S T Holgate

University of Southampton, Southampton, England, United Kingdom

Are you S T Holgate?

Claim your profile

Publications (585)3488.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics.MethodsA total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum).ResultsAfter 1 year of follow-up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1), quality of life and asthma control.Conclusion Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control.
    Allergy 07/2014; 69(9). DOI:10.1111/all.12445 · 6.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Tryptase, a major secretory product of human mast cells has been implicated as a key mediator of allergic inflammation. Genetic variation in the tryptases is extensive, and α-tryptase, an allelic variant of the more extensively studied β-tryptase, is absent in substantial numbers of the general population. The degree to which α-tryptase expression may be associated with asthma has not been studied. We have investigated the α-tryptase gene copy number variation and its potential associations with phenotypes of asthma. OBJECTIVES: Caucasian families (n=341) with at least two asthmatic siblings (n=1350) were genotyped for the α-tryptase alleles, using high resolution melting assays. Standards for the possible α-/β-tryptase ratios were constructed by cloning α-and β-tryptase PCR products to generate artificial templates. Association analysis of asthma affection status and related phenotypes (total and allergen-specific serum IgE, bronchial hyperresponsiveness to methacholine, FEV1 , and atopy and asthma severity scores) were undertaken using family based association tests (FBAT). RESULTS: Four consistent melting patterns for the α-tryptase genotype were identified with alleles carrying null, one or two copies of the α-tryptase allele. Possessing one copy of α-tryptase was significantly associated with lower serum levels of total and dust mite-specific IgE levels and higher FEV1 measurements, while two copies were related to higher serum concentrations of total and dust mite-specific IgE and greater atopy severity scores. CONCLUSIONS AND CLINICAL RELEVANCE: Associations of α-tryptase copy number with serum IgE levels, atopy scores and bronchial function may reflect roles for tryptases in regulating IgE production and other processes in asthma.
  • Winter Meeting of the British-Thoracic-Society 2012; 12/2012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.
    Allergy 11/2010; 66(4):458-68. DOI:10.1111/j.1398-9995.2010.02505.x · 6.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increased tumour necrosis factor-α levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma. In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n=132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1)% predicted. Secondary end-points included morning peak expiratory flow, FEV1% pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire. No significant differences were observed between ETN and placebo for any of the efficacy end-points. ETN treatment was well tolerated, with no unexpected safety findings observed during the study. Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.
    European Respiratory Journal 11/2010; 37(6):1352-9. DOI:10.1183/09031936.00063510 · 7.64 Impact Factor
  • Thorax 09/2010; 66(6):537. DOI:10.1136/thx.2010.136523 · 8.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: First-generation H(1)-antihistamines obtained without prescription are the most frequent form of self-medication for allergic diseases, coughs and colds and insomnia even though they have potentially dangerous unwanted effects which are not recognized by the general public. To increase consumer protection by bringing to the attention of regulatory authorities, physicians and the general public the potential dangers of the indiscriminate use first-generation H(1)-antihistamines purchased over-the counter in the absence of appropriate medical supervision. A GA(2)LEN (Global Allergy and Asthma European Network) task force assessed the unwanted side-effects and potential dangers of first-generation H1-antihistamines by reviewing the literature (Medline and Embase) and performing a media audit of US coverage from 1996 to 2008 of accidents and fatal adverse events in which these drugs were implicated. First-generation H(1)-antihistamines, all of which are sedating, are generally regarded as safe by laypersons and healthcare professionals because of their long-standing use. However, they reduce rapid eye movement (REM)-sleep, impair learning and reduce work efficiency. They are implicated in civil aviation, motor vehicle and boating accidents, deaths as a result of accidental or intentional overdosing in infants and young children and suicide in teenagers and adults. Some exhibit cardiotoxicity in overdose. This review raises the issue of better consumer protection by recommending that older first-generation H(1)-antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second- generation nonsedating H(1)-antihistamines with superior risk/benefit ratios are widely available at competitive prices.
    Allergy 02/2010; 65(4):459-66. DOI:10.1111/j.1398-9995.2009.02325.x · 6.03 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2010; 125(2). DOI:10.1016/j.jaci.2009.12.201 · 11.48 Impact Factor
  • IA Yang · K M Fong · P V Zimmerman · S T Holgate · J W Holloway
    [Show abstract] [Hide abstract]
    ABSTRACT: There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).
    Postgraduate medical journal 09/2009; 85(1006):428-36. DOI:10.1136/thx.2007.079426 · 1.45 Impact Factor
  • SA Field · JD Haywood · C Xiao · ST Holgate · DE Davies · PD Monk
    American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009
  • JA Cakebread · Y Xu · D Sammut · P Howarth · ST Holgate · DE Davies
    American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009
  • Source
    J Self · H.M. Haitchi · H Griffiths · S.T. Holgate · D.E. Davies · A Lotery
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the FERM domain containing 7 (FRMD7) genes are known to cause a significant number of cases of congenital idiopathic nystagmus (CIN). Only limited expression data exist suggesting low levels of expression in all tissues. In this study, we assess the expression profile of the murine homologue of FRMD7 (Frmd7) in tissue from three murine organs during development. cDNA was extracted from heart, lung, and brain tissues of MF-1 mice at 12 developmental time points, embryonic days 11-19, postnatal days 1 and 8, and from adult mice. Relative expression of Frmd7 mRNA was calculated using quantitative real-time PCR techniques with two normalising genes (Gapdh and Actb). Expression of Frmd7 was low in all tissues consistent with earlier reports. In heart and lung tissues, expression remained very low with an increase only in adult samples. In brain tissue, expression levels were higher at all time points with a significant increase at embryonic day 18, with no gender-specific influence on Frmd7 expression. Frmd7 is expressed at low levels in all tissues studied suggesting a role in many tissue types. However, higher overall expression and a sharp increase at ED18 in the murine brain suggest a different role in this tissue.Earlier studies have shown that genes expressed in the murine brain during development exhibit temporal functional clustering. The temporal pattern of Frmd7 expression found in this study mirrors that of genes involved in synapse formation/function, and genes related to axon growth/guidance. This suggests a role for Frmd7 in these processes and should direct further expression studies.
    Eye (London, England) 04/2009; 24(1):165-9. DOI:10.1038/eye.2009.44 · 2.08 Impact Factor
  • Y Xu · HM Haitchi · JA Cakebread · ST Holgate · GC Roberts · DE Davies
    American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009
  • American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009
  • American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ciliated Bronchial Epithelium (CBE) 1 is a novel gene, which is expressed in ciliated cells. As cilia are important during embryogenesis, the present authors characterised the murine homologue of CBE1 (Cbe1) and compared its temporal expression during murine and human lung development. Cbe1 cDNA was cloned and characterised using sequencing, standard PCR and Western blotting. Mouse and human embryonic/fetal lungs (HELs) were harvested for mRNA analysis and protein localisation in vivo and in vitro using RT-PCR and immunohistochemistry. The Cbe1 amino acid sequence was >75% identical with CBE1 and its alternative splicing and tissue distribution were highly conserved. Pulmonary expression of Cbe1 mRNA was increased at embryonic day (E)16, 1 day later than Foxj1, which is consistent with a role in ciliogenesis. In HELs, CBE1 mRNA was detectable at 8-9 weeks post-conception and increased in explant culture. CBE1 protein expression was weak at 10 weeks post-conception but strong at 12.3 weeks post-conception, in parallel with cilia formation. Additionally, Cbe1 mRNA was expressed at E11 (4-5 weeks post-conception in HELs) in the absence of Foxj1, implying a distinct role in early development. Chronological regulation of CBE1/Cbe1 expression during pulmonary differentiation suggests involvement in ciliogenesis, with an additional role during early lung development.
    European Respiratory Journal 02/2009; 33(5):1095-104. DOI:10.1183/09031936.00157108 · 7.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Asthma is a highly prevalent condition across Europe and numerous guidelines have been developed to optimise management. However, asthma can be neither cured nor prevented, treatment choices are limited and many patients have poorly controlled or uncontrolled asthma. The Brussels Declaration on Asthma, sponsored by The Asthma, Allergy and Inflammation Research Charity, was developed to call attention to the shortfalls in asthma management and to urge European policy makers to recognise that asthma is a public health problem that should be a political priority. The Declaration urges recognition and action on the following points: the systemic inflammatory component of asthma should be better understood and considered in assessments of treatment efficacy; current research must be communicated and responded to quickly; the European Medicines Agency guidance note on asthma should be updated; "real world" studies should be funded and results used to inform guidelines; variations in care across Europe should be addressed; people with asthma should participate in their own care; the impact of environmental factors should be understood; and targets should be set for improvement. The present paper reviews the evidence supporting the need for change in asthma management and summarises the ten key points contained in the Brussels Declaration.
    European Respiratory Journal 01/2009; 32(6):1433-42. DOI:10.1183/09031936.00053108 · 7.64 Impact Factor
  • J B Morjaria · AJ Chauhan · K S Babu · R Polosa · D E Davies · S T Holgate
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumour necrosis factor alpha (TNFalpha) is a cytokine recognised as a therapeutic target in chronic inflammatory diseases. A randomised, double blind, placebo controlled parallel group trial is reported of etanercept (an IgG1-TNF p75 receptor fusion protein), administered once weekly for 12 weeks in 39 patients with severe corticosteroid refractory asthma. Efficacy was measured by change from the pretreatment baseline in Asthma Related Quality of Life (AQLQ) and Asthma Control (ACQ) Questionnaire scores (the primary endpoints), lung function, peak expiratory flow (PEF) and bronchial hyperresponsiveness (BHR). Sputum and serum inflammatory cells and cytokines, serum albumin and C reactive protein (CRP) as biomarkers of inflammation were also assessed. There was a small but significant difference in reduction of ACQ scores between treatment and placebo (-1.11 (95% CI -1.56 to -0.75) and -0.52 (95% CI -0.97 to -0.07), respectively, p = 0.037). There was no significant difference in improvements in AQLQ scores, lung function, PEF, BHR or exacerbation rates between the groups. Minor adverse events, including injection site pain and skin rashes, were more frequent with etanercept. There was a significant reduction in sputum macrophages and CRP, and increases in serum TNFalpha and albumin following treatment, but not in other laboratory parameters. Etanercept therapy over 12 weeks demonstrated only a small but significant improvement in asthma control and systemic inflammation, as measured by serum albumin and CRP. Larger randomised, placebo controlled trials are required to clarify the role of TNFalpha antagonism in subjects with severe refractory asthma.
    Thorax 08/2008; 63(7):584-91. DOI:10.1136/thx.2007.086314 · 8.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl-LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB(4) in airway disease. LTA(4) hydrolase and 5-lipoxygenase activating protein have key roles in LTB(4) production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB(4) production and myocardial infarction (MI). Objective: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. Three hundred and forty-one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper-responsiveness, FEV(1)) were undertaken using the Family Based Association Test. Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042-0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41-3.32). These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB(4) in disease pathogenesis.
    Allergy 06/2008; 63(8):1046-53. DOI:10.1111/j.1398-9995.2008.01667.x · 6.03 Impact Factor

Publication Stats

25k Citations
3,488.76 Total Impact Points


  • 1981–2014
    • University of Southampton
      • Faculty of Medicine
      Southampton, England, United Kingdom
  • 1995–2010
    • University Hospital Southampton NHS Foundation Trust
      • Department of Medical Physics and Bioengineering
      Southampton, England, United Kingdom
  • 1999–2008
    • National Heart, Lung, and Blood Institute
      Maryland, United States
    • University of Otago
      • Department of Medicine (Christchurch)
      Taieri, Otago, New Zealand
  • 2007
    • St George's, University of London
      Londinium, England, United Kingdom
  • 2005
    • Νοσοκομείο Σωτηρία
      Athínai, Attica, Greece
  • 2003
    • Ghent University
      Gand, Flanders, Belgium
  • 2001
    • University of Hull
      Kingston upon Hull, England, United Kingdom
    • Umeå University
      Umeå, Västerbotten, Sweden
    • University of Bristol
      • Medical School
      Bristol, ENG, United Kingdom
  • 2000
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
    • Stellenbosch University
      • Division of General Internal Medicine
      Stellenbosch, Western Cape, South Africa
  • 1998
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1997
    • SickKids
      Toronto, Ontario, Canada
    • Indian Broiler (IB) Group India
      Bhānpuri, Chhattisgarh, India
    • University of Nottingham
      Nottigham, England, United Kingdom
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
    • Ajou University
      • Department of Allergy and Clinical Immunology
      Seoul, Seoul, South Korea
  • 1996
    • University of Catania
      Catania, Sicily, Italy
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
    • The Heart Lung Center
      Londinium, England, United Kingdom
    • Countess Of Chester Hospital NHS Foundation Trust
      Chester, England, United Kingdom
  • 1994
    • Alfred Hospital
      Melbourne, Victoria, Australia
    • Poole Hospital NHS Foundation Trust
      Poole, England, United Kingdom
    • University of Groningen
      Groningen, Groningen, Netherlands
    • Liverpool Hospital
      Liverpool, New South Wales, Australia
  • 1985
    • Clinical pharmacology of Miami
      Miami, Florida, United States