Imperial College London

ProfessorSebastianJohnston

Faculty of MedicineNational Heart & Lung Institute

Asthma UK Clinical Chair
 
 
 
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Contact

 

+44 (0)20 7594 3764s.johnston

 
 
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Assistant

 

Mr Christophe Tytgat +44 (0)20 7594 3849

 
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Location

 

343Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

720 results found

Bloom CI, Johnston SL, 2021, Decline in respiratory and cardiac admissions during the COVID-19 pandemic: what is the role of common respiratory virus infections?, Respirology, ISSN: 1323-7799

Numerous countries across the globe have introduced a variety of public health measures, non-pharmaceutical interventions (NPIs), to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and accordingly reduce coronavirus disease 2019 (COVID-19) hospitalizations and mortality. Effective NPIs have at the same time caused considerable changes in healthcare demand for non-COVID-19 conditions. In New Zealand, during the first wave of the pandemic in early 2020, their government instigated a stringent programme of restrictions, with a four-level alert system, including border closure, quarantine for returning travellers, social distancing measures and personal hygiene promotion. High public compliance with NPIs prevented COVID-19 community transmission for 102 consecutive days. In fact, they were so effective that the usual winter influenza surge was also disrupted, with an extraordinary 99.9% reduction in influenza virus detections as compared to previous years and a substantial reduction in all other respiratory viruses, including a 98% reduction in respiratory syncytial virus detections.1 Due to the key role viruses are known to play in many respiratory conditions and are postulated to play in myocardial infarctions and heart failure, it may be hypothesized that the stringent reductions implemented in New Zealand may also have mitigated the incidence of these conditions during that time.

Journal article

Delgado-Eckert E, James A, Meier-Girard D, Kupczyk M, Andersson LI, Bossios A, Mikus M, Ono J, Izuhara K, Middelveld R, Dahlen B, Gaga M, Siafakas NM, Papi A, Beghe B, Joos G, Rabe KF, Sterk PJ, Bel EH, Johnston SL, Chanez P, Gjomarkaj M, Howarth PH, Nizankowska-Mogilnicka E, Dahlen S-E, Frey Uet al., 2021, Lung function fluctuation patterns unveil asthma and COPD phenotypes unrelated to type 2 inflammation, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 148, Pages: 407-419, ISSN: 0091-6749

Journal article

Kamal F, Kumar S, Edwards MR, Veselkov K, Belluomo I, Kebadze T, Romano A, Trujillo-Torralbo M-B, Shahridan Faiez T, Walton R, Ritchie AI, Wiseman DJ, Laponogov I, Donaldson G, Wedzicha JA, Johnston SL, Singanayagam A, Hanna GBet al., 2021, Virus-induced volatile organic compounds are detectable in exhaled breath during pulmonary infection., American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation trigger is important to guide appropriate therapy but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection aetiology. METHODS: We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC production during acute respiratory viral infection. Highly sensitive gas-chromatography mass spectrometry (GC-MS) techniques were used to measure VOC production from infected airway epithelial cell cultures and in exhaled breath samples of healthy subjects experimentally challenged with rhinovirus A16 and COPD subjects with naturally-occurring exacerbations. RESULTS: We identified a novel VOC signature comprising of decane and other related long chain alkane compounds that is induced during rhinovirus infection of cultured airway epithelial cells and is also increased in the exhaled breath of healthy subjects experimentally challenged with rhinovirus and of COPD patients during naturally-occurring viral exacerbations. These compounds correlated with magnitude of anti-viral immune responses, virus burden and exacerbation severity but were not induced by bacterial infection, suggesting they represent a specific virus-inducible signature. CONCLUSION: Our study highlights the potential for measurement of exhaled breath VOCs as rapid, non-invasive biomarkers of viral infection. Further studies are needed to determine whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.

Journal article

Wirz OF, Jansen K, Satitsuksanoa P, van de Veen W, Tan G, Sokolowska M, Mirer D, Stanic B, Message SD, Kebadze T, Glanville N, Mallia P, Gern JE, Papadopoulos N, Akdis CA, Johnston SL, Nadeau K, Akdis Met al., 2021, Experimental rhinovirus infection induces an antiviral response in circulating B cells which is dysregulated in patients with asthma, ALLERGY, ISSN: 0105-4538

Journal article

Padayachee Y, Flicke S, Linton S, Cafferkey J, Min Kon O, Johnston SL, Ellis AK, Desrosiers M, Turner P, Valenta R, Scadding GKet al., 2021, Review: The nose as a route for therapy. Part 2 Immunotherapy, Frontiers in Allergy, Vol: 2, ISSN: 2673-6101

The nose provides a route of access to the body for inhalants and fluids. Unsurprisingly it has a strong immune defense system, with involvement of innate (e.g., epithelial barrier, muco- ciliary clearance, nasal secretions with interferons, lysozyme, nitric oxide) and acquired (e.g., secreted immunoglobulins, lymphocytes) arms. The lattice network of dendritic cells surrounding the nostrils allows rapid uptake and sampling of molecules able to negotiate the epithelial barrier. Despite this many respiratory infections, including SARS-CoV2, are initiated through nasal mucosal contact, and the nasal mucosa is a significant “reservoir” for microbes including Streptococcus pneumoniae, Neisseria meningitidis and SARS -CoV-2. This review includes consideration of the augmentation of immune defense by the nasal application of interferons, then the reduction of unnecessary inflammation and infection by alteration of the nasal microbiome. The nasal mucosa and associated lymphoid tissue (nasopharynx-associated lymphoid tissue, NALT) provides an important site for vaccine delivery, with cold-adapted live influenza strains (LAIV), which replicate intranasally, resulting in an immune response without significant clinical symptoms, being the most successful thus far. Finally, the clever intranasal application of antibodies bispecific for allergens and Intercellular Adhesion Molecule 1 (ICAM-1) as a topical treatment for allergic and RV-induced rhinitis is explained.

Journal article

Bloom CI, Drake TM, Docherty AB, Lipworth BJ, Johnston SL, Nguyen-Van-Tam JS, Carson G, Dunning J, Harrison EM, Baillie JK, Semple MG, Cullinan P, Openshaw PJM, Alex B, Bach B, Barclay WS, Bogaert D, Chand M, Cooke GS, Filipe AD, Fletcher T, Green CA, Harrison EM, Hiscox JA, Ho AY, Horby PW, Ijaz S, Khoo S, Klenerman P, Law A, Lim WS, Mentzer AJ, Merson L, Meynert AM, Noursadeghi M, Moore SC, Palmarini M, Paxton WA, Pollakis G, Price N, Rambaut A, Robertson DL, Russell CD, Sancho-Shimizu V, Scott JT, Silva TD, Sigfrid L, Solomon T, Sriskandan S, Stuart D, Summers C, Tedder RS, Thomson EC, Thompson AAR, Thwaites RS, Turtle LCW, Zambon M, Hardwick H, Donohue C, Lyons R, Griffiths F, Oosthuyzen W, Norman L, Pius R, Fairfield CJ, Knight SR, Mclean KA, Murphy D, Shaw CA, Dalton J, Girvan M, Saviciute E, Roberts S, Harrison J, Marsh L, Connor M, Halpin S, Jackson C, Gamble C, Leeming G, Law A, Wham M, Clohisey S, Hendry R, Scott-Brown J, Greenhalf W, Shaw V, McDonald S, Keating S, Ahmed KA, Armstrong JA, Ashworth M, Asiimwe IG, Bakshi S, Barlow SL, Booth L, Brennan B, Bullock K, Catterall BWA, Clark JJ, Clarke EA, Cole S, Cooper L, Cox H, Davis C, Dincarslan O, Dunn C, Dyer P, Elliott A, Evans A, Finch L, Fisher LWS, Foster T, Garcia-Dorival I, Greenhalf W, Gunning P, Hartley C, Jensen RL, Jones CB, Jones TR, Khandaker S, King K, Kiy RT, Koukorava C, Lake A, Lant S, Latawiec D, Lavelle-Langham L, Lefteri D, Lett L, Livoti LA, Mancini M, McDonald S, McEvoy L, McLauchlan J, Metelmann S, Miah NS, Middleton J, Mitchell J, Moore SC, Murphy EG, Penrice-Randal R, Pilgrim J, Prince T, Reynolds W, Ridley PM, Sales D, Shaw VE, Shears RK, Small B, Subramaniam KS, Szemiel A, Taggart A, Tanianis-Hughes J, Thomas J, Trochu E, Tonder LV, Wilcock E, Zhang JE, Flaherty L, Maziere N, Cass E, Carracedo AD, Carlucci N, Holmes A, Massey H, Adeniji K, Agranoff D, Agwuh K, Ail D, Alegria A, Angus B, Ashish A, Atkinson D, Bari S, Barlow G, Barnass S, Barrett N, Bassford C, Baxter D, Beadsworth Met al., 2021, Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK, The Lancet Respiratory Medicine, Vol: 9, Pages: 699-711, ISSN: 2213-2600

BackgroundStudies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use.MethodsWe analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16–49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists [SABAs], and long-acting β-agonists [LABAs]). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma.Findings75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16–49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16–49 years: adjusted odds ratio [OR] 1·20 [95% CI

Journal article

Jansen K, Wirz OF, van de Veen W, Tan G, Mirer D, Sokolowska M, Satitsuksanoa P, Message SD, Kebadze T, Glanville N, Mallia P, Skiepko R, Eljaszewicz A, Moniuszko M, Cardoso C, Gern JE, Papadopoulos NG, Akdis CA, Johnston SL, Nadeau KC, Akdis Met al., 2021, Loss of regulatory capacity in Treg cells following rhinovirus infection., J Allergy Clin Immunol

BACKGROUND: Respiratory infections with rhinoviruses (RV) are strongly associated with development and exacerbations of asthma, and they pose an additional health risk for subjects with allergy. OBJECTIVE: How RV infections and chronic allergic diseases are linked and what role RV plays in the breaking of tolerance in regulatory T (Treg) cells is unknown. Therefore, this study aims to investigate the effects of RV on Treg cells. METHODS: Treg cells were isolated from subjects with asthma and controls after experimental infection with the RV-A16 (RV16) and analyzed with next-generation sequencing. Additionally, suppression assays, quantitative PCR assays, and protein quantifications were performed with Treg cells after in vitro RV16 infection. RESULTS: RV16 induced a strong antiviral response in Treg cells from subjects with asthma and controls, including the upregulation of IFI44L, MX1, ISG15, IRF7, and STAT1. In subjects with asthma, the inflammatory response was exaggerated and showed a dysregulated immune response compared with that in the controls. Furthermore, subjects with asthma failed to upregulate several immunosuppressive molecules such as CTLA4 and CD69, and they upregulated the inflammasome-related genes PYCARD and AIM2. Additionally, RV16 reduced the suppressive capacity of Treg cells from healthy subjects and subjects with asthma in vitro and increased TH2 cell-type cytokine production. CONCLUSIONS: Treg cells from healthy subjects and subjects with asthma displayed an antiviral response after RV infection and showed reduced suppressive capacity. These data suggest that Treg cell function might be altered or impaired during RV infections, which might play an important role in the association between RV and the development of asthma and asthma exacerbations.

Journal article

Laanesoo A, Urgard E, Periyasamy K, Laan M, Bochkov YA, Aab A, Magilnick N, Pooga M, Gern JE, Johnston SL, Coquet JM, Boldin MP, Wengel J, Altraja A, Bochenek G, Jakiela B, Rebane Aet al., 2021, Dual role of the miR-146 family in rhinovirus-induced airway inflammation and allergic asthma exacerbation, CLINICAL AND TRANSLATIONAL MEDICINE, Vol: 11, ISSN: 2001-1326

Journal article

Padayachee Y, Faiez TS, Singanayagam A, Mallia P, Johnston SLet al., 2021, Asthma and viruses: A focus on rhinoviruses and SARS-CoV-2, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 147, Pages: 1648-1651, ISSN: 0091-6749

Journal article

Ogal M, Johnston SL, Klein P, Schoop Ret al., 2021, Echinacea reduces antibiotic usage in children through respiratory tract infection prevention: a randomized, blinded, controlled clinical trial, EUROPEAN JOURNAL OF MEDICAL RESEARCH, Vol: 26, ISSN: 0949-2321

Journal article

Collison AM, Sokulsky LA, Kepreotes E, Pereira de Siqueira A, Morten M, Edwards MR, Walton RP, Bartlett NW, Yang M, Nguyen TH, Johnston SL, Foster PS, Mattes Jet al., 2021, miR-122 promotes virus-induced lung disease by targeting SOCS1., JCI Insight, Vol: 6

Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma. Here, we found that RV infection induced the expression of miRNA 122 (miR-122) in mouse lungs and in human airway epithelial cells. In vivo inhibition specifically in the lung reduced neutrophilic inflammation and CXCL2 expression, boosted innate IFN responses, and ameliorated airway hyperreactivity in the absence and in the presence of allergic lung inflammation. Inhibition of miR-122 in the lung increased the levels of suppressor of cytokine signaling 1 (SOCS1), which is an in vitro-validated target of miR-122. Importantly, gene silencing of SOCS1 in vivo completely reversed the protective effects of miR-122 inhibition on RV-induced lung disease. Higher miR-122 expression in nasopharyngeal aspirates was associated with a longer time on oxygen therapy and a higher rate of treatment failure in 87 infants hospitalized with moderately severe bronchiolitis. These results suggest that miR-122 promotes RV-induced lung disease via suppression of its target SOCS1 in vivo. Higher miR-122 expression was associated with worse clinical outcomes, highlighting the potential use of anti-miR-122 oligonucleotides, successfully trialed for treatment of hepatitis C, as potential therapeutics for RV-induced bronchiolitis and asthma exacerbations.

Journal article

Johnston SL, 2021, A, B, and C Rhinoviruses: New Knowledge from an Impressive Consortium A Step Forward for Rhinovirus Vaccine Efforts or a Step Back?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 203, Pages: 786-788, ISSN: 1073-449X

Journal article

Contoli M, Papi A, Tomassetti L, Rizzo P, Dalla Sega FV, Fortini F, Torsani F, Morandi L, Ronzoni L, Zucchetti O, Pavasini R, Fogagnolo A, Volta CA, Bartlett NW, Johnston SL, Spadaro S, Campo Get al., 2021, Blood Interferon-alpha Levels and Severity, Outcomes, and Inflammatory Profiles in Hospitalized COVID-19 Patients, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224

Journal article

Marcellini A, Swieboda D, Guedan A, Farrow SN, Casolari P, Contoli M, Johnston SL, Papi A, Solari Ret al., 2021, Glucocorticoids impair type I IFN signalling and enhance rhinovirus replication, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 893, ISSN: 0014-2999

Journal article

Finney L, Glanville N, Farne H, Aniscenko J, Fenwick P, Kemp S, Trujillo Torralbo M, Loo SL, Calderazzo M, Wedzicha J, Mallia P, Bartlett N, Johnston S, Singanayagam Aet al., 2021, Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 510-519.e5, ISSN: 0091-6749

Background: The mechanisms underlying altered susceptibility and propensity to severe Coronavirus disease 2019 (COVID-19) disease in at-risk groups such as patients with chronic obstructive pulmonary disease (COPD) are poorly understood. Inhaled corticosteroids (ICS) are widely used in COPD but the extent to which these therapies protect or expose patients to risk of severe COVID-19 is unknown. Objective: The aim of this study was to evaluate the effect of ICS upon pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme (ACE)-2.Methods: We evaluated the effect of ICS administration upon pulmonary ACE2 expression in vitro in human airway epithelial cell cultures and in vivo in mouse models of ICS administration. Mice deficient in the type I interferon-α/β receptor (Ifnar1−/−) and exogenous interferon-β administration experiments were used to study the functional role of type-I IFN signalling in ACE2 expression. We compared sputum ACE2 expression in patients with COPD stratified according to use or non-use of ICS.ResultsICS administration attenuated ACE2 expression in mice, an effect that was reversed by exogenous interferon-β administration and Ifnar1−/− mice had reduced ACE2 expression, indicating that type I interferon contributes mechanistically to this effect. ICS administration attenuated expression of ACE2 in COPD airway epithelial cell cultures and in mice with elastase-induced COPD-like changes. COPD patients taking ICS also had reduced sputum expression of ACE2 compared to non-ICS users.Conclusion: ICS therapies in COPD reduce expression of the SARS-CoV-2 entry receptor ACE2. This effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD.

Journal article

Bloom C, Tom D, Docherty A, Lipworth B, Johnston S, Nguyen-Van-Tam J, Carson G, Dunning J, Harrison E, Baillie K, Semple M, Cullinan P, Openshaw Pet al., 2021, Risk of adverse outcomes in patients with underlying respiratory conditions hospitalised with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: a national, multicentre prospective cohort, The Lancet Respiratory Medicine, ISSN: 2213-2600

BackgroundStudies of hospitalised COVID-19 patients have found inconsistencies in mortality associated with underlying respiratory conditions and inhaled corticosteroid (ICS) use. We sought to investigate this relationship using a national, multicentre, prospective cohort. MethodsProspective, multicentre UK cohort of hospitalised COVID-19 patients. Patients with asthma, chronic pulmonary disease (CPD), or both, were identified and stratified by age (years): <16, 16-49 and ≥50. In-hospital mortality was measured using multilevel Cox proportional hazards, adjusting for demographics, comorbidities and medications (ICS, short-acting-beta-agonists (SABA), long-acting-beta-agonists (LABA)). Asthma patients using ICS+LABA+another asthma medication were considered ‘severe’.Findings75,463 patients were included: <16 years, 860 patients (8.6% asthma); 16-49 years, 8,950 patients (20.9% asthma), ≥50 years, 65,653 patients (9.0% asthma, 15.6% CPD, 3.2% asthma & CPD). Asthma patients were significantly more likely to receive critical care, CPD patients were significantly less likely to. In patients 16-49 years, only those with severe asthma had a significant increase in mortality (adjusted HR (95%CI): no therapy=1.21 (0.78-1.88), SABA-only=1.03 (0.66-1.62), ICS-only=1.01 (0.68-1.51), ICS+LABA=1.06 (0.70-1.61), severe=2.07 (1.35-3.18)). In patients ≥50 years, there was increased mortality associated with CPD and severe asthma. ICS use was associated with lower mortality (adjusted HR (95% CI): asthma+no_ICS=0.97 (0.90-1.04), asthma+ICS=0.87 (0.81-0.93), CPD+no_ICS=1.16 (1.11-1.21), CPD+ICS=1.10 (1.04-1.17), asthma+CPD+no_ICS=1.13 (1.00-1.27), asthma+CPD+ICS=0.98 (0.89-1.07).InterpretationUnderlying respiratory conditions are common in hospitalised COVID-19 patients. Regardless of admission severity and comorbidities, asthma patients were more likely to receive critical care than patients without underlying respiratory disease; CPD patients were less

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., 2021, 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, Vol: 9, Pages: 57-68, 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

Coultas JA, Cafferkey J, Mallia P, Johnston SLet al., 2021, Experimental Antiviral Therapeutic Studies for Human Rhinovirus Infections., J Exp Pharmacol, Vol: 13, Pages: 645-659, ISSN: 1179-1454

Rhinovirus infection is common and usually causes mild, self-limiting upper respiratory tract symptoms. Rhinoviruses can cause exacerbation of chronic respiratory diseases, such as asthma or chronic obstructive pulmonary disease, leading to a significant burden of morbidity and mortality. There has been a great deal of progress in efforts to understand the immunological basis of rhinovirus infection. However, despite a number of in vitro and in vivo attempts, there have been no effective treatments developed. This review article summarises the up to date virological and immunological understanding of these infections. We discuss the challenges researchers face, and key solutions, in their work to investigate potential therapies including in vivo rhinovirus challenge studies. Finally, we explore past and present experimental therapeutic strategies employed in the treatment of rhinovirus infections and highlight promising areas of future work.

Journal article

McErlean P, Kelly A, Dhariwal J, Kirtland M, Watson J, Ranz I, Smith J, Saxena A, Cousins DJ, Van Oosterhout A, Solari R, Edwards MR, Johnston SL, Lavender Pet al., 2020, Profiling of H3K27Ac Reveals the Influence of Asthma on the Epigenome of the Airway Epithelium, FRONTIERS IN GENETICS, Vol: 11

Journal article

Williams TC, Jackson DJ, Maltby S, Walton RP, Ching Y-M, Glanville N, Singanayagam A, Brewins JJ, Clarke D, Hirsman AG, Loo S-L, Wei L, Beale JE, Casolari P, Caramori G, Papi A, Belvisi M, Wark PAB, Johnston SL, Edwards MR, Bartlett NWet al., 2020, Rhinovirus-induced CCL17 and CCL22 in asthma exacerbations and differential regulation by STAT6., American Journal of Respiratory Cell and Molecular Biology, Vol: 64, Pages: 344-356, ISSN: 1044-1549

The interplay of type-2 inflammation and anti-viral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma, however mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild-to-moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then employed to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface (ALI) differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression: increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6 which was required for CCL17, but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-kB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, findings suggest therapeutic targeting of type-2-STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

Journal article

Singanayagam A, Johnston SL, 2020, Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 146, Pages: 1292-1294, ISSN: 0091-6749

Journal article

Johnston SL, McKay PF, Kebadze T, Hu K, Samnuan K, Aniscenko J, Cameron A, Patel N, Randell P, Shattock RJ, Edwards MRet al., 2020, Evaluation of the Abbott Architect, Roche Elecsys and Virtus S1 SARS-CoV-2 antibody tests in community-managed COVID-19 cases

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Antibody testing can help define how protective immunity to SARS-CoV-2 is and how long this immunity lasts. Many antibody tests have been evaluated in hospitalised rather than community based COVID-19 cases. Virtus Respiratory Research Ltd (Virtus) has developed its own quantitative IgM and IgG SARS CoV-2 antibody assay. We report its validation and performance characteristics and compare its performance with the Abbott Architect and Roche Elecsys assays in community COVID cases.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We developed a quantitative antibody test to detect IgM and IgG to the SARS-CoV-2 S1 spike protein (the Virtus test) and validated this test in 107 “true positive” sera from 106 community-managed and 1 hospitalised COVID-19 cases and 208 “true negative” serum samples. We validated the Virtus test against a neutralising antibody test. We determined sensitivities of the Abbott test in the 107 true positive samples and the Roche test in a subset of 75 true positive samples.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The Virtus quantitative test was positive in 93 of 107 (87%) community cases of COVID-19 and both IgM and IgG levels correlated strongly with neutralising antibody titres (r=0.75 for IgM, r=0.71 for IgG, <jats:italic>P</jats:italic>&lt;0.0001 for both antibodies). The specificity of the Virtus test was 98.6% for low level antibody positives, 99.5% for moderate positives and 100% for high or very high positives. The Abbott test had a sensitivity of 68%. In the 75 sample subset, the Virtus test was positive in 91%, the Roche test in 69%.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The Abbott and R

Journal article

Bardin PG, Johnston SL, 2020, Attenuating COVID-19 infection and inflammation: Lessons from asthma, RESPIROLOGY, Vol: 25, Pages: 1233-1234, ISSN: 1323-7799

Journal article

Zhu J, Mallia P, Footitt J, Yusheng Q, Message SD, Kebadze T, Aniscenko J, Barnes PJ, Adcock I, Kon OM, Johnson M, Contoli M, Stanciu L, Papi A, Jeffery PK, Johnston Set al., 2020, Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD, Journal of Allergy and Clinical Immunology, Vol: 146, Pages: 840-850.e7, ISSN: 0091-6749

BackgroundRespiratory viral infection causes chronic obstructive pulmonary disease (COPD) exacerbations. We previously reported increased bronchial mucosa eosinophil and neutrophil inflammation in patients with COPD experiencing naturally occurring exacerbations. But it is unclear whether virus per se induces bronchial mucosal inflammation, nor whether this relates to exacerbation severity.ObjectivesWe sought to determine the extent and nature of bronchial mucosal inflammation following experimental rhinovirus (RV)-16–induced COPD exacerbations and its relationship to disease severity.MethodsBronchial mucosal inflammatory cell phenotypes were determined at preinfection baseline and following experimental RV infection in 17 Global Initiative for Chronic Obstructive Lung Disease stage II subjects with COPD and as controls 20 smokers and 11 nonsmokers with normal lung function. No subject had a history of asthma/allergic rhinitis: all had negative results for aeroallergen skin prick tests.ResultsRV infection increased the numbers of bronchial mucosal eosinophils and neutrophils only in COPD and CD8+ T lymphocytes in patients with COPD and nonsmokers. Monocytes/macrophages, CD4+ T lymphocytes, and CD20+ B lymphocytes were increased in all subjects. At baseline, compared with nonsmokers, subjects with COPD and smokers had increased numbers of bronchial mucosal monocytes/macrophages and CD8+ T lymphocytes but fewer numbers of CD4+ T lymphocytes and CD20+ B lymphocytes. The virus-induced inflammatory cells in patients with COPD were positively associated with virus load, illness severity, and reductions in lung function.ConclusionsExperimental RV infection induces bronchial mucosal eosinophilia and neutrophilia only in patients with COPD and monocytes/macrophages and lymphocytes in both patients with COPD and control subjects. The virus-induced inflammatory cell phenotypes observed in COPD positively related to virus load and illness severity. Antiviral/anti-inflamma

Journal article

Farne H, Kumar K, Ritchie AI, Finney LJ, Johnston SL, Singanayagam Aet al., 2020, Repurposing existing drugs for the treatment of COVID-19, Annals of the American Thoracic Society, Vol: 17, Pages: 1186-1194, ISSN: 1546-3222

The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by SARS-CoV-2 viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist, thus development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and anti-inflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date only dexamethasone and remedesivir have been shown to be effective, but several other promising candidates are in trials.

Journal article

Riggioni C, Comberiati P, Giovannini M, Agache I, Akdis M, Alves-Correia M, Antó JM, Arcolaci A, Kursat Azkur A, Azkur D, Beken B, Boccabella C, Bousquet J, Breiteneder H, Carvalho D, De Las Vecillas L, Diamant Z, Eguiluz-Gracia I, Eiwegger T, Eyerich S, Fokkens W, Gao Y-D, Hannachi F, Johnston SL, Jutel M, Karavelia A, Klimek L, Moya B, Nadeau K, O'Hehir R, O'Mahony L, Pfaar O, Sanak M, Schwarze J, Sokolowska M, Torres MJ, van de Veen W, van Zelm MC, Wang DY, Zhang L, Jiménez-Saiz R, Akdis CAet al., 2020, A compendium answering 150 questions on COVID-19 and SARS-CoV-2., Allergy, Vol: 75, Pages: 2503-2541, ISSN: 0105-4538

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date it has resulted in ~6.5 million confirmed cases and caused almost 400,000 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socio-economic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a "cytokine storm" leading to acute respiratory distress syndrome, endothelitis, thrombo-embolic complications and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19 and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development and epidemiology. Over 140 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.

Journal article

Regis E, Fontanella S, Lin L, Howard R, Haider S, Curtin JA, Edwards MR, Rattray M, Simpson A, Custovic A, Johnston SLet al., 2020, Sex differences in innate anti-viral immune responses to respiratory viruses

<jats:title>Abstract</jats:title><jats:p>Males have excess morbidity and mortality from respiratory viral infections and especially so in COVID-19. The mechanisms explaining this excess in disease burden in males are unknown. Innate immune responses are likely critical in protection against a novel virus like SARS-CoV-2. We hypothesised that innate immune responses may be deficient in males relative to females. To test this we stimulated peripheral blood mononuclear cells (PBMCs) from participants in a population-based birth cohort with three respiratory viruses (rhinoviruses-RV-A16 and RV-A1, and respiratory syncytial virus-RSV) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2). We measured interferon (IFN) and IFN-induced chemokine responses and investigated sex differences in virus-induced responses. IFN-α, IFN-β and IFN-γ responses to RV-A16 were deficient in males compared to females, fold-inductions being 1.92-fold (<jats:italic>P&lt;</jats:italic>0.001), 2.04-fold (<jats:italic>P</jats:italic>&lt;0.001) and 1.77-fold (<jats:italic>P</jats:italic>=0.003) lower in males than females, respectively. Similar significant deficiencies in innate immune responses were observed in males for eleven other cytokine-stimulus pairs. Responses in males were greater than those in females in only one of 35 cytokine-stimulus pairs investigated. Review of healthcare records revealed that 12.1% of males but only 6.6% of females were admitted to hospital with respiratory infections in the first year of life (<jats:italic>P</jats:italic>=0.017). Impaired innate anti-viral immunity in males likely results in high morbidity and mortality from respiratory viruses including COVID-19. Males may preferentially benefit from therapies that boost innate anti-viral immune responses.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p

Journal article

Kamal F, Glanville N, Xia W, Bakhsoliani E, Aniscenko J, Bartlett NW, Edwards MR, Johnston SL, Singanayagam Aet al., 2020, Beclomethasone has lesser suppressive effects on inflammation and anti-bacterial immunity than Fluticasone or Budesonide in experimental infection models., Chest, Vol: 158, Pages: 947-951, ISSN: 0012-3692

Journal article

Kumar K, Losa F, Kebadze T, Del Giacco S, Mallia P, Singanayagam A, Edwards MR, Johnston SLet al., 2020, Differences in induction of asthma-relevant pro-inflammatory mediators by beta 2-agonists and muscarinic antagonists in human bronchial epithelial cells, European-Academy-of-Allergology-and-Clinical-Immunology Digital Congress (EAACI), Publisher: WILEY, Pages: 163-164, ISSN: 0105-4538

Conference paper

Kumar K, Singanayagam A, Johnston SL, 2020, Respiratory Virus Infections in Asthma: Research Developments and Therapeutic Advances., Acta Med Acad, Vol: 49, Pages: 130-143

In this review, we discuss the latest developments in research pertaining to virus-induced asthma exacerbations and consider recent advances in treatment options. Asthma is a chronic disease of the airways that continues to impose a substantial clinical burden worldwide. Asthma exacerbations, characterised by an acute deterioration in respiratory symptoms and airflow obstruction, are associated with significant morbidity and mortality. These episodes are most commonly triggered by respiratory virus infections. The mechanisms underlying the pathogenesis of virus-induced exacerbations have been the focus of extensive biomedical research. Developing a robust understanding of the interplay between respiratory viruses and the host immune response will be critical for developing more efficacious, targeted therapies for exacerbations. CONCLUSION: There has been significant recent progress in our understanding of the mechanisms underlying virus-induced airway inflammation in asthma and these advances will underpin the development of future clinical therapies.

Journal article

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