Imperial College London

ProfessorFanChung

Faculty of MedicineNational Heart & Lung Institute

Professor of Respiratory Medicine
 
 
 
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Contact

 

+44 (0)20 7594 7954f.chung Website

 
 
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Assistant

 

Miss Carolyn Green +44 (0)20 7594 7959

 
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Location

 

227BGuy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
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1319 results found

Qiu M, Wei S, Lai Z, Huang P, Wang Z, Zhong C, Chen Y, Zhang X, Lin X, Zeng Q, Chung KF, Zhang Q, Xie J, Li Set al., 2020, Early radiologic and bronchoscopic changes after bronchial thermoplasty in patients with severe asthma., Exp Ther Med, Vol: 20, ISSN: 1792-0981

Bronchial thermoplasty (BT) is a treatment to reduce the airway smooth muscle mass by delivering radiofrequency thermal energy to the airways. BT is used in patients with severe asthma. The present study reported on cases of pneumothorax directly after BT and retrospectively analyzed early radiologic and bronchoscopic modifications after BT. The clinical data and radiologic and bronchoscopic findings of 12 patients with severe asthma who were subjected to BT between July 2014 and October 2017 were analyzed. A total of 33 chest radiographs were collected within 18-24 h after BT. Radiological abnormalities were observed in 32 radiographs as atelectasis (53.1%), peribronchial consolidations (84.4%), pleural effusion (18.8%), effusion in oblique fissures (3.1%), pleural thickening (6.3%) and pneumothorax (3.1%). Of note, one patient suffered pneumothorax after the third BT session and underwent chest drain insertion, followed by mechanical ventilation at the intensive care unit and multiple bronchoscopic interventions, which revealed extensive phlegm plugs. A total of six patients with worsened symptoms and lobar atelectasis also required bronchoscopic intervention, which revealed that phlegm plugs occluded the bronchus in the treated lobe. No bronchoscopic intervention was required in the remaining five patients. During 16-30 days of follow-up, 95.7% of the findings on chest radiography were resolved. To the best of our knowledge, the present study reported the first case of pneumothorax following BT. Early radiologic modifications such as atelectasis and peribronchial consolidations appear common after BT. However, whether bronchoscopic intervention is required for atelectasis following BT warrants further investigation. Of note, BT should be audited and recorded in detail to ideally contribute to a framework of clinical trials to improve risk-benefit evaluations and the selection of patients likely to benefit from treatment.

Journal article

Xiao D, Chen Z, Wu S, Huang K, Xu J, Yang L, Xu Y, Zhang X, Bai C, Kang J, Ran P, Shen H, Wen F, Yao W, Sun T, Shan G, Yang T, Lin Y, Zhu J, Wang R, Shi Z, Zhao J, Ye X, Song Y, Wang Q, Hou G, Zhou Y, Li W, Ding L, Wang H, Chen Y, Guo Y, Xiao F, Lu Y, Peng X, Zhang B, Wang Z, Zhang H, Bu X, Zhang X, An L, Zhang S, Cao Z, Zhan Q, Yang Y, Liang L, Liu Z, Zhang X, Cheng A, Cao B, Dai H, Chung KF, He J, Wang C, China Pulmonary Health Study Groupet al., 2020, Prevalence and risk factors of small airway dysfunction, and association with smoking, in China: findings from a national cross-sectional study., Lancet Respir Med, Vol: 8, Pages: 1081-1093

BACKGROUND: Small airway dysfunction is a common but neglected respiratory abnormality. Little is known about its prevalence, risk factors, and prognostic factors in China or anywhere else in the world. We aimed to estimate the prevalence of small airway dysfunction using spirometry before and after bronchodilation, both overall and in specific population subgroups; assess its association with a range of lifestyle and environmental factors (particularly smoking); and estimate the burden of small airway dysfunction in China. METHODS: From June, 2012, to May, 2015, the nationally representative China Pulmonary Health study invited 57 779 adults to participate using a multistage stratified sampling method from ten provinces (or equivalent), and 50 479 patients with valid lung function testing results were included in the analysis. We diagnosed small airway dysfunction on the basis of at least two of the following three indicators of lung function being less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow (FEF) 50%, and FEF 75%. Small airway dysfunction was further categorised into pre-small airway dysfunction (defined as having normal FEV1 and FEV1/forced vital capacity [FVC] ratio before bronchodilator inhalation), and post-small airway dysfunction (defined as having normal FEV1 and FEV1/FVC ratio both before and after bronchodilator inhalation). Logistic regression yielded adjusted odds ratios (ORs) for small airway dysfunction associated with smoking and other lifestyle and environmental factors. We further estimated the total number of cases of small airway dysfunction in China by applying present study findings to national census data. FINDINGS: Overall the prevalence of small airway dysfunction was 43·5% (95% CI 40·7-46·3), pre-small airway dysfunction was 25·5% (23·6-27·5), and post-small airway dysfunction was 11·3% (10·3-12·5). After multifactor regression analysis, the r

Journal article

Haji G, Wiegman C, Michaeloudes C, Patel M, Curtis K, Bhavsar P, Polkey M, Adcock I, Chung Ket al., 2020, Mitochondrial dysfunction in airways and quadriceps muscle of patients with Chronic Obstructive Pulmonary Disease, Respiratory Research, ISSN: 1465-9921

Journal article

Kermani NZ, Pavlidis S, Xie J, Sun K, Loza M, Baribaud F, Fowler SJ, Shaw DE, Fleming LJ, Howarth PH, Sousa AR, Corfield J, Auffray C, De Meulder B, Sterk PJ, Guo Y, Uddin M, Djukanovic R, Adcock IM, Chung KF, U-BIOPRED study groupet al., 2020, Instability of sputum molecular phenotypes in U-BIOPRED severe asthma, European Respiratory Journal, ISSN: 0903-1936

Journal article

Roberts G, Fontanella S, Selby A, Howard R, Filippi S, Hedlin G, Nordlund B, Howarth P, Hashimoto S, Brinkman P, Fleming LJ, Murray C, Bush A, Frey U, Singer F, Schoos A-MM, van Aalderen W, Djukanovic R, Chung KF, Sterk PJ, Adnan C, U-BIOPRED Consortiumet al., 2020, Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma, Journal of Allergy and Clinical Immunology, Vol: 146, Pages: 821-830, ISSN: 0091-6749

BACKGROUND: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. OBJECTIVE: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. METHODS: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. RESULTS: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. CONCLUSIONS: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.

Journal article

Ramu S, Calvén J, Michaeloudes C, Menzel M, Akbarshahi H, Chung KF, Uller Let al., 2020, TLR3/TAK1 signalling regulates rhinovirus-induced interleukin-33 in bronchial smooth muscle cells., ERJ Open Res, Vol: 6, ISSN: 2312-0541

Background: Asthma exacerbations are commonly associated with rhinovirus (RV) infection. Interleukin-33 (IL-33) plays an important role during exacerbation by enhancing Type 2 inflammation. Recently we showed that RV infects bronchial smooth muscle cells (BSMCs) triggering production of interferons and IL-33. Here we compared levels of RV-induced IL-33 in BSMCs from healthy and asthmatic subjects, and explored the involvement of pattern-recognition receptors (PRRs) and downstream signalling pathways in IL-33 expression. Method: BSMCs from healthy and severe and non-severe asthmatic patients were infected with RV1B or stimulated with the PRR agonists poly(I:C) (Toll-like receptor 3 (TLR3)), imiquimod (TLR7) and poly(I:C)/LyoVec (retinoic acid-inducible gene 1 (RIG-I)/melanoma differentiation-associated protein 5 (MDA5)). Knockdown of TLR3, RIG-I and MDA5 was performed, and inhibitors targeting TBK1, nuclear factor-κB (NF-κB) and transforming growth factor (TGF)-β-activated kinase 1 (TAK1) were used. Gene and protein expression were assessed. Results: RV triggered IL-33 gene and protein expression in BSMCs. BSMCs from patients with non-severe asthma showed higher baseline and RV-induced IL-33 gene expression compared to cells from patients with severe asthma and healthy controls. Furthermore, RV-induced IL-33 expression in BSMCs from healthy and asthmatic individuals was attenuated by knockdown of TLR3. Inhibition of TAK1, but not NF-κB or TBK1, limited RV-induced IL-33. The cytokine secretion profile showed higher production of IL-33 in BSMCs from patients with non-severe asthma compared to healthy controls upon RV infection. In addition, BSMCs from patients with non-severe asthma had higher levels of RV-induced IL-8, TNF-α, IL-1β, IL-17A, IL-5 and IL-13. Conclusion: RV infection caused higher levels of IL-33 and increased pro-inflammatory and Type 2 cytokine release in BSMCs from patients with non-severe asthma. RV-induced IL-33 exp

Journal article

Heaney LG, Busby J, Hanratty CE, Djukanovic R, Woodcock A, Walker SM, Hardman TC, Arron JR, Choy DF, Bradding P, Brightling CE, Chaudhuri R, Cowan DC, Mansur AH, Fowler SJ, Niven RM, Howarth PH, Lordan JL, Menzies-Gow A, Harrison TW, Robinson DS, Holweg CTJ, Matthews JG, Pavord ID, investigators for the MRC Refractory Asthma Stratification Programmeet al., 2020, Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial, The Lancet Respiratory Medicine, ISSN: 2213-2600

BACKGROUND: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). METHODS: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defi

Journal article

Wiegman CH, Li F, Ryffel B, Togbe D, Chung KFet al., 2020, Oxidative Stress in Ozone-Induced Chronic Lung Inflammation and Emphysema: A Facet of Chronic Obstructive Pulmonary Disease, Frontiers in Immunology, Vol: 11

Journal article

Kermani NZ, Saqi M, Agapow P, Pavlidis S, Kuo C, Tan KS, Mumby S, Sun K, Loza M, Baribaud F, Sousa AR, Riley J, Wheelock AM, Wheelock CE, De Meulder B, Schofield J, Sánchez-Ovando S, Louise Simpson J, Baines KJ, Wark PA, Auffray C, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock IM, Guo Y-K, Chung KF, U-BIOPRED project teamet al., 2020, Type 2-low asthma phenotypes by integration of sputum transcriptomics and serum proteomics., Allergy, ISSN: 0105-4538

Journal article

Prihandoko R, Kaur D, Wiegman CH, Alvarez-Curto E, Donovan C, Chachi L, Ulven T, Tyas MR, Euston E, Dong Z, Alharbi AGM, Kim RY, Lowe JG, Hansbro PM, Chung KF, Brightling CE, Milligan G, Tobin ABet al., 2020, Pathophysiological regulation of lung function by the free fatty acid receptor FFA4., Science Translational Medicine, Vol: 12, Pages: 1-13, ISSN: 1946-6234

Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein-coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

Journal article

Wu S-M, Feng P-H, Chuang H-C, Ho S-C, Chung KF, Chen K-Y, Wu G-S, Chen T-T, Tseng C-H, Liu W-T, Lee K-Yet al., 2020, Impaired lnc-IL7R modulatory mechanism of Toll-like receptors is associated with an exacerbator phenotype of chronic obstructive pulmonary disease, FASEB JOURNAL, ISSN: 0892-6638

Journal article

Tiotiu A, Zounemat Kermani N, Badi Y, Pavlidis S, Hansbro PM, Guo Y-K, Chung KF, Adcock IM, U-BIOPRED consortium project teamet al., 2020, Sputum macrophage diversity and activation in asthma: role of severity and inflammatory phenotype., Allergy, ISSN: 0105-4538

BACKGROUND: Macrophages control innate and acquired immunity but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort. METHODS: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically- and alternatively-activated macrophages: M1 and M2 respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome-associated clusters (TACs). RESULTS: Macrophage numbers were significantly decreased in severe asthma compared to mild-moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll-like receptors via NF-κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL-2 biosynthesis (all p<0.01). Sputum macrophage number and the ES for most macrophage signatures were higher in the TAC3 group compared to TAC1 and TAC2 asthmatics. However, a high enrichment was found in TAC1 for 3 modules showing inflammatory pathways linked to Toll-like and TNF receptor activation and arachidonic acid metabolism (p<0.001) and in TAC2 for the inflammasome- and interferon-signalling pathways (p<0.001). Data was validated in the ADEPT cohort. Module analysis provides additional information compared to conventional M1 and M2 classification. TR-Mφ were enriched in TAC3 and associated with mitochondrial function. CONCLUSIONS: Macrophage activation is attenuated in severe granulocytic asthma highlighting defective innate immunity except for specific subsets characterised by distinct inflammatory pathways.

Journal article

Kolmert J, Gómez C, Balgoma D, Sjödin M, Bood J, Konradsen JR, Ericsson M, Thörngren J-O, James A, Mikus M, Sousa AR, Riley JH, Bates S, Bakke PS, Pandis I, Caruso M, Chanez P, Fowler SJ, Geiser T, Howarth P, Horváth I, Krug N, Montuschi P, Sanak M, Behndig A, Shaw DE, Knowles RG, Holweg CTJ, Wheelock ÅM, Dahlén B, Nordlund B, Alving K, Hedlin G, Chung KF, Adcock IM, Sterk PJ, Djukanovic R, Dahlén S-E, Wheelock CE, U-BIOPRED Study Groupet al., 2020, Urinary leukotriene E4 and prostaglandin D2 metabolites increase in adult and childhood severe asthma characterized by type-2 inflammation, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

RATIONALE: New approaches are needed to guide personalized treatment of asthma. OBJECTIVE: To test if urinary eicosanoid metabolites can direct asthma phenotyping. METHODS: Urinary metabolites of prostaglandins (PGs), cysteinyl-leukotrienes (LTs) and isoprostanes were quantified in the Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy controls (HC). Validation was performed internally in 302 SA subjects followed-up after 12-18 months, and externally in 95 adolescents with asthma. MEASUREMENT AND MAIN RESULTS: Metabolite levels in HC were unrelated to age, BMI and sex, except for the PGE2-pathway. Eicosanoid levels were generally greater in MMA relative to HC, with further elevations in SA. However, PGE2-metabolite levels were either the same or lower in male non-smoking asthmatics as in HC. Metabolite levels were unchanged in asthmatics adherent to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas SA treated with omalizumab had lower levels of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High levels of LTE4 and PGD2-metabolites were associated with lower lung-function, and increased levels of exhaled nitric oxide and eosinophil markers in blood, sputum and urine in U-BIOPRED and in adolescents with asthma. These type-2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study, and found to be as sensitive to detect T2 inflammation as the established biomarkers. CONCLUSIONS: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new non-invasive approach for molecular phenotyping of adult and adolescent asthma. 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

Roth-Walter F, Adcock IM, Benito-Villalvilla C, Bianchini R, Bjermer L, Boyman O, Caramori G, Cari L, Chung KF, Diamant Z, Eguiluz-Gracia I, Knol EF, Kolios A, Levi-Schaffer F, Nocentini G, Palomares O, Redegeld F, Van Esch B, Stellato Cet al., 2020, Immune modulation via T regulatory cell enhancement: disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases - An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)., Allergy, ISSN: 0105-4538

Therapeutic advances using targeted biologicals and small molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in non-oncological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in non-oncological settings such as cardiovascular disease, obesity and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.

Journal article

Abdel-Aziz MI, Brinkman P, Vijverberg SJH, Neerincx AH, de Vries R, Dagelet YWF, Riley JH, Hashimoto S, Chung KF, Djukanovic R, Fleming LJ, Murray CS, Frey U, Bush A, Singer F, Hedlin G, Roberts G, Dahlén S-E, Adcock IM, Fowler SJ, Knipping K, Sterk PJ, Kraneveld AD, Maitland-van der Zee AH, U-BIOPRED Study Group, Amsterdam UMC Breath Research Groupet al., 2020, eNose breath prints as a surrogate biomarker for classifying patients with asthma by atopy, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749

BACKGROUND: Electronic noses (eNoses) are emerging point-of-care tools that may help in the subphenotyping of chronic respiratory diseases such as asthma. OBJECTIVE: We aimed to investigate whether eNoses can classify atopy in pediatric and adult patients with asthma. METHODS: Participants with asthma and/or wheezing from 4 independent cohorts were included; BreathCloud participants (n = 429), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes adults (n = 96), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes pediatric participants (n = 100), and Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory Effects 2 participants (n = 30). Atopy was defined as a positive skin prick test result (≥3 mm) and/or a positive specific IgE level (≥0.35 kU/L) for common allergens. Exhaled breath profiles were measured by using either an integrated eNose platform or the SpiroNose. Data were divided into 2 training and 2 validation sets according to the technology used. Supervised data analysis involved the use of 3 different machine learning algorithms to classify patients with atopic versus nonatopic asthma with reporting of areas under the receiver operating characteristic curves as a measure of model performance. In addition, an unsupervised approach was performed by using a bayesian network to reveal data-driven relationships between eNose volatile organic compound profiles and asthma characteristics. RESULTS: Breath profiles of 655 participants (n = 601 adults and school-aged children with asthma and 54 preschool children with wheezing [68.2% of whom were atopic]) were included in this study. Machine learning models utilizing volatile organic compound profiles discriminated between atopic and nonatopic participants with areas under the receiver operating characteristic curves of at least 0.84 and 0.72 in the training and validation sets, respectively. The unsupervised approach revealed t

Journal article

Niespodziana K, Borochova K, Pazderova P, Schlederer T, Astafyeva N, Baranovskaya T, Barbouche M-R, Beltyukov E, Berger A, Borzova E, Bousquet J, Bumbacea RS, Bychkovskaya S, Caraballo L, Chung KF, Custovic A, Docena G, Eiwegger T, Evsegneeva I, Emelyanov A, Errhalt P, Fassakhov R, Fayzullina R, Fedenko E, Fomina D, Gao Z, Giavina-Bianchi P, Gotua M, Greber-Platzer S, Hedlin G, Ilina N, Ispayeva Z, Idzko M, Johnston SL, Kalayci O, Karaulov A, Karsonova A, Khaitov M, Kovzel E, Kowalski ML, Kudlay D, Levin M, Makarova S, Matricardi PM, Nadeau KC, Namazova-Baranova L, Naumova O, Nazarenko O, O'Byrne PM, Osier F, Pampura AN, Panaitescu C, Papadopoulos NG, Park H-S, Pawankar R, Pohl W, Renz H, Riabova K, Sampath V, Sekerel BE, Sibanda E, Siroux V, Sizyakina LP, Sun J-L, Szepfalusi Z, Umanets T, Van Bever HPS, van Hage M, Vasileva M, von Mutius E, Wang J-Y, Wong GWK, Zaikov S, Zidarn M, Valenta Ret al., 2020, Toward personalization of asthma treatment according to trigger factors, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 145, Pages: 1529-1534, ISSN: 0091-6749

Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.

Journal article

Carlsten C, Salvi S, Wong GWK, Chung KFet al., 2020, Personal strategies to minimise effects of air pollution on respiratory health: advice for providers, patients and the public, EUROPEAN RESPIRATORY JOURNAL, Vol: 55, ISSN: 0903-1936

Journal article

Khusial RJ, Honkoop PJ, Usmani O, Soares M, Simpson A, Biddiscombe M, Meah S, Bonini M, Lalas A, Polychronidou E, Koopmans JG, Moustakas K, Snoeck-Stroband JB, Ortmann S, Votis K, Tzovaras D, Chung KF, Fowler S, Sont JKet al., 2020, Effectiveness of myAirCoach: A mHealth Self-Management System in Asthma, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, Vol: 8, Pages: 1972-+, ISSN: 2213-2198

Journal article

Song W-J, Chung KF, 2020, Pharmacotherapeutic Options for Chronic Refractory Cough, EXPERT OPINION ON PHARMACOTHERAPY, Vol: 21, Pages: 1345-1358, ISSN: 1465-6566

Journal article

Xie J, Zhang J, Zhang X, Zhang Q, Chung KF, Wang C, Lai Ket al., 2020, Cough in hypereosinophilic syndrome: case report and literature review, BMC PULMONARY MEDICINE, Vol: 20, ISSN: 1471-2466

Journal article

Abdel-Aziz MI, Brinkman P, Vijverberg SJH, Neerincx AH, Riley JH, Bates S, Hashimoto S, Kermani NZ, Chung KF, Djukanovic R, Dahlén S-E, Adcock IM, Howarth PH, Sterk PJ, Kraneveld AD, Maitland-van der Zee AH, U-BIOPRED Study Groupet al., 2020, Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12-18 months, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749

BACKGROUND: Asthma is a heterogeneous disease characterized by distinct phenotypes with associated microbial dysbiosis. OBJECTIVES: To identify severe asthma phenotypes based on sputum microbiome profiles and assess their stability after 12-18 months. Furthermore, to evaluate clusters' robustness after inclusion of an independent mild-to-moderate asthmatics. METHODS: In this longitudinal multicenter cohort study, sputum samples were collected for microbiome profiling from a subset of the U-BIOPRED adult patient cohort at baseline and after 12-18 months of follow-up. Unsupervised hierarchical clustering was performed using the Bray-Curtis β-diversity measure of microbial profiles. For internal validation, partitioning around medoids, consensus cluster distribution, bootstrapping and topological data analysis were applied. Follow-up samples were studied to evaluate within-patient clustering stability in severe asthmatics. Cluster robustness was evaluated by an independent mild-moderate asthma cohort. RESULTS: Data were available for 100 severe asthma subjects (median age: 55 yrs, 42% males). Two microbiome-driven clusters were identified, characterized by differences in asthma onset, smoking status, residential locations, percentage of blood and/or sputum neutrophils and macrophages, lung spirometry, and concurrent asthma medications (all p-values <.05). Cluster 2 patients displayed a commensal-deficient bacterial profile which was associated with worse asthma outcomes compared to cluster 1. Longitudinal clusters revealed high relative stability after 12-18 months in the severe asthmatics. Further inclusion of 24 independent mild-to-moderate asthmatics was consistent with the clustering assignments. CONCLUSION: Unbiased microbiome-driven clustering revealed two distinct robust severe asthma phenotypes, which exhibited relative overtime stability. This suggests that the sputum microbiome may serve as a biomarker for better characterizing asthma phenotypes.

Journal article

Jolliffe DA, Stefanidis C, Wang Z, Kermani NZ, Dimitrov V, White JH, McDonough JE, Janssens W, Pfeffer P, Griffiths CJ, Bush A, Guo Y, Christenson S, Adcock IM, Chung KF, Thummel KE, Martineau ARet al., 2020, Vitamin D Metabolism is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease., Am J Respir Crit Care Med

RATIONALE: Vitamin D deficiency is common in patients with asthma and COPD. Low 25-hydroxyvitamin D (25[OH]D) levels may represent a cause or a consequence of these conditions. OBJECTIVE: To determine whether vitamin D metabolism is altered in asthma or COPD. METHODS: We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D3, administered over one year, differed between those with asthma or COPD vs. controls. Serum concentrations of vitamin D3, 25(OH)D3 and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) were determined pre- and post-supplementation in 93 adults with asthma, COPD or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed fourteen datasets to compare expression of 1α,25[OH]2D3-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD vs. controls. MEASUREMENTS AND MAIN RESULTS: The mean post-supplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in controls (39.8 nmol/L; P=0.001). Compared with controls, patients with asthma and COPD had lower molar ratios of 25(OH)D3-to-vitamin D3 and higher molar ratios of 1α,25(OH)2D3-to-25(OH)D3 both pre- and post-supplementation (P≤0.005). Inter-group differences in 1α,25[OH]2D3-inducible gene expression signatures were modest and variable where statistically significant. CONCLUSIONS: Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D3-to-vitamin D3 and increased molar ratios of 1α,25(OH)2D3-to-25(OH)D3 in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.

Journal article

Tan KS, Lim RL, Liu J, Ong HH, Tan VJ, Lim HF, Chung KF, Adcock IM, Chow VT, Wang DYet al., 2020, Respiratory viral infections in exacerbation of chronic airway inflammatory diseases: novel mechanisms and insights from the upper airway epithelium., Front Cell Dev Biol, Vol: 8, Pages: 99-99, ISSN: 2296-634X

Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.

Journal article

George L, Taylor AR, Esteve-Codina A, Soler Artigas M, Andri Thun G, Bates S, Pavlidis S, Wagers S, Boland A, Prasse A, Boschetto P, Parr DG, Nowinski A, Barta I, Hohlfeld J, Greulich T, van den Berge M, Hiemstra PS, Timens W, Hinks T, Wenzel S, Siddiqui S, Richardson M, Venge P, Heath S, Gut I, Tobin MD, Edwards L, Riley JH, Djukanovic R, Auffray C, De-Meulder B, Erik-Dahlen S, Adcock IM, Chung KF, Ziegler-Heitbrock L, Sterk PJ, Singh D, Brightling CEet al., 2020, Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma, Allergy, Vol: 75, Pages: 370-380, ISSN: 0105-4538

BackgroundWhether the clinical or pathophysiologic significance of the “treatable trait” high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.MethodsSubjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U‐BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U‐BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut‐off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).ResultsThere were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U‐BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.ConclusionDespite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

Journal article

Zein J, Gaston B, Bazeley P, DeBoer MD, Igo RP, Bleecker ER, Meyers D, Comhair S, Marozkina NV, Cotton C, Patel M, Alyamani M, Xu W, Busse WW, Calhoun WJ, Ortega V, Hawkins GA, Castro M, Chung KF, Fahy JV, Fitzpatrick AM, Israel E, Jarjour NN, Levy B, Mauger DT, Moore WC, Noel P, Peters SP, Teague WG, Wenzel SE, Erzurum SC, Sharifi Net al., 2020, HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 2187-2193, ISSN: 0027-8424

Journal article

Song W-J, Chung KF, 2020, Exploring the clinical relevance of cough hypersensitivity syndrome, EXPERT REVIEW OF RESPIRATORY MEDICINE, Vol: 14, Pages: 275-284, ISSN: 1747-6348

Journal article

Ponzi E, Vineis P, Chung K, Blangiardo Met al., 2020, Accounting for measurement error to assess the effect of air pollution on omics signals, PLoS One, Vol: 15, Pages: 1-16, ISSN: 1932-6203

Studies on the effects of air pollution and more generally environmental exposures onhealth require measurements of pollutants, which are affected by measurement error.This is a cause of bias in the estimation of parameters relevant to the study and canlead to inaccurate conclusions when evaluating associations among pollutants, diseaserisk and biomarkers. Although the presence of measurement error in such studies hasbeen recognized as a potential problem, it is rarely considered in applications andpractical solutions are still lacking. In this work, we formulate Bayesian measurementerror models and apply them to study the link between air pollution and omic signals.The data we use stem from the “Oxford Street II Study”, a randomized crossover trialin which 60 volunteers walked for two hours in a traffic-free area (Hyde Park) and in abusy shopping street (Oxford Street) of London. Metabolomic measurements were madein each individual as well as air pollution measurements, in order to investigate theassociation between short-term exposure to traffic related air pollution and perturbationof metabolic pathways. We implemented error-corrected models in a classical frameworkand used the flexibility of Bayesian hierarchical models to account for dependenciesamong omic signals, as well as among different pollutants. Models were implementedusing traditional Markov Chain Monte Carlo (MCMC) simulative methods as well asintegrated Laplace approximation. The inclusion of a classical measurement error termresulted in variable estimates of the association between omic signals and traffic relatedair pollution measurements, where the direction of the bias was not predictable a priori.The models were successful in including and accounting for different correlationstructures, both among omic signals and among different pollutant exposures. Ingeneral, more associations were identified when the correlation among omics and amongpollutants were modeled, and their number

Journal article

Cruz AA, Riley JH, Barisal AT, Ponte E, Souza-Machado A, Almeida PCA, Biao-Lima V, Davis M, Bates S, Adcock IM, Sterk PJ, Chung KFet al., 2020, Asthma similarities across ProAR (Brazil) and U-BIOPRED (Europe) adult cohorts of contrasting locations, ethnicity and socioeconomic status, Respiratory Medicine, Vol: 161, Pages: 1-8, ISSN: 0954-6111

BackgroundAsthma prevalence is 339 million globally. ‘Severe asthma’ (SA) comprises subjects with uncontrolled asthma despite proper management.ObjectivesTo compare asthma from diverse ethnicities and environments.MethodsA cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED.ResultsAmong SA subjects, age, weight, proportion of former smokers and FEV1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV1/FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%.ConclusionsProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.

Journal article

van Bragt JJMH, Adcock IM, Bel EHD, Braunstahl G-J, Ten Brinke A, Busby J, Canonica GW, Cao H, Chung KF, Csoma Z, Dahlen B, Davin E, Hansen S, Heffler E, Horvath I, Korn S, Kots M, Kuna P, Kwon N, Louis R, Plaza V, Porsbjerg C, Ramos-Barbon D, Richards LB, Skrgat S, Sont JK, Vijverberg SJH, Weersink EJ, Yasinska V, Wagers SS, Djukanovic R, Maitland-van der Zee AH, SHARP CRCet al., 2020, Characteristics and treatment regimens across ERS SHARP severe asthma registries, European Respiratory Journal, Vol: 55, ISSN: 0903-1936

Little is known about the characteristics and treatments of patients with severe asthma across Europe but both are likely to vary. This is the first study in the ERS Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals. This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases. Analysis of data from 3233 patients showed many differences in characteristics and life style factors. Current smokers ranged from 0% (Poland, PL, Sweden, SE) to 9.5% (Belgium, BE), mean BMI ranged from 26.2 (Italy) to 30.6 kg·m-2 (UK) and the largest difference in mean pre-bronchodilator FEV1% pred. was 20.9% (Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean ICS dose ranged from 700 to 1335 µg·day-1 between those from Slovenia (SL) versus PL when starting anti-IL-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (SL versus Spain). Maintenance OCS use ranged from 21.0% (BE) to 63.0% (SE) and from 9.1% (Denmark) to 56.1% (UK) in patients starting anti-IL-5 and anti-IgE, respectively. The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current ERS/ATS guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Journal article

Michaeloudes C, Bhavsar PK, Mumby S, Xu B, Hui CKM, Chung KF, Adcock IMet al., 2020, Role of metabolic reprogramming in pulmonary innate immunity and Its impact on lung diseases, Journal of Innate Immunity, Vol: 12, Pages: 1-16, ISSN: 1662-811X

Lung innate immunity is the first line of defence against inhaled allergens, pathogens and environmental pollutants. Cellular metabolism plays a key role in innate immunity. Catabolic pathways, including glycolysis and fatty acid oxidation (FAO), are interconnected with biosynthetic and redox pathways. Innate immune cell activation and differentiation trigger extensive metabolic changes that are required to support their function. Pro-inflammatory polarisation of macrophages and activation of dendritic cells, mast cells and neutrophils are associated with increased glycolysis and a shift towards the pentose phosphate pathway and fatty acid synthesis. These changes provide the macromolecules required for proliferation and inflammatory mediator production and reactive oxygen species for anti-microbial effects. Conversely, anti-inflammatory macrophages use primarily FAO and oxidative phosphorylation to ensure efficient energy production and redox balance required for prolonged survival. Deregulation of metabolic reprogramming in lung diseases, such as asthma and chronic obstructive pulmonary disease, may contribute to impaired innate immune cell function. Understanding how innate immune cell metabolism is altered in lung disease may lead to identification of new therapeutic targets. This is important as drugs targeting a number of metabolic pathways are already in clinical development for the treatment of other diseases such as cancer.

Journal article

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