Imperial College London

ProfessorPhilipMolyneaux

Faculty of MedicineNational Heart & Lung Institute

Professor of 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

Publication Type
Year
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261 results found

Wu Z, Smith DJF, Yazbeck L, Saunders P, Smith JA, Maher TM, Molyneaux PLet al., 2024, Cough Severity Visual Analogue Scale Assesses Cough Burden and Predicts Survival in Idiopathic Pulmonary Fibrosis., Am J Respir Crit Care Med

Journal article

Darawshy F, Molyneaux PL, Segal LN, 2024, Looking Beyond the Lower Airways for Microbes Affecting Pulmonary Fibrosis., Am J Respir Crit Care Med

Journal article

Wu Z, Spencer LG, Banya W, Westoby J, Tudor VA, Rivera-Ortega P, Chaudhuri N, Jakupovic I, Patel B, Thillai M, West A, Wijsenbeek M, Maher TM, Smith JA, Molyneaux PLet al., 2024, Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial, The Lancet Respiratory Medicine, ISSN: 2213-2600

BackgroundIdiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis.MethodsThe PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40–90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed.FindingsBetween Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82%

Journal article

Lord JM, Veenith T, Sullivan J, Sharma-Oates A, Richter AG, Greening NJ, McAuley HJC, Evans RA, Moss P, Moore SC, Turtle L, Gautam N, Gilani A, Bajaj M, Wain LV, Brightling C, Raman B, Marks M, Singapuri A, Elneima O, Openshaw PJM, Duggal NA, PHOSP-COVID Study collaborative group, ISARIC4C investigatorset al., 2024, Accelarated immune ageing is associated with COVID-19 disease severity, Immunity and Ageing, Vol: 21, ISSN: 1742-4933

BACKGROUND: The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. RESULTS: We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3-5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28-ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 sur

Journal article

Dixon G, Hague S, Mulholland S, Adamali H, Khin AMN, Thould H, Connon R, Minnis P, Murtagh E, Khan F, Toor S, Lawrence A, Naqvi M, West A, Coker RK, Ward K, Yazbeck L, Hart S, Garfoot T, Newman K, Rivera-Ortega P, Stranks L, Beirne P, Bradley J, Rowan C, Agnew S, Ahmad M, Spencer LG, Aigbirior J, Fahim A, Wilson AM, Butcher E, Chong SG, Saini G, Zulfikar S, Chua F, George PM, Kokosi M, Kouranos V, Molyneaux P, Renzoni E, Vitri B, Wells AU, Nicol LM, Bianchi S, Kular R, Liu H, John A, Barth S, Wickremasinghe M, Forrest IA, Grimes I, Simpson AJ, Fletcher SV, Jones MG, Kinsella E, Naftel J, Wood N, Chalmers J, Crawshaw A, Crowley LE, Dosanjh D, Huntley CC, Walters GI, Gatheral T, Plum C, Bikmalla S, Muthusami R, Stone H, Rodrigues JCL, Tsaneva-Atanasova K, Scotton CJ, Gibbons MA, Barratt SLet al., 2024, Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK., ERJ Open Res, Vol: 10, ISSN: 2312-0541

BACKGROUND: Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting. METHODS: 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey. RESULTS: 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD. CONCLUSION: We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD h

Journal article

Guillen-Guio B, Paynton ML, Allen RJ, Chin DPW, Donoghue LJ, Stockwell A, Leavy OC, Hernandez-Beeftink T, Reynolds C, Cullinan P, Martinez F, Booth HL, Fahy WA, Hall IP, Hart SP, Hill MR, Hirani N, Hubbard RB, McAnulty RJ, Millar AB, Navaratnam V, Oballa E, Parfrey H, Saini G, Sayers I, Tobin MD, Whyte MKB, Adegunsoye A, Kaminski N, Ma S-F, Strek ME, Zhang Y, Fingerlin TE, Molina-Molina M, Neighbors M, Sheng XR, Oldham JM, Maher TM, Molyneaux PL, Flores C, Noth I, Schwartz DA, Yaspan BL, Jenkins RG, Wain LV, Hollox EJet al., 2024, Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis., ERJ Open Res, Vol: 10, ISSN: 2312-0541

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. METHODS: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. RESULTS: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. CONCLUSION: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Journal article

Koudstaal T, Funke-Chambour M, Kreuter M, Molyneaux PL, Wijsenbeek MSet al., 2023, Pulmonary fibrosis: from pathogenesis to clinical decision-making., Trends Mol Med, Vol: 29, Pages: 1076-1087

Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life (QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.

Journal article

Hunter B, Argyros C, Inglese M, Linton-Reid K, Pulzato I, Nicholson AG, Kemp SV, L Shah P, Molyneaux PL, Mcnamara C, Burn T, Guilhem E, Mestas Nunez M, Hine J, Choraria A, Ratnakumar P, Bloch S, Jordan S, Padley S, Ridge CA, Robinson G, Robbie H, Barnett J, Silva M, Desai S, Lee RW, Aboagye EO, Devaraj Aet al., 2023, Radiomics-based decision support tool assists radiologists in small lung nodule classification and improves lung cancer early diagnosis, BRITISH JOURNAL OF CANCER, ISSN: 0007-0920

Journal article

Barnett JL, Maher TM, Quint JK, Adamson A, Wu Z, Smith DJF, Rawal B, Nair A, Walsh SLF, Desai SR, George PM, Kokosi M, Jenkins G, Kouranos V, Renzoni EA, Rice A, Nicholson AG, Chua F, Wells AU, Molyneaux PL, Devaraj Aet al., 2023, Combination of BAL and computed tomography differentiates progressive and non-progressive fibrotic lung diseases, American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 975-982, ISSN: 1073-449X

Rationale: Identifying patients with pulmonary fibrosis (PF) at risk of progression can guide management. Objectives: To explore the utility of combining baseline BAL and computed tomography (CT) in differentiating progressive and nonprogressive PF. Methods: The derivation cohort consisted of incident cases of PF for which BAL was performed as part of a diagnostic workup. A validation cohort was prospectively recruited with identical inclusion criteria. Baseline thoracic CT scans were scored for the extent of fibrosis and usual interstitial pneumonia (UIP) pattern. The BAL lymphocyte proportion was recorded. Annualized FVC decrease of >10% or death within 1 year was used to define disease progression. Multivariable logistic regression identified the determinants of the outcome. The optimum binary thresholds (maximal Wilcoxon rank statistic) at which the extent of fibrosis on CT and the BAL lymphocyte proportion could distinguish disease progression were identified. Measurements and Main Results: BAL lymphocyte proportion, UIP pattern, and fibrosis extent were significantly and independently associated with disease progression in the derivation cohort (n = 240). Binary thresholds for increased BAL lymphocyte proportion and extensive fibrosis were identified as 25% and 20%, respectively. An increased BAL lymphocyte proportion was rare in patients with a UIP pattern (8 of 135; 5.9%) or with extensive fibrosis (7 of 144; 4.9%). In the validation cohort (n = 290), an increased BAL lymphocyte proportion was associated with a significantly lower probability of disease progression in patients with nonextensive fibrosis or a non-UIP pattern. Conclusions: BAL lymphocytosis is rare in patients with extensive fibrosis or a UIP pattern on CT. In patients without a UIP pattern or with limited fibrosis, a BAL lymphocyte proportion of ⩾25% was associated with a lower likelihood of progression.

Journal article

C-MOREPHOSP-COVID Collaborative Group, 2023, Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study, The Lancet Respiratory Medicine, Vol: 11, Pages: 1003-1019, ISSN: 2213-2600

INTRODUCTION: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. METHODS: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. FINDINGS: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MR

Journal article

Brightling CE, Evans RA, Singapuri A, Smith N, Wain LV, PHOSP-COVID Collaborative Groupet al., 2023, Long COVID research: an update from the PHOSP-COVID Scientific Summit., Lancet Respir Med, Vol: 11, Pages: e93-e94

Journal article

Hewitt R, Puttur F, Gaboriau D, Fercoq F, Fresquet M, Traves W, Yates LL, Walker S, Molyneaux P, Kemp S, Nicholson A, Rice A, Roberts E, Lennon R, Carlin L, Byrne A, Maher T, Lloyd Cet al., 2023, Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis, Nature Communications, Vol: 14, ISSN: 2041-1723

Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

Journal article

Saunders P, Wu Z, Fahy WA, Stewart ID, Saini G, Smith DJF, Braybrooke R, Stock C, Renzoni EA, Johnson SR, Jenkins RG, Belvisi MG, Smith JA, Maher TM, Molyneaux PLet al., 2023, The burden and impact of cough in patients with idiopathic pulmonary fibrosis: an analysis of the prospective observational PROFILE study, Annals of the American Thoracic Society, Vol: 20, Pages: 1267-1273, ISSN: 1546-3222

RATIONALE: Cough is a commonly reported symptom in idiopathic pulmonary fibrosis (IPF) that negatively impacts patient-reported quality of life. However, both the burden of cough at diagnosis and the behaviour of cough over time have not been systematically described in patients with IPF. OBJECTIVES: By utilising data prospectively collected as part of the PROFILE study we sought to assess cough burden and the impact that this has on quality of life within a cohort of patients with newly diagnosed IPF. We also re-examined the previously described relationship between cough and mortality and the association of cough with the MUC5B promoter polymorphism. METHODS: The PROFILE study is a multicentre, prospective, observational, longitudinal cohort study of incident IPF. Leicester cough questionnaire (LCQ) scores were recorded at baseline in 632 subjects and then repeated 6 monthly in a subset (n=216) of the cohort. RESULTS: The median LCQ at diagnosis was 16.1 (inter-quartile range 6.5). LCQ scores remained stable over the subsequent year in the majority of patients. There was a weak association between LCQ score and baseline lung function with worse cough related quality of life associating with more severe physiological impairment. Cough scores were not associated with subsequent mortality after correcting for baseline lung function. Furthermore, there was no relationship between LCQ score and MUC5B promotor polymorphism status. CONCLUSION: The burden of cough in IPF is high. Although cough is weakly associated with disease severity at baseline, cough-specific QoL as measured by the LCQ, confers no prognostic value. Cough-specific QoL burden remains relatively stable over time and does not associate with MUC5B promotor polymorphism.

Journal article

Jackson C, Stewart ID, Plekhanova T, Cunningham PS, Hazel AL, Al-Sheklly B, Aul R, Bolton CE, Chalder T, Chalmers JD, Chaudhuri N, Docherty AB, Donaldson G, Edwardson CL, Elneima O, Greening NJ, Hanley NA, Harris VC, Harrison EM, Ho L-P, Houchen-Wolloff L, Howard LS, Jolley CJ, Jones MG, Leavy OC, Lewis KE, Lone NI, Marks M, McAuley HJC, McNarry MA, Patel BV, Piper-Hanley K, Poinasamy K, Raman B, Richardson M, Rivera-Ortega P, Rowland-Jones SL, Rowlands AV, Saunders RM, Scott JT, Sereno M, Shah AM, Shikotra A, Singapuri A, Stanel SC, Thorpe M, Wootton DG, Yates T, Gisli Jenkins R, Singh SJ, Man WD-C, Brightling CE, Wain LV, Porter JC, Thompson AAR, Horsley A, Molyneaux PL, Evans RA, Jones SE, Rutter MK, Blaikley JF, PHOSP-COVID Study Collaborative Groupet al., 2023, Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study, The Lancet Respiratory Medicine, Vol: 11, Pages: 673-684, ISSN: 2213-2600

BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended

Journal article

Guillen-Guio B, Paynton ML, Allen RJ, Chin DPW, Donoghue LJ, Stockwell A, Leavy OC, Hernandez-Beeftink T, Reynolds C, Cullinan P, Martinez F, CleanUP-IPF Investigators of the Pulmonary Trials Cooperative, Booth HL, Fahy WA, Hall IP, Hart SP, Hill MR, Hirani N, Hubbard RB, McAnulty RJ, Millar AB, Navaratnam V, Oballa E, Parfrey H, Saini G, Sayers I, Tobin MD, Whyte MKB, Adegunsoye A, Kaminski N, Shwu-Fan M, Strek ME, Zhang Y, Fingerlin TE, Molina-Molina M, Neighbors M, Sheng XR, Oldham JM, Maher TM, Molyneaux PL, Flores C, Noth I, Schwartz DA, Yaspan BL, Jenkins RG, Wain LV, Hollox EJet al., 2023, Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis., medRxiv

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. METHODS: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. RESULTS: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. CONCLUSION: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Journal article

Nolan CM, Schofield SJ, Maddocks M, Patel S, Barker RE, Walsh JA, Polgar O, George PM, Molyneaux PL, Maher TM, Cullinan P, Man WD-Cet al., 2023, Change in gait speed and adverse outcomes in patients with idiopathic pulmonary fibrosis: a prospective cohort study, Respirology, Vol: 28, Pages: 649-658, ISSN: 1323-7799

BACKGROUND AND OBJECTIVE: Gait speed is associated with survival in individuals with idiopathic pulmonary fibrosis (IPF). The extent to which four-metre gait speed (4MGS) decline predicts adverse outcome in IPF remains unclear. We aimed to examine longitudinal 4MGS change and identify a cut-point associated with adverse outcome. METHODS: In a prospective cohort study, we recruited 132 individuals newly diagnosed with IPF and measured 4MGS change over 6 months. Death/first hospitalization at 6 months were composite outcome events. Complete data (paired 4MGS plus index event) were available in 85 participants; missing 4MGS data were addressed using multiple imputation. Receiver-Operating Curve plots identified a 4MGS change cut-point. Cox proportional-hazard regression assessed the relationship between 4MGS change and time to event. RESULTS: 4MGS declined over 6 months (mean [95% CI] change: -0.05 [-0.09 to -0.01] m/s; p = 0.02). A decline of 0.07 m/s or more in 4MGS over 6 months had better discrimination for the index event than change in 6-minute walk distance, forced vital capacity, Composite Physiologic Index or Gender Age Physiology index. Kaplan-Meier curves demonstrated a significant difference in time to event between 4MGS groups (substantial decline: >-0.07 m/s versus minor decline/improvers: ≤-0.07 m/s; p = 0.007). Those with substantial decline had an increased risk of hospitalization/death (adjusted hazard ratio [95% CI] 4.61 [1.23-15.83]). Similar results were observed in multiple imputation analysis. CONCLUSION: In newly diagnosed IPF, a substantial 4MGS decline over 6 months is associated with shorter time to hospitalization/death at 6 months. 4MGS change has potential as a surrogate endpoint for interventions aimed at modifying hospitalization/death.

Journal article

Oldham JM, Johnson KW, Albers GJ, Calamita E, Mah J, Ghai P, Hewitt RJ, Maher TM, Molyneaux PL, Huang M, Byrne AJet al., 2023, Airway soluble CSF1R predicts progression in patients with idiopathic pulmonary fibrosis, ERJ OPEN RESEARCH, Vol: 9

Journal article

Oldham JM, Allen RJ, Lorenzo-Salazar JM, Molyneaux PL, Ma S-F, Joseph C, Kim JS, Guillen-Guio B, Hernández-Beeftink T, Kropski JA, Huang Y, Lee CT, Adegunsoye A, Pugashetti JV, Linderholm AL, Vo V, Strek ME, Jou J, Muñoz-Barrera A, Rubio-Rodriguez LA, Hubbard R, Hirani N, Whyte MKB, Hart S, Nicholson AG, Lancaster L, Parfrey H, Rassl D, Wallace W, Valenzi E, Zhang Y, Mychaleckyj J, Stockwell A, Kaminski N, Wolters PJ, Molina-Molina M, Banovich NE, Fahy WA, Martinez FJ, Hall IP, Tobin MD, Maher TM, Blackwell TS, Yaspan BL, Jenkins RG, Flores C, Wain LV, Noth Iet al., 2023, PCSK6 and survival in idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 207, Pages: 1515-1524, ISSN: 1073-449X

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. OBJECTIVE: To identify and validate molecular determinants of IPF survival. METHODS: A staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5x10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5x10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. MAIN RESULTS: After quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45x10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression and plasma concentration were associated with reduced transplant-free survival. CONCLUSIONS: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/lic

Journal article

Zheng B, Vivaldi G, Daines L, Leavy OC, Richardson M, Elneima O, McAuley HJC, Shikotra A, Singapuri A, Sereno M, Saunders RM, Harris VC, Houchen-Wolloff L, Greening NJ, Pfeffer PE, Hurst JR, Brown JS, Shankar-Hari M, Echevarria C, De Soyza A, Harrison EM, Docherty AB, Lone N, Quint JK, Chalmers JD, Ho L-P, Horsley A, Marks M, Poinasamy K, Raman B, Heaney LG, Wain LV, Evans RA, Brightling CE, Martineau A, Sheikh A, Abel K, Adamali H, Adeloye D, Adeyemi O, Adrego R, Aguilar Jimenez LA, Ahmad S, Ahmad Haider N, Ahmed R, Ahwireng N, Ainsworth M, Al-Sheklly B, Alamoudi A, Ali M, Aljaroof M, All AM, Allan L, Allen RJ, Allerton L, Allsop L, Almeida P, Altmann D, Alvarez Corral M, Amoils S, Anderson D, Antoniades C, Arbane G, Arias A, Armour C, Armstrong L, Armstrong N, Arnold D, Arnold H, Ashish A, Ashworth A, Ashworth M, Aslani S, Assefa-Kebede H, Atkin C, Atkin P, Aul R, Aung H, Austin L, Avram C, Ayoub A, Babores M, Baggott R, Bagshaw J, Baguley D, Bailey L, Baillie JK, Bain S, Bakali M, Bakau M, Baldry E, Baldwin D, Baldwin M, Ballard C, Banerjee A, Bang B, Barker RE, Barman L, Barratt S, Barrett F, Basire D, Basu N, Bates M, Bates A, Batterham R, Baxendale H, Bayes H, Beadsworth M, Beckett P, Beggs M, Begum M, Beirne P, Bell D, Bell R, Bennett K, Beranova E, Bermperi A, Berridge A, Berry C, Betts S, Bevan E, Bhui K, Bingham M, Birchall K, Bishop L, Bisnauthsing K, Blaikely J, Bloss A, Bolger A, Bolton CE, Bonnington J, Botkai A, Bourne C, Bourne M, Bramham K, Brear L, Breen G, Breeze J, Briggs A, Bright E, Brightling CE, Brill S, Brindle K, Broad L, Broadley A, Brookes C, Broome M, Brown A, Brown J, Brown JS, Brown M, Brown V, Brugha T, Brunskill N, Buch M, Buckley P, Bularga A, Bullmore E, Burden L, Burdett T, Burn D, Burns G, Burns A, Busby J, Butcher R, Butt A, Byrne S, Cairns P, Calder PC, Calvelo E, Carborn H, Card B, Carr C, Carr L, Carson G, Carter P, Casey A, Cassar M, Cavanagh J, Chablani M, Chalder T, Chalmers JD, Chambers RC, Chan F, Channon KM, Chapman Ket al., 2023, Determinants of recovery from post-COVID-19 dyspnoea: analysis of UK prospective cohorts of hospitalised COVID-19 patients and community-based controls, The Lancet Regional Health. Europe, Vol: 29, Pages: 1-13, ISSN: 2666-7762

BackgroundThe risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea.MethodsWe used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up.FindingsWe included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission).InterpretationFactors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19.FundingPHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publica

Journal article

Chua F, Low S, Chai GT, Inoue Y, Ong V, Wongkarnjana A, Kawkitinarong K, Song JW, Hamid ZA, Aziz AA, Campomanes M, Maher TM, Molyneaux PL, Syakirin Set al., 2023, Knowledge gaps in fibrotic interstitial lung disease in pan-Asian populations: data not missing at random?, The Lancet Respiratory Medicine, Vol: 11, Pages: 502-504, ISSN: 2213-2600

Journal article

Zhang D, Li Q, Povysil G, Newton CA, Maher TM, Molyneaux PL, Noth I, Martinez FJ, Raghu G, Todd JL, Palmer SM, Platt A, Petrovski S, Goldstein DB, Garcia CKet al., 2023, Genome-wide Enrichment of TERT Rare Variants in Idiopathic Pulmonary Fibrosis Patients of Latino Ancestry (vol 10, 1411, 2023), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 207, Pages: 1411-1411, ISSN: 1073-449X

Journal article

Myall KJ, West AG, Martinovic JL, Lam JL, Roque D, Wu Z, Maher TM, Molyneaux PL, Suh E-S, Kent BDet al., 2023, Nocturnal hypoxemia associates with symptom progression and mortality in patients with progressive fibrotic interstitial lung disease., Chest, Pages: 1-34, ISSN: 0012-3692

BACKGROUND: Obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are common in patients with fibrotic interstitial lung disease (F-ILD), but their relationship with disease outcomes remains unclear. RESEARCH QUESTIONS: What is the relationship between NH and OSA and clinical outcomes in patients with F-ILD? STUDY DESIGN AND METHODS: Prospective observational cohort study of patients with F-ILD and without daytime hypoxemia. Subjects underwent home sleep study at baseline and were followed up for at least one year or until death. NH was defined as ≥ 10% of sleep with SpO2 <90%. OSA was defined as an apnea-hypopnea index of ≥ 15/hour. RESULTS: Among 102 (male 74.5%; age 73.0 ± 8.7 years; FVC 2.74 ± 0.78L; 91.1% idiopathic pulmonary fibrosis) participants, 20 (19.6%) demonstrated prolonged nocturnal hypoxemia (NH), and 32 (31.4%) had obstructive sleep apnea (OSA). There were no significant differences between those with and without NH or OSA at baseline. Despite this, nocturnal hypoxemia was associated with a more rapid decline in both quality of life as measured by the King's Brief Interstitial Lung Disease questionnaire (change -11.3 ± 5.3 points in the NH group vs -6.7 ± 6.5 in those without NH, p=0.005) and higher all-cause mortality at one year (HR 8.21; 95% CI 2.40-28.1, p<0.001). No statistically significant difference was seen between the groups in annualised change in measures of pulmonary function testing. INTERPRETATION: Prolonged NH but not OSA is associated with worsening disease-related quality of life and increased mortality in patients with F-ILD.

Journal article

Maher TM, Ford P, Brown KK, Costabel U, Cottin V, Danoff SK, Groenveld I, Helmer E, Jenkins RG, Milner J, Molenberghs G, Penninckx B, Randall MJ, Van Den Blink B, Fieuw A, Vandenrijn C, Rocak S, Seghers I, Shao L, Taneja A, Jentsch G, Watkins TR, Wuyts WA, Kreuter M, Verbruggen N, Prasad N, Wijsenbeek MS, Chambers D, Chia M, Corte T, Glaspole I, Goh N, Holmes M, Malouf M, Thien F, Veitch E, Bondue B, Dahlqvist C, Froidure A, Slabbynck H, Wuyts W, Cartagena Salinas C, Feijoó Seoane R, Martínez V, Maturana R, Pavie Gallegos J, Rosenblut A, Silva R, Undurraga Pereira A, Doubkova M, Pauk N, Plackova M, Sterclova M, Bendstrup E, Shaker SB, Titlestad I, Budweiser S, Grohé C, Koschel D, Kreuter M, Prasse A, Weber M, Wirtz H, Antoniou K, Daniil Z, Gaga M, Papakosta D, Izumi S, Okamoto M, Guerreros Benavides A, Iberico Barrera C, Peña Villalobos AM, Campo Ezquibela A, Cifrian Martinez JM, Fernandez Fabrellas E, Leiro V, Molina-Molina M, Nieto Barbero A, Sellares Torres J, Valenzuela C, Cheng S-L, Kuo P-H, Lee K-Y, Sheu C-C, Gunen H, Mogulkoc Bishop N, Nayci S, Adamali H, Bianchi S, Chaudhuri N, Gibbons M, Hart S, Molyneaux P, Parfrey H, Saini G, Spencer LG, Wiscombe S, Antin-Ozerkis D, Bascom R, Belperio J, Britt E, Fitzgerald J, Gomez Manjarres D, Gotfried M, Gupta N, Hotchkin D, Kaye M, Kreider M, Kureishy S, Lacamera P, Lancaster L, Lasky J, Lorch D, Mannem H, Morrow L, Moua T, Nambiar A, Raghu G, Raj R, Ramaswamy M, Reddy R, Russell T, Scholand MB, Shea B, Suliman S, Swigris J, Thavarajah K, Tolle L, Tomic R, Warshoff N, Wesselius L, Yung G, Bergna M, De Salvo M, Fernandez Acquier M, Rodriguez A, Saez Scherbovsky P, Assayag D, Dhar A, Khalil N, Morisset J, Provencher S, Ryerson C, Shapera S, Bourdin A, Crestani B, Lebargy F, Reynaud-Gaubert M, Bonella FT, Claussen M, Hammerl P, Karagiannidis C, Keller C, Randerath W, Stubbe B, Csánky E, Medgyasszay B, Muller V, Adir Y, Bar-Shai A, Berkman N, Fink G, Kramer M, Shitrit D, Bargagli E, Gasparini S, Harari S, Ravaglia C, Richet al., 2023, Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis, JAMA: Journal of the American Medical Association, Vol: 329, Pages: 1567-1578, ISSN: 0098-7484

Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL

Journal article

van der Vis JJ, Prasse A, Renzoni EA, Stock CJW, Caliskan C, Maher TM, Bonella F, Borie R, Crestani B, Petrek M, Wuyts WA, Wind AE, Molyneaux PL, Grutters JC, van Moorsel CHMet al., 2023, MUC5B rs35705950 minor allele associates with older age and better survival in idiopathic pulmonary fibrosis, Respirology, Vol: 28, Pages: 455-464, ISSN: 1323-7799

Background and Objective:The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients.Methods:In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed.Results:In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42–49]) compared to non-carriers (29 months [CI: 26–33]; p = 4 × 10−12).Conclusion:MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.

Journal article

Reynolds CJ, Del Greco M F, Allen RJ, Flores C, Jenkins RG, Maher TM, Molyneaux PL, Noth I, Oldham JM, Wain LV, An J, Ong J-S, MacGregor S, Yates TA, Cullinan P, Minelli Cet al., 2023, The causal relationship between gastro-esophageal reflux disease and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study., Eur Respir J

BACKGROUND: Gastro-esophageal reflux disease (GERD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GERD causes IPF, or IPF causes GERD, or because of confounding by factors, such as smoking, associated with both GERD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GERD and IPF are causally related. METHODS AND RESULTS: A bidirectional two-sample MR was performed to estimate the causal effect of GERD on IPF risk, and of IPF on GERD risk, using genetic data from the largest GERD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available. GERD increased the risk of IPF, with an odds ratio (OR) of 1.6 (95% Confidence Interval, CI: 1.04-2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GERD, with an OR of 0.999 (95%CI: 0.997-1.000; p=0.245). CONCLUSION: We found that GERD increases the risk of IPF, but found no evidence that IPF increases the risk of GERD. GERD should be considered in future studies of IPF risk, and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GERD on IPF should also be investigated.

Journal article

Garfield BE, Bianchi P, Arachchillage DJ, Caetano F, Desai S, Doyle J, Hernandez Caballero C, Doyle A-M, Mehta S, Law A, Jaggar S, Kokosi M, Molyneaux PL, Passariello M, Naja M, Ridge C, Alçada J, Patel B, Singh S, Ledot Set al., 2023, A comparison of long-term outcomes in patients managed with venovenous extracorporeal membrane oxygenation in the first and second waves of the COVID-19 pandemic in the United Kingdom.., Critical Care Medicine, Vol: 51, Pages: 1064-1073, ISSN: 0090-3493

OBJECTIVES: Early studies of venovenous extracorporeal membrane oxygenation (ECMO) in COVID-19 have revealed similar outcomes to historical cohorts. Changes in the disease and treatments have led to differences in the patients supported on venovenous ECMO in the first and second waves. We aimed to compare these two groups in both the acute and follow-up phase. DESIGN: Retrospective single-center cohort study comparing mortality at censoring date (November 30, 2021) and decannulation, patient characteristics, complications and lung function and quality of life (QOL-by European Quality of Life 5 Dimensions 3 Level Version) at first follow-up in patients supported on venovenous ECMO between wave 1 and wave 2 of the COVID-19 pandemic. SETTING: Critical care department of a severe acute respiratory failure service. PATIENTS: Patients supported on ECMO for COVID-19 between wave 1 (March 17, 2020, to August 31, 2020) and wave 2 (January 9, 2020, to May 25, 2021). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients were included in our analysis. Survival at censoring date (χ2, 6.35; p = 0.012) and decannulation (90.4% vs 70.0%; p < 0.001) was significantly lower in the second wave, while duration of ECMO run was longer (12.0 d [18.0-30.0 d] vs 29.5 d [15.5-58.3 d]; p = 0.005). Wave 2 patients had longer application of noninvasive ventilation (NIV) prior to ECMO and a higher frequency of barotrauma. Patient age and NIV use were independently associated with increased mortality (odds ratio 1.07 [1.01-1.14]; p = 0.025 and 3.37 [1.12-12.60]; p = 0.043, respectively). QOL and lung function apart from transfer coefficient of carbon monoxide corrected for hemoglobin was similar at follow-up across the waves. CONCLUSIONS: Most patients with COVID-19 supported on ECMO in both waves survived in the short and longer term. At follow-up patients had similar lung function and QOL across the two waves. This suggests that ECMO has an ongoing role in

Journal article

Stewart I, Molyneaux PL, Fabbri L, Quint JK, Walsh SLF, Weeks M, Jenkins RGet al., 2023, Residual lung abnormalities following COVID-19 hospitalization: interim analysis of the UKILD Post-COVID study, American Journal of Respiratory and Critical Care Medicine, Vol: 207, Pages: 693-703, ISSN: 1073-449X

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage.Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post–COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata.Methods: The PHOSP–COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP–COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up.Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83–155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05–1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00–1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07–1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6–9.5), rising to 11.7% (95% CrI, 10.3–13.1) in the sensitivity analysis.Conclusions: Residual lung abnormalities were estimated in up to 11% of

Journal article

Dawes TJW, McCabe C, Dimopoulos K, Stewart I, Bax S, Harries C, Samaranayake CB, Kempny A, Molyneaux PL, Seitler S, Semple T, Li W, George PM, Kouranos V, Chua F, Renzoni EA, Kokosi M, Jenkins G, Wells AU, Wort SJ, Price LCet al., 2023, Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study, Respirology, Vol: 28, Pages: 262-272, ISSN: 1323-7799

Background and ObjectivePulmonary hypertension is a life-limiting complication of interstitial lung disease (ILD-PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD-PH was associated with improved survival.MethodsConsecutive incident patients with ILD-PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow-up and survival data modelled by Bayesian methods.ResultsThe diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non-specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint-modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity-matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: −0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04).ConclusionPDE5i treatment in ILD-PH should be investigated by a prospective randomized trial.

Journal article

McAuley HJC, Evans RA, Bolton CE, Brightling CE, Chalmers JD, Docherty AB, Elneima O, Greenhaff PL, Gupta A, Harris VC, Harrison EM, Ho L-P, Horsley A, Houchen-Wolloff L, Jolley CJ, Leavy OC, Lone NI, Man WD-C, Marks M, Parekh D, Poinasamy K, Quint JK, Raman B, Richardson M, Saunders RM, Sereno M, Shikotra A, Singapuri A, Singh SJ, Steiner M, Tan AL, Wain LV, Welch C, Whitney J, Witham MD, Lord J, Greening NJ, PHOSP-COVID Study Collaborative Groupet al., 2023, Prevalence of physical frailty, including risk factors, up to 1 year after hospitalisation for COVID-19 in the UK: a multicentre, longitudinal cohort study., EClinicalMedicine, Vol: 57, Pages: 1-13, ISSN: 2589-5370

BACKGROUND: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. METHODS: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group-robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)-at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. FINDINGS: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. INTERPRETATION: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although

Journal article

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