Imperial College London

ProfessorIanAdcock

Faculty of MedicineNational Heart & Lung Institute

Professor of Respiratory Cell & Molecular Biology
 
 
 
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Contact

 

+44 (0)20 7594 7840ian.adcock Website

 
 
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Location

 

304Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

893 results found

Mathioudakis AG, Tsilochristou O, Adcock IM, Bikov A, Bjermer L, Clini E, Flood B, Herth F, Horvath I, Kalayci O, Papadopoulos NG, Ryan D, Sanchez Garcia S, Correia-de-Sousa J, Tonia T, Pinnock H, Agache I, Janson Cet al., 2021, ERS/EAACI statement on adherence to international adult asthma guidelines, European Respiratory Review, Vol: 30, Pages: 210132-210132, ISSN: 0905-9180

<jats:p>Guidelines aim to standardise and optimise asthma diagnosis and management. Nevertheless, adherence to guidelines is suboptimal and may vary across different healthcare professional (HCP) groups.</jats:p><jats:p>Further to these concerns, this European Respiratory Society (ERS)/European Academy of Allergy and Clinical Immunology (EAACI) statement aims to: 1) evaluate the understanding of and adherence to international asthma guidelines by HCPs of different specialties <jats:italic>via</jats:italic> an international online survey; and 2) assess strategies focused at improving implementation of guideline-recommended interventions, and compare process and clinical outcomes in patients managed by HCPs of different specialties <jats:italic>via</jats:italic> systematic reviews.</jats:p><jats:p>The online survey identified discrepancies between HCPs of different specialties which may be due to poor dissemination or lack of knowledge of the guidelines but also a reflection of the adaptations made in different clinical settings, based on available resources. The systematic reviews demonstrated that multifaceted quality improvement initiatives addressing multiple challenges to guidelines adherence are most effective in improving guidelines adherence. Differences in outcomes between patients managed by generalists or specialists should be further evaluated.</jats:p><jats:p>Guidelines need to consider the heterogeneity of real-life settings for asthma management and tailor their recommendations accordingly. Continuous, multifaceted quality improvement processes are required to optimise and maintain guidelines adherence. Validated referral pathways for uncontrolled asthma or uncertain diagnosis are needed.</jats:p>

Journal article

Güney TG, Herranz AM, Mumby S, Dunlop IE, Adcock IMet al., 2021, Epithelial-stromal cell interactions and ECM mechanics drive the formation of airway-mimetic tubular morphology in lung organoids, iScience, Pages: 103061-103061, ISSN: 2589-0042

Complex human airway cellular organisation where extracellular matrix (ECM), epithelial and stromal lineages interact present challenges for organ study in vitro. Current in vitro lung models, that focus on the lung epithelium do not represent complex airway morphology and cell-ECM interactions seen in vivo.Models including stromal populations often separate them via a semipermeable barrier precluding cell-cell interaction or the effect of ECM mechanics. We investigated the effect of stromal cells on basal epithelial cell-derived bronchosphere structure and function through a triple culture of human bronchial epithelial, lung fibroblast and airway smooth muscle cells. Epithelial-stromal cross-talk resulted in epithelial cell-driven branching tubules with stromal cells surrounding epithelial cells termed bronchotubules. Agarose-matrigel scaffold (Agrigel) formed a mechanically tuneable ECM, with adjustable viscoelasticity and stiffness enabling long-term tubule survival. Bronchotubule models may enable research into how epithelial-stromal cell and cell-ECM communication drive tissue patterning, repair and development of disease.

Journal article

Perry MM, Tildy B, Papi A, Casolari P, Caramori G, Rempel KL, Halayko AJ, Adcock I, Chung KFet al., 2021, The anti-proliferative and anti-inflammatory response of COPD airway smooth muscle cells to hydrogen sulfide (Retraction of Vol 19, art no 85, 2018), Respiratory Research, Vol: 22, Pages: 1-1, ISSN: 1465-9921

Journal article

Xu J, Meng Y, Jia M, Jiang J, Yang Y, Ou Y, Wu Y, Yan X, Huang M, Adcock IM, Yao Xet al., 2021, Epithelial expression and role of secreted STC1 on asthma airway hyperresponsiveness through calcium channel modulation., Allergy, Vol: 76, Pages: 2475-2487, ISSN: 0105-4538

BACKGROUND: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and airway remodeling. AHR results from enhanced airway smooth muscle (ASM) contraction potentially under the control of an epithelium-derived relaxing factor (EpDRF). However, relatively rare is known about EpDRF. We aimed to elucidate the role of epithelium-derived stanniocalcin-1 (STC1) on AHR and ASM contraction. METHODS: STC1 levels in the serum of asthmatic patients and healthy volunteers and in bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)-challenged mice were measured by ELISA. The effects of exogenous STC1 on AHR and on inflammation were examined in mice. IL-13 modulation of STC1 mRNA and protein levels was studied in human bronchial epithelial cell lines (16HBE). The function of STC1 on Ca2+ influx and ASM contraction was examined ex vivo. RESULTS: Serum STC1 was decreased in asthma (n=93) compared with healthy volunteers (1071±30.4 vs 1414±75.1pg/ml, p<0.0001, n=23) and correlated with asthma control (p=0.0270), lung function (FEV1, p=0.0130) and serum IL-13 levels (p=0.0009). Treatment of ten asthmatic subjects with inhaled corticosteroids/long- acting beta2-agonists (ICS/LABA) for one year enhanced STC1 expression which correlated with improved asthma control (p=0.022). STC1 was mainly expressed in bronchial epithelium and intranasal administration of recombinant human STC1 (rhSTC1) reduced AHR and inflammation in mice. IL-13 suppressed STC1 release from 16HBE, whereas rhSTC1 blocked store-operated Ca2+ entry (SOCE) by suppressing stromal interaction molecule 1 (STIM1) and further inhibited ASM cell contractility by suppressing Ca2+ -dependent myosin light chain (MLC) phosphorylation. CONCLUSION: Our data indicate that STC1 deficiency in asthmatic airways promotes STIM1 hyperactivity, enhanced ASM contraction and AHR. STC1 may be a candidate EpDRF.

Journal article

Alipoor SD, Mortaz E, Varahram M, Garssen J, Adcock IMet al., 2021, The immunopathogenesis of neuroinvasive lesions of SARS-CoV-2 infection in COVID-19 patients, Frontiers in Neurology, Vol: 12, Pages: 1-10, ISSN: 1664-2295

The new coronavirus disease COVID-19 was identified in December 2019. It subsequently spread across the world with over 125 M reported cases and 2.75 M deaths in 190 countries. COVID-19 causes severe respiratory distress; however, recent studies have reported neurological consequences of infection by the COVID-19 virus SARS-CoV-2 even in subjects with mild infection and no initial neurological effects. It is likely that the virus uses the olfactory nerve to reach the CNS and that this transport mechanism enables virus access to areas of the brain stem that regulates respiratory rhythm and may even trigger cell death by alteration of these neuronal nuclei. In addition, the long-term neuronal effects of COVID-19 suggest a role for SARS-CoV-2 in the development or progression of neurodegerative disease as a result of inflammation and/or hypercoagulation. In this review recent findings on the mechanism(s) by which SARS-CoV-2 accesses the CNS and induces neurological dysregulation are summarized.

Journal article

Mortaz E, Bezemer G, Alipoor SD, Varahram M, Mumby S, Folkerts G, Garssen J, Adcock Iet al., 2021, Nutritional impact and its potential consequences on COVID-19 severity, Frontiers in Nutrition, Vol: 8, ISSN: 2296-861X

Background: During late 2019 a viral disease due to a novel coronavirus was reported in Wuhan, China, which rapidly developed into an exploding pandemic and poses a severe threat to human health all over the world. Until now (May 2021), there are insufficient treatment options for the management of this global disease and shortage of vaccines. Important aspects that help to defeat coronavirus infection seems to be having a healthy, strong, and resilient immune system. Nutrition and metabolic disorders such as obesity and diabetes play a crucial role on the community health situation in general and especially during this new pandemic. There seems to be an enormous impact of lifestyle, metabolic disorders, and immune status on coronavirus disease 2019 (COVID-19) severity and recovery. For this reason, it is important to consider the impact of lifestyle and the consumption of well-defined healthy diets during the pandemic.Aims: In this review, we summarise recent findings on the effect of nutrition on COVID-19 susceptibility and disease severity and treatment. Understanding how specific dietary features might help to improve the public health strategies to reduce the rate and severity of COVID-19.

Journal article

An J, Do AR, Kang HY, Kim WJ, Lee S, Lee J-H, Song W-J, Kwon H-S, Cho YS, Moon H-B, Hu S, Adcock IM, Chung KF, Won S, Kim T-Bet al., 2021, Genome-wide association study of Korean asthmatics: a comparison with UK asthmatics, Allergy, asthma & immunology research, Vol: 13, Pages: 609-622, ISSN: 2092-7363

PurposeAlthough genome-wide association studies (GWASs) represent the most powerful approach for identifying genes that influence asthma, to date, no studies have established genetic susceptibility to asthma in the Korean population. This study aimed to identify genetic variants associated with adult Korean asthmatics and compare them with the significant single nucleotide polymorphisms (SNPs) of UK asthmatics from the UK Biobank.MethodsPatients were defined as having asthma if they were diagnosed by a doctor or taking medications for asthma. Controls were defined as individuals without asthma or chronic obstructive pulmonary disease. We performed quality control, genotype imputation, GWAS, and PrediXcan analyses. In the GWAS, a P value of < 5 × 10−8 was considered significant. We compared significant SNPs between Korean and UK patients with asthma.ResultsA total of 1,386 asthmatic patients and 5,205 controls were analyzed. The SNP rs1770, located near the human leukocyte antigen (HLA)-DQB1, was the most significant SNP (P = 4.5 × 10−10). In comparison with 24 SNPs in a GWAS of UK asthmatics, six SNPs were significant with the same odds ratio (OR) direction, including signals related to type 2 inflammation (e.g., IL1RL1, TSLP, and GATA3) and mucus plugging (e.g., MUC5AC). HLA-DQA1 showed an opposite OR direction. The HLA-DQB1 gene demonstrated significantly imputed mRNA expression in the lung tissue and whole blood.ConclusionsThe SNP rs1770 of HLA-DQB1 was the most significant in Korean asthmatics. Similarities and discrepancies were found in the genetic variants between Korean and UK asthmatics. GWAS of Korean asthmatics should be replicated and compared with those of GWAS of other ethnicities.

Journal article

Alahmadi FH, Simpson AJ, Gomez C, Ericsson M, Thörngren J-O, Wheelock C, Shaw DE, Fleming LJ, Roberts G, Riley J, Bates S, Sousa AR, Knowles R, Bansal AT, Corfield J, Pandis I, Sun K, Bakke PS, Caruso M, Chanez P, Dahlén B, Horvath I, Krug N, Montuschi P, Singer F, Wagers S, Adcock IM, Djukanovic R, Chung KF, Sterk PJ, Dahlen S-E, Fowler SJ, U-BIOPRED Study Groupet al., 2021, Medication adherence in patients with severe asthma prescribed oral corticosteroids in the U-BIOPRED cohort, Chest, Vol: 160, Pages: 53-64, ISSN: 0012-3692

BACKGROUND: Whilst estimates of sub-optimal adherence to oral corticosteroids in asthma range from 30 to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. RESEARCH QUESTIONS: 1. What is the prevalence of suboptimal adherence detected using self-reporting and direct measures? 2. Is suboptimal adherence associated with disease activity? STUDY DESIGN AND METHODS: Data were included from individuals with severe asthma taking part in the U-BIOPRED study prescribed daily oral corticosteroids. Participants completed the MARS, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid-chromatography mass spectrometry. RESULTS: Data from 166 participants were included in this study, mean (SD) age 54.2 (11.9) years, FEV1 65.1 (20.5) % predicted, 58% female. 37% completing the MARS reported sub-optimal adherence, and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 35% participants who had both performed; adherence detection did not match between methods in 53%. Self-reported high-adherers had better asthma control and quality of life, whereas directly-measured high-adherers had lower blood eosinophils. INTERPRETATION: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.

Journal article

Zakarya R, Chan YL, Rutting S, Reddy K, Bozier J, Woldhuis RR, Xenaki D, Van Ly D, Chen H, Brandsma C-A, Adcock IM, Oliver BGet al., 2021, BET proteins are associated with the induction of small airway fibrosis in COPD, Thorax, Vol: 76, Pages: 647-655, ISSN: 0040-6376

RATIONALE: In COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed. OBJECTIVES: Determine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1). METHODS: Primary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC. Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed. MEASUREMENTS AND MAIN RESULTS: COPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC. CONCLUSIONS: BET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny.

Journal article

Yang Y, Man J, Yingwei O, Adcock IM, Xin Yet al., 2021, Mechanisms and biomarkers of airway epithelial cell damage in asthma: a review., The Clinical Respiratory Journal, ISSN: 1752-6981

Bronchial asthma is a heterogeneous disease with complex pathological mechanisms representing different phenotypes, including severe asthma. The airway epithelium is a major site of complex pathological changes in severe asthma due, in part, to activation of inflammatory and immune mechanisms in response to noxious agents. Current imaging procedures are unable to accurately measure epithelial and airway remodeling. Damage of airway epithelial cells occurs is linked to specific phenotypes and endotypes which provides an opportunity for the identification of biomarkers reflecting epithelial, and airway, remodeling. Identification of patients with more severe epithelial disruption using biomarkers may also provide personalized therapeutic opportunities and/or markers of successful therapeutic intervention. Here, we review the evidence for ongoing epithelial cell dysregulation in the pathogenesis of asthma, the sentinel role of the airway epithelium and how understanding these molecular mechanisms provides the basis for the identification of candidate biomarkers for asthma prediction, prevention, diagnosis, treatment and monitoring.

Journal article

Adcock IM, Mumby S, 2021, MicroRNAs in human disease: commentary, Iranian Journal Of Allergy, Asthma and Immunology, Vol: 20, Pages: 259-262, ISSN: 1735-1502

Journal article

Adcock I, Caramori G, Nucera F, Mumby S, Lo Bello Fet al., 2021, Corticosteroid resistance in asthma: cellular and molecular mechanisms, Molecular Aspects of Medicine, ISSN: 0098-2997

Inhaled glucocorticoids (GCs) are drugs widely used as treatment for asthma patients. They prevent the recruitment and activation of lung immune and inflammatory cells and, moreover, have profound effects on airway structural cells to reverse the effects of disease on airway inflammation. GCs bind to a specific receptor, the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and modulates pro- and anti-inflammatory gene transcription through a number of distinct and complementary mechanisms. Targets genes include many pro-inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. Inhaled GCs are very effective for most asthma patients with little, if any, systemic side effects depending upon the dose. However, some patients show poor asthma control even after the administration of high doses of topical or even systemic GCs. Several mechanisms relating to inflammation have been considered to be responsible for the onset of the relative GC resistance observed in these patients. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness.

Journal article

Abdel-Aziz MI, Zounemat Kermani N, Neerincx AH, Vijverberg SJH, Guo Y, Howarth P, Dahlen S-E, Djukanovic R, Sterk PJ, Kraneveld AD, Maitland-van der Zee AH, Chung KF, Adcock IM, U-BIOPRED Consortiumet al., 2021, Association of endopeptidases, involved in SARS-CoV-2 infection, with microbial aggravation in sputum of severe asthma, Allergy, Vol: 76, Pages: 1917-1921, ISSN: 0105-4538

Journal article

Nomani M, Varahram M, Tabarsi P, Hashemian SM, Jamaati H, Malekmohammad M, Ghazi M, Adcock IM, Mortaz Eet al., 2021, Decreased neutrophil-mediated bacterial killing in COVID-19 patients, Scandinavian Journal of Immunology, Vol: 94, Pages: 1-10, ISSN: 0300-9475

The coronavirus disease COVID-19 was first described in December 2019. The peripheral blood of COVID-19 patients have increased numbers of neutrophils which are important in controlling the bacterial infections observed in COVID-19. We sought to evaluate the cytotoxic capacity of neutrophils in COVID-19 patients. 34 confirmed COVID-19 patients (29 severe, five mild disease), and nine healthy controls were recruited from the Masih Daneshvari Hospital (Tehran, Iran) from March to May 2020. Polymorphonuclear (PMN) cells were isolated from whole blood and incubated with green fluorescent protein (GFP)-labelled methicillin-resistant Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). Bacterial growth was determined by measuring the florescence of co-cultures of bacteria and neutrophils and reported as the lag time before exponential growth. The number of viable bacteria was determined after 70 hours as colony-forming units (CFU). The immunophenotype of tested cells was evaluated by flow cytometry. Isolated neutrophils have higher surface expression of CD16 and CD62L with negative markers for PMN-MDSC. Bacterial growth in the presence of SA (22 ± 0.9 versus 9.2 ± 0.5 h, P < .01) and PA (12.4 ± 0.6 versus 4.5 ± 0.22, P < .01) was significantly reduced in COVID-19 patients. After 70 h incubation of PMN with bacteria (SA and PA), CFUs were significant increased in COVID-19 patients SA (2.6 ± 0.09 × 108 CFU/mL-severe patients and 1.4 ± 0.06 × 108 CFU/mL-mild patients, P < .001) and PA (2.2 ± 0.09 × 109 CFU/mL-severe patients and 1.6 ± 0.03 × 109 CFU/mL-mild patients, P < .001). Gentamycin proliferation assays confirmed the presence of intracellular bacteria. Reduced bacterial killing by neutrophils from COVID-19 patients may be responsible for the high bacterial yield seen in these patients.

Journal article

Mortaz E, Tabarsi P, Jamaati H, Roofchayee ND, Dezfuli NK, Hashemian SM, Moniri A, Marjani M, Malkmohammad M, Mansouri D, Varahram M, Folkerts G, Adcock Iet al., 2021, Increased serum levels of soluble TNF-α receptor is associated with mortality of ICU COVID-19 patients, Frontiers in Immunology, Vol: 12, ISSN: 1664-3224

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm.Objectives: To elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity.Methods: We determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran.Results: Serum levels of sTNFRI were significantly higher in ICU patients (P<0.0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P<0.0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p<0.0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR.Conclusions: The study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.

Journal article

Mortaz E, Bassir A, Roofchayee ND, Dezfuli NK, Jamaati H, Tabarsi P, Moniri A, Rezaei M, Mehrian P, Varahram M, Marjani M, Mumby S, Adcock IMet al., 2021, Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra, International Immunopharmacology, Vol: 93, Pages: 1-7, ISSN: 1567-5769

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected 86,4 M patients and resulted in 1,86 M deaths worldwide. Severe COVID-19 patients have elevated blood levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)α, IL-8 and interferon (IFN)γ.ObjectiveTo investigate the effect of antiviral treatment serum cytokines in severe COVID-19 patients.MethodsBlood was obtained from 29 patients (aged 32–79 yr) with laboratory-confirmed COVID-19 upon admission and 7 days after antiviral (Favipiravir or Lopinavir/Ritonavir) treatment. Patients also received standard supportive treatment in this retrospective observational study. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations of COVID-19. Serum was also obtained and cytokines levels were evaluated. 19 age- and gender-matched healthy controls were studied.ResultsAnti-viral therapy significantly reduced CT scan scores and the elevated serum levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH). In contrast, serum levels of IL-6, IL-8 and IFNγ were elevated at baseline in COVID-19 subjects compared to healthy subjects with IL-6 (p = 0.006) and IL-8 (p = 0.011) levels being further elevated after antiviral therapy. IL-1β (p = 0.01) and TNFα (p = 0.069) levels were also enhanced after treatment but baseline levels were similar to those of healthy controls. These changes occurred irrespective of whether patients were admitted to the intensive care unit.ConclusionAntiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. There was limited evidence for a viral-mediated cytokine storm in these COVID-19 subjects.

Journal article

Baumann R, Untersmayr E, Zissler UM, Eyerich S, Adcock IM, Brockow K, Biedermann T, Ollert M, Chaker AM, Pfaar O, Garn H, Thwaites RS, Togias A, Kowalski ML, Hansel T, Jakwerth C, Schmidt-Weber CBet al., 2021, Non-invasive and minimally-invasive techniques for the diagnosis and management of allergic diseases., Allergy, Vol: 76, Pages: 1010-1023, ISSN: 0105-4538

Allergic diseases of the (upper and lower) airways, the skin as well as the gastrointestinal tract, are on the rise, resulting in impaired quality of life, decreased productivity and increased healthcare costs. As allergic diseases are mostly tissue specific, local sampling methods for respective biomarkers offer the potential for increased sensitivity and specificity. Additionally, local sampling using non-invasive or minimally-invasive methods can be cost-effective and well tolerated, which may even be suitable for primary or home care sampling. Non- or minimally-invasive local sampling and diagnostics may enable a more thorough endotyping, may help to avoid under- or overdiagnosis, and may provide the possibility to approach precision prevention, due to early diagnosis of these local diseases even before they get systemically manifested and detectable. At the same time, dried blood samples may help to facilitate minimal-invasive primary or home care sampling for classical systemic diagnostic approaches. This EAACI position paper contains a thorough review of the various technologies in allergy diagnosis available on the market, which analytes or biomarkers are employed, and which samples or matrices can be used. Based on this assessment, EAACIs position is to drive these developments to efficiently identify allergy and possibly later also viral epidemics and take advantage of comprehensive knowledge to initiate preventions and treatments.

Journal article

Xu M, Wang X, Xu L, Zhang H, Li C, Liu Q, Chen Y, Chung KF, Adcock IM, Li Fet al., 2021, Chronic lung inflammation and pulmonary fibrosis after multiple intranasal instillation of PM2.5 in mice, ENVIRONMENTAL TOXICOLOGY, Vol: 36, Pages: 1434-1446, ISSN: 1520-4081

Journal article

Bousquet J, Anto JM, Czarlewski W, Haahtela T, Fonseca SC, Iaccarino G, Blain H, Vidal A, Sheikh A, Akdis CA, Zuberbier T, ARIA groupet al., 2021, Cabbage and fermented vegetables: From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19, Allergy, Vol: 76, Pages: 735-750, ISSN: 0105-4538

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT1 R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT1 R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.

Journal article

Mazein A, Ivanova O, Balaur I, Ostaszewski M, Berzhitskaya V, Serebriyskaya T, Ligon T, Hasenauer J, De Meulder B, Overall RW, Roy L, Knowles RG, Wheelock CE, Dahlen S-E, Chung KF, Adcock IM, Roberts G, Djukanovic R, Pellet J, Gawron P, Balling R, Maitland-van der Zee AH, Schneider R, Sterk PJ, Auffray Cet al., 2021, AsthmaMap: An interactive knowledge repository for mechanisms of asthma, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 147, Pages: 853-856, ISSN: 0091-6749

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., 2021, Sputum macrophage diversity and activation in asthma: role of severity and inflammatory phenotype, Allergy, Vol: 76, Pages: 775-788, 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

Kumar P, Kalaiarasan G, Porter AE, Pinna A, Kłosowski MM, Demokritou P, Chung KF, Pain C, Arvind DK, Arcucci R, Adcock IM, Dilliway Cet al., 2021, An overview of methods of fine and ultrafine particle collection for physicochemical characterisation and toxicity assessments., Science of the Total Environment, Vol: 756, Pages: 1-22, ISSN: 0048-9697

Particulate matter (PM) is a crucial health risk factor for respiratory and cardiovascular diseases. The smaller size fractions, ≤2.5 μm (PM2.5; fine particles) and ≤0.1 μm (PM0.1; ultrafine particles), show the highest bioactivity but acquiring sufficient mass for in vitro and in vivo toxicological studies is challenging. We review the suitability of available instrumentation to collect the PM mass required for these assessments. Five different microenvironments representing the diverse exposure conditions in urban environments are considered in order to establish the typical PM concentrations present. The highest concentrations of PM2.5 and PM0.1 were found near traffic (i.e. roadsides and traffic intersections), followed by indoor environments, parks and behind roadside vegetation. We identify key factors to consider when selecting sampling instrumentation. These include PM concentration on-site (low concentrations increase sampling time), nature of sampling sites (e.g. indoors; noise and space will be an issue), equipment handling and power supply. Physicochemical characterisation requires micro- to milli-gram quantities of PM and it may increase according to the processing methods (e.g. digestion or sonication). Toxicological assessments of PM involve numerous mechanisms (e.g. inflammatory processes and oxidative stress) requiring significant amounts of PM to obtain accurate results. Optimising air sampling techniques are therefore important for the appropriate collection medium/filter which have innate physical properties and the potential to interact with samples. An evaluation of methods and instrumentation used for airborne virus collection concludes that samplers operating cyclone sampling techniques (using centrifugal forces) are effective in collecting airborne viruses. We highlight that predictive modelling can help to identify pollution hotspots in an urban environment for the efficient collection of PM mass. This review provides

Journal article

Kermani NZ, Song W-J, Badi Y, Versi A, Guo Y, Sun K, Bhavsar P, Howarth P, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock IM, Chung KF, U-BIOPRED Consortiumet al., 2021, Correction to: Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma., Respiratory Research, Vol: 22, Pages: 1-3, ISSN: 1465-9921

Journal article

Mumby S, Perros F, Hui C, Xu B, Xu W, Elyasigomari V, Hautefort A, Manaud G, Humbert M, Chung KF, Wort SJ, Adcock Iet al., 2021, Extracellular matrix degradation pathways and fatty acid metabolism regulate distinct pulmonary vascular cell types in Pulmonary Arterial Hypertension, Pulmonary Circulation, Vol: 11, Pages: 1-16, ISSN: 2045-8940

Pulmonary arterial hypertension (PAH) describes a group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles. Left untreated, patients die from right heart failure. Pulmonary vascular remodelling involves all cell types but to date the precise roles of the different cells is unknown. This study investigated differences in basal gene expression between PAH and controls using both human pulmonary microvascular endothelial (HPMEC) and pulmonary artery smooth muscle cells (HPASMC). HPMEC and HPASMC from PAH patients and controls were cultured to confluence, harvested and RNA extracted. Whole genome sequencing was performed and after transcript quantification and normalization, we examined differentially expressed genes (DEGs) and applied gene set enrichment analysis (GSEA) to the DEGs to identify putative activated pathways.HPMEC displayed 1008 significant (p≤0.0001) DEGs in PAH samples compared to controls. In HPASMC there were 229 significant (p≤0.0001) DEGs between PAH and controls. Pathway analysis revealed distinctive differences: HPMEC display down-regulation of extracellular matrix organisation, collagen formation and biosynthesis, focal- and cell- adhesion molecules suggesting severe endothelial barrier dysfunction and vascular permeability in PAH pathogenesis. In contrast pathways in HPASMC were mainly up-regulated, including those for fatty acid metabolism, biosynthesis of unsaturated fatty acids, cell-cell and adherens junction interactions suggesting a more energy-driven proliferative phenotype. This suggests that the two cell types play different mechanistic roles in PAH pathogenesis and further studies are required to fully elucidate the role each plays and the interactions between these cell types in vascular remodelling in disease progression.

Journal article

Adcock I, alipoor S, Mortaz E, Jamaati H, Tabarsi P, Bayram H, Adcock Iet al., 2021, COVID-2019: Molecular and cellular response, Frontiers in Cellular and Infection Microbiology, Vol: 11, Pages: 1-16, ISSN: 2235-2988

In late December 2019 a viral pneumonia with an unknown agent was reported in Wuhan, China. A novel coronavirus was identified as the causative agent. Because of the human-to-human transmission and rapid spread; coronavirus disease 2019 (COVID-19) has rapidly increased to an epidemic scale and poses a severe threat to human health; it has been declared a public health emergency of international concern (PHEIC) by the World Health Organization (WHO). This review aims to summarize the recent research progress of COVID-2019 molecular features and immunopathogenesis to provide a reference for further research in prevention and treatment of SARS coronavirus2 ( SARS-CoV-2) infection based on the knowledge from researches on SARS-CoV and Middle East respiratory syndrome-related coronavirus(MERS-CoV.)

Journal article

Roofchayee ND, Marjani M, Dezfuli NK, Tabarsi P, Moniri A, Varahram M, Adcock IM, Mortaz Eet al., 2021, Potential diagnostic value of pleural fluid cytokines levels for tuberculous pleural effusion, Scientific Reports, Vol: 11, Pages: 1-8, ISSN: 2045-2322

Patients with tuberculous pleural effusion (TPE) or malignant pleural effusions (MPE) frequently have similar pleural fluid profiles. New biomarkers for the differential diagnosis of TPE are required. We determined whether cytokine profiles in the PE of patients could aid the differential diagnosis of TPE. 30 patients with TPE, 30 patients with MPE, 14 patients with empyema (EMP) and 14 patients with parapneumonic effusion (PPE) were enrolled between Dec 2018 and 2019. The levels of interleukin (IL)-6, IL-18, IL-27, CXCL8, CCL-1 and IP-10 were determined in PE by ELISA along with measurements of adenosine deaminase (ADA). The best predictors of TPE were combined ADA.IL-27 [optimal cut-off value = 42.68 (103 U ng/l2), sensitivity 100%, specificity 98.28%], ADA [cut off value 27.5 (IU/l), sensitivity 90%, specificity 96.5%] and IL-27 [cut-off value = 2363 (pg/ml), sensitivity 96.7%, specificity 98.3%, p ≤ 0.0001]. A high level of IL-6 [cut-off value = 3260 (pg/ml), sensitivity 100%, specificity 67.2%], CXCL8 [cut-off value = 144.5 (pg/ml), sensitivity 93.3%, specificity 58.6%], CCL1 [cut-off value = 54 (pg/ml), sensitivity 100%, specificity 70.7%] and IP-10 [cut-off value = 891.9 (pg/ml), sensitivity 83.3%, specificity 48.3%] were also predictive of TPE. High ADA.IL-27, ADA and IL-27 levels differentiate between TPE and non-TPE with improved specificity and diagnostic accuracy and may be useful clinically.

Journal article

Kermani N, Song W-J, Badi Y, Versi A, Guo Y, Sun K, Bhavsar P, Howarth P, Dahlen S-E, Sterk PJ, Djukanovic R, Adcock I, Chung KFet al., 2021, Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma, Respiratory Research, Vol: 22, ISSN: 1465-9921

BackgroundPatients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.MethodsWe examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels.ResultsACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes.ConclusionLevels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.

Journal article

Holguin F, Cardet JC, Chung KF, Diver S, Ferreira DS, Fitzpatrick A, Gaga M, Kellermeyer L, Khurana S, Knight S, McDonald VM, Morgan RL, Ortega VE, Rigau D, Subbarao P, Tonia T, Adcock IM, Bleecker ER, Brightling C, Boulet LP, Cabana M, Castro M, Chanez P, Custovic A, Djukanovic R, Frey U, Frankemölle B, Gibson P, Hamerlijnck D, Jarjour N, Konno S, Shen H, Vitary C, Bush Aet al., 2021, Management of severe asthma: A European Respiratory Society/American Thoracic Society guideline, Pulmonologiya, Vol: 31, Pages: 272-295, ISSN: 0869-0189

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: • suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; • suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma; • suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; • suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; • suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; • suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These reco

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., 2021, Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12-18 months, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 123-134, 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.

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