness and activities and KBILD-Total score were 5.4, 4.4 and 3.9 respectively. Using distribution-based methods, the MCID estimate for KBILD-Chest symptoms was 9.8. The MCID estimates for KBILD in IPF patients were similar.In patients with ILD and IPF, KBILD is responsive to intervention with an estimated MCID of 3.9 for the total score.

Journal article

Mackintosh JA, Desai SR, Adamali H, Patel K, Chua F, Devaraj A, Kouranos V, Kokosi M, Margaritopoulos G, Renzoni EA, Wells AU, Molyneaux PL, Kumar S, Maher TM, George PMet al., 2019, In patients with idiopathic pulmonary fibrosis the presence of hiatus hernia is associated with disease progression and mortality, European Respiratory Journal, Vol: 53, ISSN: 0903-1936

Journal article

George PM, Patterson CM, Reed AK, Thillai Met al., 2019, Lung transplantation for idiopathic pulmonary fibrosis, LANCET RESPIRATORY MEDICINE, Vol: 7, Pages: 271-282, ISSN: 2213-2600

Journal article

Nolan CM, Maddocks M, Maher TM, Banya W, Patel S, Barker RE, Jones SE, George P, Cullinan P, Man WD-Cet al., 2018, Gait speed and prognosis in patients with idiopathic pulmonary fibrosis: a prospective cohort study, European Respiratory Journal, Vol: 53, Pages: 1-10, ISSN: 0903-1936

The four metre gait speed (4 MGS), a simple physical performance measure and surrogate marker of frailty, consistently predicts adverse prognosis in older adults. We hypothesised that 4 MGS could predict all-cause mortality and non-elective hospitalisation in patients with idiopathic pulmonary fibrosis (IPF).4 MGS and lung function were measured at baseline in 130 outpatients newly diagnosed with IPF. Survival status and non-elective hospital admissions were recorded over one year. We assessed the predictive value of 4 MGS (as a continuous variable and as a binary variable: slow versus preserved 4 MGS) by calculating hazard ratios (HR) using Cox proportional regression, adjusting for potential confounding variables. Receiver Operating Characteristic curves assessed discrimination between the multivariable regression models and established prognostic indices.Continuous 4 MGS and slow 4 MGS were independent predictors of all-cause mortality (4 MGS: HR 0.03 (0.01-0.31), p=0.004; slow 4 MGS: 2.63 (1.01-6.87), p=0.049) and hospitalisation (4 MGS: HR 0.02 (0.01-0.14), p<0.001; slow 4 MGS: 2.76 (1.16-6.58), p=0.02). Multivariable models incorporating 4 MGS or slow 4 MGS had better discrimination for predicting mortality than either the Gender Age Physiology index or Composite Physiologic Index.In patients with IPF, 4 MGS is an independent predictor of all-cause mortality and non-elective hospitalisation.

Journal article

Macaluso C, Furcada JM, Alzaher O, Chaube R, Chua F, Wells AU, Maher TM, George PM, Renzoni EA, Molyneaux PLet al., 2018, The potential impact of azithromycin in idiopathic pulmonary fibrosis, European Respiratory Journal, Vol: 53, Pages: 1-3, ISSN: 0903-1936

Journal article

Visca D, Mori L, Tsipouri V, Fleming S, Firouzi A, Bonini M, Pavitt MJ, Alfieri V, Canu S, Bonifazi M, Boccabella C, De Lauretis A, Stock CJW, Saunders P, Montgomery A, Hogben C, Stockford A, Pittet M, Brown J, Chua F, George PM, Molyneaux PL, Margaritopoulos GA, Kokosi M, Kouranos V, Russell AM, Birring SS, Chetta A, Maher TM, Cullinan P, Hopkinson NS, Banya W, Whitty JA, Adamali H, Spencer LG, Farquhar M, Sestini P, Wells AU, Renzoni EAet al., 2018, Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial, Lancet Respiratory Medicine, Vol: 6, Pages: 759-770, ISSN: 2213-2600

BACKGROUND: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was ass

Journal article

Shanks A-M, Desai SR, Rice A, Thomas SR, Polkey MI, George PMet al., 2018, Restrictive lung defects: parenchymal, chest wall and neuromuscular, THORAX, Vol: 73, Pages: 989-991, ISSN: 0040-6376

Journal article

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