Imperial College London

DrAranSinganayagam

Faculty of MedicineDepartment of Infectious Disease

MRC Clinician Scientist Fellow.
 
 
 
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a.singanayagam

 
 
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Flowers buildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
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83 results found

Prendecki M, Clarke C, Edwards H, McIntyre S, Mortimer P, Gleeson S, Martin P, Thomson T, Randell P, Shah A, Singanayagam A, Lightstone L, Cox A, Kelleher P, Willicombe M, McAdoo SPet al., 2021, Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression., Annals of the Rheumatic Diseases, Vol: 80, Pages: 1322-1329, ISSN: 0003-4967

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.

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

Pinto AL, Rai RK, Brown JC, Griffin P, Edgar JR, Shah A, Singanayagam A, Hogg C, Barclay WS, Futter CE, Burgoyne Tet al., 2021, Ultrastructural insight into SARS-CoV-2 attachment, entry and budding in human airway epithelium

<jats:title>Abstract</jats:title><jats:p>Ultrastructural studies of SARS-CoV-2 infected cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Many studies are limited by the lack of access to appropriate cellular models. As the airway epithelium is the primary site of infection it is essential to study SARS-CoV-2 infection of these cells. Here, we examined human airway epithelium, grown as highly differentiated air-liquid interface cultures and infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant (Variant of Concern 202012/01) by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Two key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistent with these observations, extracellular virions were frequently seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion at the apical plasma membrane demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Profiles strongly suggesting viral budding from the membrane was observed in these compartments and this may explain how virions gain their S glycoprotein containing envelope.</jats:p>

Journal article

Farne H, Singanayagam A, 2021, Gateway to the lungs: Viral entry receptors and susceptibility to COVID-19, RESPIROLOGY, Vol: 26, Pages: 404-405, ISSN: 1323-7799

Journal article

Farne H, Singanayagam A, 2021, Inhaled corticosteroids and angiotensin-converting enzyme-2 in COPD Reply, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 147, Pages: 1117-1118, ISSN: 0091-6749

Journal article

Brown JC, Goldhill DH, Zhou J, Peacock TP, Frise R, Goonawardane N, Baillon L, Kugathasan R, Pinto AL, McKay PF, Hassard J, Moshe M, Singanayagam A, Burgoyne T, Barclay WSet al., 2021, Increased transmission of SARS-CoV-2 lineage B.1.1.7 (VOC 2020212/01) is not accounted for by a replicative advantage in primary airway cells or antibody escape

<jats:title>Abstract</jats:title><jats:p>Lineage B.1.1.7 (Variant of Concern 202012/01) is a new SARS-CoV-2 variant which was first sequenced in the UK in September 2020 before becoming the majority strain in the UK and spreading worldwide. The rapid spread of the B.1.1.7 variant results from increased transmissibility but the virological characteristics which underpin this advantage over other circulating strains remain unknown. Here, we demonstrate that there is no difference in viral replication between B.1.1.7 and other contemporaneous SARS-CoV-2 strains in primary human airway epithelial (HAE) cells. However, B.1.1.7 replication is disadvantaged in Vero cells potentially due to increased furin-mediated cleavage of its spike protein as a result of a P681H mutation directly adjacent to the S1/S2 cleavage site. In addition, we show that B.1.1.7 does not escape neutralisation by convalescent or post-vaccination sera. Thus, increased transmission of B.1.1.7 is not caused by increased replication, as measured on HAE cells, or escape from serological immunity.</jats:p>

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

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

Farne H, Singanayagam A, 2020, Why asthma might surprisingly protect against poor outcomes in COVID-19, EUROPEAN RESPIRATORY JOURNAL, Vol: 56, ISSN: 0903-1936

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

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

Ritchie AI, Singanayagam A, 2020, Metagenomic Characterization of the Respiratory Microbiome A Piece de Resistance, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 321-322, ISSN: 1073-449X

Journal article

Finney LJ, Glanville N, Farne H, Aniscenko J, Fenwick P, Kemp SV, Trujillo-Torralbo M-B, Calderazzo MA, Wedzicha JA, Mallia P, Bartlett NW, Johnston SL, Singanayagam Aet al., 2020, Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:p>Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a new rapidly spreading infectious disease. Early reports of hospitalised COVID-19 cases have shown relatively low frequency of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) but increased risk of adverse outcome. The mechanisms of altered susceptibility to viral acquisition and/or severe disease in at-risk groups are poorly understood. Inhaled corticosteroids (ICS) are widely used in the treatment of COPD but the extent to which these therapies protect or expose patients with a COPD to risk of increased COVID-19 severity is unknown. Here, using a combination of human and animal <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> disease models, we show that ICS administration attenuates pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme (ACE)-2. This effect was mechanistically driven by suppression of type I interferon as exogenous interferon-β reversed ACE2 downregulation by ICS. Mice deficient in the type I interferon-α/β receptor (<jats:italic>Ifnar1</jats:italic><jats:sup>−/−</jats:sup>) also had reduced expression of ACE2. Collectively, these data suggest that use of ICS therapies in COPD reduces expression of the SARS-CoV-2 entry receptor ACE2 and this effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD.</jats:p>

Working paper

Kumar K, Hinks TSC, Singanayagam A, 2020, Treatment of COVID-19-exacerbated asthma: should systemic corticosteroids be used?, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 318, Pages: L1244-L1247, ISSN: 1040-0605

Journal article

Mathioudakis AG, Janssens W, Sivapalan P, Singanayagam A, Dransfield MT, Jensen J-US, Vestbo Jet al., 2020, Acute exacerbations of chronic obstructive pulmonary disease: in search of diagnostic biomarkers and treatable traits, THORAX, Vol: 75, Pages: 520-527, ISSN: 0040-6376

Journal article

Ritchie AI, Singanayagam A, 2020, Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?, LANCET, Vol: 395, Pages: 1111-1111, ISSN: 0140-6736

Journal article

Singanayagam A, Johnston SL, 2019, Not just the common cold: Rhinovirus infection in lung allograft recipients, RESPIROLOGY, Vol: 24, Pages: 1134-1135, ISSN: 1323-7799

Journal article

Singanayagam A, Loo S-L, Calderazzo MA, Finney LJ, Trujillo Torralbo M-B, Bakhsoliani E, Girkin J, Veerati PC, Pathinayake PS, Nichol KS, Reid AT, Footitt J, Johnston SL, Bartlett NW, Mallia Pet al., 2019, Antiviral immunity is impaired in COPD patients with frequent exacerbations, American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol: 317, Pages: L893-L903, ISSN: 1040-0605

Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (>2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro RV-infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate anti-microbial immunity in the lung could be a viable strategy for prevention/treatment of frequent exacerbations.

Journal article

Patel DF, Peiro T, Bruno N, Vuononvirta J, Akthar S, Puttur F, Pyle CJ, Suveizdyte K, Walker SA, Singanayagam A, Carlin LM, Gregory LG, Lloyd CM, Snelgrove Ret al., 2019, Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation, Science Immunology, Vol: 4, Pages: 1-18, ISSN: 2470-9468

Neutrophil mobilization, recruitmentand clearancemust be tightly regulated asover-exuberant neutrophilic inflammation isimplicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophilstherapeutically have failed to consider theirpleiotropic functions and theimplications of disrupting fundamental regulatory pathways that govern their turnover duringhomeostasisand inflammation.Using thehouse dust mite(HDM)model of allergic airways disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated TH2 inflammation, epithelial remodelling and airway resistance. Mechanistically, this was attributable to astriking increase insystemic G-CSF concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increasedG-CSF augmented allergic sensitization in HDM exposed animals bydirectly acting on airway ILC2s toelicitcytokine production.Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool.By modelling the effects of neutrophil depletion, our studies have therefore uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly,they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.

Journal article

Singanayagam A, Snelgrove RJ, 2019, Less burn, more fat: electronic cigarettes and pulmonary lipid homeostasis, JOURNAL OF CLINICAL INVESTIGATION, Vol: 129, Pages: 4077-4079, ISSN: 0021-9738

Journal article

Singanayagam A, Glanville N, Cuthbertson L, Bartlett NW, Finney LJ, Turek E, Bakhsoliani E, Calderazzo MA, Trujillo-Torralbo M-B, Footitt J, James PL, Fenwick P, Kemp SV, Clarke TB, Wedzicha JA, Edwards MR, Moffatt M, Cookson WO, Mallia P, Johnston SLet al., 2019, Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease, Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234

Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

Journal article

Singanayagam A, Footitt J, Kasdorf BT, Marczynski M, Cross MT, Finney LJ, Trujillo Torralbo M-B, Calderazzo M, Zhu J, Aniscenko J, Clarke TB, Molyneaux PL, Bartlett NW, Moffatt MF, Cookson WO, Wedzicha J, Evans CM, Lieleg O, Mallia P, Johnston SLet al., 2019, MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation

<jats:title>ABSTRACT</jats:title><jats:p>The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus that is rich in mucin glycoproteins. Disrupted mucus production is a cardinal feature of chronic respiratory diseases but how this alteration affect interactions between mucins and pathogens is complex and poorly understood. Here, we identify a central and unexpected role for the major airway mucin MUC5AC in pathogenesis of virus-induced exacerbations of chronic obstructive pulmonary disease (COPD). Virus induction of MUC5AC is augmented in COPD compared to healthy subjects, is enhanced in frequent exacerbators and correlates with inflammation, symptom severity and secondary bacterial infection during exacerbation. MUC5AC is functionally related to inflammation as MUC5AC-deficient (<jats:italic>Muc5ac</jats:italic>-/-) mice had attenuated rhinovirus-induced airway inflammation whilst exogenous MUC5AC glycoprotein administration augmented virus-induced inflammatory responses and bacterial load. Mechanistically, MUC5AC-augmentation of rhinovirus-induced inflammation occurred through release of extracellular adenosine triphosphate (ATP). Therapeutic suppression of virus-induced MUC5AC release using an epidermal growth factor receptor (EGFR) inhibitor ameliorated exaggerated pro-inflammatory responses in a mouse COPD exacerbation model. Collectively, these studies demonstrate previously unrecognised pro-inflammatory effects of MUC5AC during infection and thus highlight a key unforeseen role in driving COPD exacerbation severity.</jats:p>

Journal article

Singanayagam A, Loo S-L, Calderazzo M, Finney LJ, Trujillo Torralbo M-B, Bakhsoliani E, Girkin J, Veerati P, Pathinayake PS, Nichol KS, Reid A, Foottit J, Johnston SL, Bartlett NW, Mallia Pet al., 2019, Anti-microbial immunity is impaired in COPD patients with frequent exacerbations

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. <jats:italic>Ex vivo</jats:italic> immune responses to rhinovirus infection in differentiated bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (&lt;2 exacerbations in the preceding year) with comparisons made between these groups.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Frequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. RV-induction of interferon and ISGs <jats:italic>ex vivo</jats:italic> was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators also had reduced sputum levels of the anti-microbial peptide mannose-binding lectin (MBL)-2 with an associated increase in sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. MBL-2 levels correlated negatively with bacterial loads during exacerbation.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These data

Journal article

Calderazzo MA, Trujillo-Torralbo M-B, Finney LJ, Singanayagam A, Bakhsoliani E, Padmanaban V, Kebadze T, Aniscenko J, Elkin SL, Johnston SL, Mallia Pet al., 2019, Inflammation and infections in unreported chronic obstructive pulmonary disease exacerbations, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 2019, Pages: 823-832, ISSN: 1176-9106

Purpose: COPD patients often do not report acute exacerbations to healthcare providers – unreported exacerbations. It is not known whether variances in symptoms, airway obstruction, aetiology and inflammatory responses account for differences in reporting of COPD exacerbations. The aims of the study were to compare symptoms, lung function changes, aetiology and inflammatory markers between exacerbations that were reported to healthcare providers or treated, with those that were unreported and untreated.Patients and methods: We recruited a cohort of COPD patients and collected clinical data and blood and airway samples when stable and during acute exacerbations. Virological and bacterial analyses were carried out and inflammatory markers measured.Results: We found no differences in symptoms, lung function, incidence of infection and inflammatory markers between reported and unreported exacerbations. Subjects who reported all exacerbations had higher BODE scores, lower FEV1 and more exacerbations compared with those who did not.Conclusion: The failure to report exacerbations is not related to the severity, aetiology or inflammatory profile of the exacerbation. Patients with less severe COPD and less frequent exacerbations are less likely to report exacerbations. The decision to report an exacerbation is not an objective marker of exacerbation severity and therefore studies that do not count unreported exacerbations will underestimate the frequency of clinically significant exacerbations. A better understanding of the factors that determine non-reporting of exacerbations is required to improve exacerbation reporting.

Journal article

Jewell P, Dixon L, Singanayagam A, Ghani R, Wong E, Coleman M, Pichon B, Kearns A, Russell G, Hatcher Jet al., 2019, Severe disseminated infection with emerging lineage of methicillin-sensitive staphylococcus aureus, Emerging Infectious Diseases, Vol: 25, Pages: 187-189, ISSN: 1080-6040

We report a case of severe disseminated infection in an immunocompetent man caused by an emerging lineage of methicillin-sensitive Staphylococcus aureus clonal complex 398. Genes encoding classic virulence factors were absent. The patient made a slow recovery after multiple surgical interventions and a protracted course of intravenous flucloxacillin.

Journal article

Tregoning JS, Mallia P, Webber J, Gill SK, Trujillo-Torralbo, Calderazzo MA, Finney L, Bakhsoliani E, Farne H, Singanayagam A, Footitt J, Hewitt R, Kebadze, Aniscenko J, Padmanaban V, Molyneaux PL, Adcock, Barnes PJ, Ito K, Elkin SL, Kon OM, Cookson WO, MOffatt MF, Johnston SLet al., 2018, Role of airway glucose in bacterial infections in chronic obstructive pulmonary disease, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 815-823.e6, ISSN: 0091-6749

BackgroundPatients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear.ObjectivesThe aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection.MethodsWe measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined.ResultsSputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro.ConclusionsAirway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prev

Journal article

Singanayagam A, Glanville N, Girkin J, Ching YM, Marcellini A, Porter J, Toussaint M, Walton R, Finney L, Julia A, Zhu J, Trujillo-Torralbo M, Calderazzo M, Grainge C, Loo S-L, Veerati PC, Pathinayake P, Nichol K, Reid A, James P, Solari R, Wark P, Knight D, Moffatt M, Cookson W, Edwards M, Mallia P, Bartlett N, Johnston SLet al., 2018, Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations, Nature Communications, Vol: 9, Pages: 1-16, ISSN: 2041-1723

Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.

Journal article

Ritchie AI, Singanayagam A, Wiater E, Edwards MR, Montminy M, Johnston SLet al., 2018, beta(2)-agonists enhance asthma-relevant inflammatory mediators in human airway epithelial cells, American Journal of Respiratory Cell and Molecular Biology, Vol: 58, Pages: 128-132, ISSN: 1044-1549

Journal article

Garcia-Basteiro AL, Wong E, Van Oort PM, Cilloniz C, Migliori GB, Singanayagam Aet al., 2017, Respiratory infection: insights from Assembly 10 of the European Respiratory Society 2017 Annual Congress, JOURNAL OF THORACIC DISEASE, Vol: 9, Pages: S1559-S1562, ISSN: 2072-1439

Journal article

Singanayagam A, Aliberti S, Cillóniz C, Torres A, Blasi F, Chalmers JDet al., 2017, Evaluation of severity score-guided approaches to macrolide use in community-acquired pneumonia, European Respiratory Journal, Vol: 50, ISSN: 0903-1936

International guidelines including those in the UK, Japan, Australia and South Africa recommend the avoidance of macrolides in patients with low-severity community-acquired pneumonia (CAP). We hypothesised that severity scores are poor predictors of atypical pneumonia and response to macrolide therapy, and thus, inadequate tools for guiding antibiotic prescriptions.Secondary analysis of four independent prospective CAP datasets was conducted. The predictive values of the CURB-65 and pneumonia severity index (PSI) for clinically important groups of causative pathogens were evaluated. The effect of macrolide use according to risk class was assessed by multivariable analysis. Patients (3297) were evaluated, and the predictive values of CURB-65 and PSI for atypical pathogens were poor (AUC values of 0.37 and 0.42, respectively). No significant differences were noted among the effects of macrolide use on mortality in patients with mild, moderate and severe CAP, according to either CURB-65 (interaction testing severe versus mild disease OR=0.74 (0.29–1.89)) or PSI (severe versus mild disease OR=3.4 (0.055–2.10)), indicating that severity scores were not significant modifiers of response to macrolide therapy.Severity scores did not accurately predict response to macrolide therapy in CAP, suggesting that current guidance to use these tools for empirical antibiotic choices might not be justified.

Journal article

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