As a clinical scientist, Stephen Holgate has contributed greatly to the understanding and treatment of allergic and respiratory diseases, including asthma, COPD and COVID-19. His contributions span science, medicine, public health, and policy initiatives, all for the benefit of patients and society. As a true physician-scientist, he has contributed to the promotion of respiratory and environmental health at multiple levels: discovery of new scientific principles; translating these to more effective therapy not only for asthma and COPD but also for COVID-19; forming and leading organisations that promote lung health and chairing committees that write reports aiming to influence Government Policy for promoting health both in his own speciality and beyond.
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- Unravelling the Pathogenesis of Asthma
- Respiratory Virus Infection as Asthma and COPD Exacerbation
- Translating Insights from Asthma to SARS-CoV-2-induced COVID-19
- Battling the scourge of air pollution
- Epithelial Injury and Aberrant Repair Drives Airway Wall Remodelling in Asthma
Unravelling the Pathogenesis of Asthma
With over 300m patients worldwide and increasing, asthma is the commonest chronic lung disease affecting all age groups and varying in severity from mild intermittent to life-threatening. In the 1970s, at the start of Stephen Holgate’s research career, asthma was regarded largely as a disorder of intermittent bronchospasm relieved with inhaled bronchodilators. However, their overuse led to increased asthma mortality. To gain insight into why asthmatic airways experience variable airflow obstruction, he documented the importance of allergen driven IgE-dependent inflammation (subsequently designated Type-2) involving activation of human airway mucosal mast cells and T helper cells with recruitment of eosinophils and basophils, whose mediators and cytokines led to non-specific bronchial hyperresponsiveness (BHR) with airflow obstruction (1), and all being responsive to inhaled corticosteroids (ICS) (2). As a founder Expert Panel Member of the newly formed WHO/NHLBI Global Initiative for Asthma (GINA) in 1993, Holgate’s research contributed to asthma being redefined as an inflammatory disorder requiring ICS for disease control and, in 1995, this formed the basis of the first GINA International Management Guidelines which have evolved further to target IgE itself and the Type 2 cytokines.
Building on inflammation, the Southampton Team were the first to identify defective epithelial barrier function(s) (3) as a constitutive feature of asthma. In being upstream of the mucosal Type-2 response, a dysfunctional epithelium provides a unifying platform for how environmental stressors, such as allergens, viruses and air pollutants, initiate and exacerbate asthma (e.g. through oxidant stress and enhanced production of alarmins to trigger Type-2 inflammation) as well as driving airway wall remodelling in chronic and severe disease. Recognition of the critical importance of the epithelium in orchestrating different asthma phenotypes in response to environmental stressors has opened a new era of precision/stratified asthma management in which biologics (e.g., Interferon [IFN]-b, anti-alarmins [TSLP - Tezepelumab; IL-33 - Itepekimab, IL-25 - Brodalumab, and ADAM33 Anti-Sense Oligonucleotides] are now being effectively targeted to epithelial and mesenchymal pathways responsible for initiating, exacerbating and perpetuating asthma across the lifecourse.
Respiratory Virus Infection as Asthma and COPD Exacerbation
After developing the first PCR-based method to detect human rhinoviruses (HRVs) in airway secretions, Holgate’s team showed that in both children and adults, virus infection accounted for most asthma exacerbations, the majority being HRVs (4). Using controlled nasal HRV-16 infection in volunteers, they showed that in asthmatic but not in normal subjects, HRVs preferentially colonised the lower airways epithelium with amplification of the Type-2 inflammatory response, thereby replicating the asthma exacerbation (5). Using asthmatic primary epithelial cells in monolayer culture, they then found that infection with HRVs was the consequence of impaired epithelial cell triggering of anti-viral interferon (IFN)-b production (6). Since this abnormality involved an initial Toll-like receptor (TLR) 3 step that recognises viral dsRNA, the second amplification step (involving the common IFN receptor [IFNAR]) inducing hundreds of protective IFN-stimulated genes [ISGs]), remained intact. Thus, addition of exogenous IFN-b to the asthmatic epithelium was able to fully restore ISG-mediated anti-viral protection (7). To exploit this discovery, in 2003 Holgate and two Southampton colleagues formed Synairgen with the aim of bringing these advances to patients. In a RCT they showed that inhaled human IFN-b1a in asthma not only accelerated viral clearance with multi-fold increases in ISG biomarkers in airway secretions but also attenuated asthma exacerbation (8). Because the airways in COPD patients also proved more vulnerable to respiratory viruses, again due to reduced epithelial innate immunity, anti-viral protection was similarly restored with exogenous IFN-b1a. A Phase II trial of inhaled IFN-b1a in exacerbating COPD patients with confirmed respiratory viral infection had to be paused in early 2020 because of COVID-19. However, Interim analysis has revealed significant improvements in lung function, reduced serum C-reactive protein and increased viral clearance. In addition to impaired IFN-b in response to viral dsRNA, asthma and COPD airway epithelial cells were biased towards higher TSLP production to direct a Type-2 inflammatory response as they had shown in response to viral infection (5).
Translating Insights from Asthma to SARS-CoV-2-induced COVID-19
SARS-CoV-2 has evolved mechanisms to evade the first step of the IFN-b response in addition to host genetic and acquired factors limiting Type 1 IFN production. Thus, in 2020 Holgate’s team investigated daily treatment with inhaled IFN-b1a vs placebo once daily for 14 days in hospitalised patients with COVID-19. Not only was inhaled IFN-b1a well tolerated but by day 28 there was significant clinical improvement, accelerated recovery to no limitation of activity and reduced breathlessness (8). While a follow-on RCT (SPRINTER) did not meet primary endpoints due to progressive improvements in overall standard of care since their Phase II trial, in the 30% of COVID-19 patients with impaired lung function, stratification revealed that inhaled IFN-b1a significantly reduced progression to severe disease or death by 70%. At 60-90 days, those trial patients who had received active treatment also experienced significantly reduced symptoms of long-COVID. Since inhaled IFN-b1a is agnostic to SARS-CoV-2 variants (and other respiratory viruses), it is now being developed as the first broad-spectrum antiviral to prevent progression to severe disease and death in severe viral respiratory infections, including COVID-19. With the emergence of a pandemic, the GCSA asked Holgate to chair Academy of Medical Sciences Expert Advisory Groups (EAGs) to advise on NHS and social care planning as the COVID-19 pandemic evolved: 2020 - Preparing for a challenging winter 2020/21; 2021 - Preparing for the future: Looking ahead to winter 2021/22, and 2022 - COVID-19: what next?. These Reports were commended by SAGE and equivalent bodies in the Devolved Administrations and distributed widely to central and local governments.
Battling the scourge of air pollution
Starting with the 6 Cities Study in 1993, accumulating epidemiological studies provided new evidence that air pollution - especially NO2 O3, and particulate matter (PM10, PM2.5) from fossil fuel combustion - was becoming one of the greatest environmental risks to human health (9). However, establishing causality was limited by lack of human toxicology. In 1998, Holgate’s team was among the first to address this gap in humans using controlled exposures, bronchial biopsy and lavage to track lung responses to air pollutants. Beginning with ozone (O3) (a secondary photochemical pollutant linked to worsening asthma) exposure for 2 hours caused immediate reflex bronchoconstriction followed by neutrophilic airways inflammation driven by the chemokines, CXCL-1 and -8 (10). Short term inhalation of NO2 also induced neutrophilic airways inflammation similarly driven by epithelial-derived CXCL-8, whereas repeated NO2 exposures induced a pro-asthmatic Type-2 inflammatory profile accompanied by upregulation of Intercellular Adhesion Molecule-1 (CD54) to promote leukocyte influx (11). Induction of Type-2 mechanisms (possibly via TSLP and IL-33 alarmins) helps explain the role of NO2 in traffic-related air pollution driving new asthma, while CD54, as the receptor for the major class of HRV, provides a mechanism for enhanced viral exacerbation observed in asthmatic children exposed to high personal levels of NO2 (12). In the case of particles, there were indirect inflammatory effects on human airways. Two hours exposure to diesel exhaust particles (DEPs) or concentrated ambient PM2.5 provoked neutrophilic airway inflammation (13) from oxidant damage to the airway epithelium, autocrine activation of the epidermal growth factor receptor (EGFR) and subsequent release of CXCL-1 and -8. Oxidant stress is an integrative biological pathway shared by all three pollutants with the epithelium exhibiting greater sensitivity in asthma (14). This research informed the 2004 WHO Project Systematic Review of Health Aspects of Air Pollution in Europe and the later 2013 WHO REVIHAAP Report, both of which Holgate was a principal contributor, and used to support the EC's Clean Air for Europe (CAFÉ) programme and the 2005 WHO Global Air Quality Guidelines. The clear need for greater awareness of the major health impacts of air pollution also led Holgate and Robert Maynard to initiate Air Pollution and Health, the first comprehensive international textbook on this subject.
With increasing health concerns over the “new” air pollutants, Holgate was asked to chair the Department of Health (DH) Advisory Group on Air Pollution Episodes (MAAPE 1989-92) which published reports on SO2, O3, NO2, PM and air pollutant mixtures. Appreciating the importance of chronic exposure to ambient air pollutants on health, he was then asked to chair a new advisory body, the DH Committee on the Medical Effects of Air Pollutants (COMEAP, Chair 1992-2001, Member to 2008) which produced key reports e.g. Asthma (1995), Non-Biological Particles (1995), Quantification of Health Effects (1998), Indoor Air Pollutants (2001), Cardiovascular Disease and Air Pollution (2006). In 2011, he chaired the COMEAP subgroup which produced the currently used UK Daily Air Quality Index (DAQI) to inform the public about prevailing air pollution and is currently advising DEFRA on its update. The importance of providing evidence-informed knowledge to the public and other key stakeholders on issues relating to air pollution enabled Holgate to lead an influential 2016 RCP/RCPCH Report - Every breath we take: the lifelong impact of air pollution highlighting the 40,000 annual deaths attributed to UK air pollution with a cost of £20 billion, followed in 2020 by - The inside story: Health effects of indoor air quality on children and young people. Both Reports are proving highly effective in bringing air pollution to the forefront of policy development and were used to provide health evidence for new air quality research, the UKRI/Met Office Clean Air Strategic Priority Programme (2019-25, £42.5m) for which Holgate is UKRI Champion.
Based on his asthma and air pollution research expertise, Holgate provided a large part of the medical and scientific evidence on Ella Adoo-Kissi-Debrah, a 9-year-old London girl who died of asthma in 2013 after 28 hospital admissions over 30 months. This identified air pollution as a likely cause leading the Attorney General to overturn the original 2013 inquest. In a landmark 2nd inquest on December 16th 2020 Holgate’s clinical and scientific evidence (including his own research on NO2, DEPs and PM2.5) played a pivotal role in the Coroner’s conclusion that air pollution was a major contributory factor to the induction and repeated exacerbation of Ella’s asthma, culminating in her death. Ella was the first person in the UK (and possibly worldwide) to have air pollution listed as the cause of death on their death certificate. Subsequent responses to a Prevention of Future Deaths Report, issued by the Coroner on April 20th 2021, are proving to be a powerful influence for increasing awareness of the insidious health dangers of air pollution and are impacting upon policy change.
Epithelial Injury and Aberrant Repair Drives Airway Wall Remodelling in Asthma
Direct access to airway tissue and cells enabled Holgate’s team recognised the importance of airway epithelial disruption and tissue remodelling by subepithelial myofibroblasts (1, 15) as new features of severe and chronic asthma. Using cultured primary airway epithelial cells, an abnormal asthmatic epithelium responds to injury, not only by enhancing inflammatory pathways (via oxidant stress and releasing alarmins), but also by initiating a chronic wound-like repair response with secretion of epidermal (EGF, HB-EGF, amphiregulin), fibrogenic (TGF-b1, basic-FGF), angiogenic (VEGF), and neurotrophic (NGF family) growth factors indicating activation of the epithelial mesenchymal trophic unit (EMTU) (16). In being unable to repair seamlessly, the asthmatic epithelium loses its barrier function(s) (3) to render it especially sensitive to the environmental determinants of asthma (17). In this state, even in the absence of inflammation, physical distortion of the asthmatic epithelium from repeated bronchoconstriction alone proved sufficient to invoke airway remodelling via the EMTU (18) and supported the use of inhaled long-acting b2-agonists with ICS for treating moderate-severe disease. Holgate’s Group also showed that TGF-b produced by the EMTU in asthma was important in reducing the IFN-b response to viral infection thereby connecting impaired innate immunity with dysfunctional epithelial repair.
With asthma’s high heritability, the Southampton group uncovered the importance of genetic drivers of remodelling in asthma. Using positional cloning (and before GWAS), they identified the first novel asthma susceptibility gene, A Disintegrin Metalloprotease 33 (ADAM33) on chromosome 20p13 (19). ADAM33 encodes a 120 kD proteolytic enzyme selectively expressed in airway fibroblasts, myofibroblasts and smooth muscle and whose expression increases in response to eosinophilic Type-2 inflammation. Association of ADAM33 polymorphism with asthma has been replicated in >100 populations worldwide and also in Meta-analyses, with disease variants being associated with bronchial hyperresponsiveness, reduced lung function in childhood and its decline over time indicating a key role for this protease in the natural history of asthma and airway remodelling. Membrane-associated full-length ADAM33 protein is upregulated in proportion to disease severity and cleaved to release a soluble 55kD enzymatic fragment which, in initiating airway remodelling (20) and a hypercontractile phenotype, makes ADAM33 an attractive therapeutic target for chronic severe asthma e.g., through inhaled Locked Nucleic Aicid Gapmer Antisense Oligonucleotides which effectively silence ADAM33.
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This takes the form of keynote lectures, plenary lectures and talks on specialist areas of asthma allergic diseases, pollution and translational medicine including participation in postgraduate courses.
Educational activities also extend to editorships of major texts in asthma, allergy and respiratory medicine. Examples include “Allergy” (4 editions) and “Middleton’s Allergy:Principles and Practice” (4 editions) (see below).
Editor of Clinical and Experimental Allergy (25 years to 2009) and current Associate Editor, Clinical Science.
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Stephen Holgate is Medical Research Council Clinical Professor of Immunopharmacology at the Faculty of Medicine, Southampton, UK. After completing his medical training in London he spent 2 years at Harvard Medical School to acquire skills in allergic disease mechanisms. On returning to Southampton in 1980, he set up a research group focused on the mechanisms of asthma. He has utilized many approaches to study this disease including epidemiology, genetics, pathology, microbiology and immunology, pharmacology and experimental medicine. This research has informed guidelines on asthma management and has identified and validated novel therapeutic targets. Notable research contributions include the role of mast cells and their mediators in asthma and allied disorders, the regulation and pharmacology of mast cells, placing inflammation at the core of asthma pathophysiology, uncovering the role of respiratory viruses, allergens and pollutants in asthma exacerbation, the discovery of defects in innate immune responses in asthmatic airways, mechanisms of airway wall remodelling and the discovery of novel asthma susceptibility genes such as ADAM33.
His current research focuses on stratified medicine, the role of the epithelium in orchestrating asthma and the evolution of asthma across the lifecourse. His work has resulted in over 980 peer reviewed publications (H index 133), 60 Book editorships, 453 Book Chapters and Reviews, 48 Editorials, 76 Official and Government Reports. He holds an MRC programme grant focused on the pathogenesis of asthma.
He is a Past President of the British Society of Allergy and Clinical Immunology and British Thoracic Society, was Chair of the MRC Population and Systems Medicine Board (PSMB). Stephen is Chair of Main Panel A (Medicine, Health and Life Sciences) of the UK Research Excellence Framework 2014, Chairs the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), the British Lung Foundation Research Committee, the Hazardous Substances Advisory Committee (HSAC), and from 2014, will join the Science and Innovation Strategy Board of the Natural Environment Research Council (NERC). He is Chair of the European Respiratory Society Scientific Committee, Treasurer of the World Allergy Organization and Member of the Medical Science Committee of Science Europe. In 2003 he cofounded of Synairgen a publically quoted respiratory drug development company with a particular focus on lung antiviral defense in asthma, COPD and severe viral infections.
House Physician, Charing Cross Hospital, London, 1971-2
Senior House Officer (Neurology), National Hospital for Nervous Diseases,
Senior House Officer (Respiratory Medicine & Cardiology), Brompton Hospital, London, 1973-4
Registrar (General Medicine), General Infirmary, Salisbury & Southampton General Hospital, 1974-5
Lecturer and Honorary Senior Registrar in Medicine, Southampton General and Western Hospitals, 1975-80
MRC and Wellcome Trust Overseas Research Fellow, Harvard University, Boston, USA, 1978-80
Lecturer in Medicine and Honorary Senior Registrar, University of Southampton Hospitals, 1975-80
Senior Lecturer, Reader then Professor of Medicine and Hon Consultant Physician, Southampton University Hospitals, 1980-6
MRC Clinical Professor of Medicine and Honorary Consultant Physician, Southampton University and Foundation Trust, 1987-present
- The David Barker Lifetime Achievement Award (2014)
- The David Barker Lifetime Achievement Award (2014)
- J. Allyn Taylor International Prize in Medicine (2016)
- Deutsche Gesellschaft fur Allergologie und klinische Immunologie DGAKI (German Society for Allergy and Clinical Immunology) Medal (2016)
- Honorary Fellow RCP Faculty of Public Health (2016)
- Marquis Who’s Who Lifetime Achievement Award (2017)
- Presidents Medal for Outstanding Service, Royal College of Physicians (2018)
- Presidents Medal for Outstanding Service (2018)
- - American College of Allergy, Asthma and immunology International Distinguished Fellow Award (2019)
- 32nd Khwarizmi International Award (KIA) for medicine, a research award given annually (2019)
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