Asthma and Chronic Obstructive Pulmonary Disease (COPD): characterising a new clinical syndrome and contributing to a new conceptual framework for developing drugs
Submitting Institution
University of LeicesterUnit of Assessment
Clinical MedicineSummary Impact Type
HealthResearch Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology
Summary of the impact
Asthma and Chronic Obstructive Pulmonary Disease (COPD) are common,
global diseases which cause considerable morbidity and mortality.
Worldwide, around 235 million people suffer from asthma, while COPD
accounts for 3 million, or 5% of all, global deaths, according to the
World Health Organization (WHO). The relationship between inflammation and
airway dysfunction is central to an understanding of their pathogenesis
and treatment. The respiratory medicine group in the Department of
Infection, Immunity and Inflammation has shown that optimal management of
these conditions requires measurement of airway inflammation to stratify
treatment regimes, an approach incorporated into national guidelines in
2012. In the late 1990s the group characterised a new clinical syndrome:
`eosinophilic bronchitis', which is one of the commonest causes of chronic
cough. The group's work has helped to launch a new class of drugs for
asthma and to change the conceptual framework by which anti-inflammatory
drugs for asthma are being developed.
Underpinning research
Asthma and COPD comprise disordered airway function (a combination of
variable and fixed airflow obstruction) associated with chronic airway
inflammation. It had been assumed for at least two decades that the
disordered airway function was secondary to the inflammation, which was
regarded as being eosinophilic in nature and driven by a specific type of
immune response directed by a subset of lymphocytes (Th2 cells) to inhaled
allergens. However, these concepts were based on small numbers of mild
asthmatics and animal models of allergen challenge. The group was one of
the first to routinely measure airway inflammation in all types and
severity of asthma and relate the degree and pattern of inflammation to
the airway physiology. Using this approach the Leicester researchers made
a number of important and novel observations.
In `classic' eosinophilic asthma, the group has shown that:
- Eosinophilic inflammation is closely associated with severe
exacerbations of asthma and yet can be clinically silent, hence sputum
eosinophilia can provide an early-warning indicator of impending
exacerbation (3.4).
- Treatment response to corticosteroids is closely associated with the
presence of eosinophils in the sputum (3.1-3.7).
- Suppression of sputum eosinophilia, either with corticosteroids or
drugs which specifically inhibit eosinophil production, prevents
exacerbations of asthma, demonstrating for the first time that
eosinophils are causal in the exacerbation process (3.6).
The research also indicated that about 20% of people with asthma do not
have eosinophilic inflammation. The group was one of the first to
recognise such non-eosinophilic asthma and to demonstrate that this
phenotype did not respond well to treatment with corticosteroids (3.1,
3.5).
Similar findings apply to COPD where stratification into eosinophilic
(about 30%) and non-eosinophilic (infective) based on sputum analysis
results in different patterns of treatment response to steroids and
antibiotics (3.3).
The group showed that eosinophils were not sufficient to cause the
variable airway obstruction and airway hyper-responsiveness (AHR) that
characterises asthma (which appears to require additional processes such
as mast cell infiltration), and that a distinct sub-set of patients with
eosinophilia have only chronic cough — hence defining a new condition of
`eosinophilic bronchitis' (3.2).
This work demonstrated the importance of measuring inflammation
(inflammometry) in assessing asthma (and now into COPD), which has since
been incorporated into a number of asthma guidelines. It has influenced
the study design of clinical trials of anti-inflammatory medications which
now focus on severe exacerbations as the primary outcome.
Key staff:
Professor Peter Bradding, Professor of Respiratory Medicine (Leicester
1998 - present)
Professor Chris Brightling, Professor of Respiratory Medicine (Leicester
1999 - present)
Dr Ruth Green, Consultant Respiratory Physician (Leicester 01/07/2005 -
30/05/2010)
Dr Pranab Haldar, Senior Lecturer in Respiratory Medicine (Leicester
01/08/2009 - present)
Professor Ian Pavord, Professor of Respiratory Medicine (Leicester
01/04/2005 - present)
Professor Andrew Wardlaw, Professor of Allergy and Respiratory Medicine
(Leicester 31/12/2009 - present)
Notable grants are:
National Institute for Health Research: Leicester Respiratory Biomedical
Research Unit (2012-2017) £4.5 million
AirProm: European Framework 7. PI Christopher Brightling (2011-2016)
£1.44 million
GlaxoSmithKline: Wardlaw, Pavord and Brightling as PIs (2005-2011) £1.22
million
References to the research
1. Pavord ID; Brightling CE; Woltmann G, Wardlaw AJ
Non-eosinophilic corticosteroid unresponsive asthma Lancet 1999;
353:2213-2214 (198 citations)
2. Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord
ID. Eosinophilic bronchitis is an important cause of chronic cough.
Am J Respir Crit Care Med. 1999;160:406-10. (257)
3. Brightling CE, Monteiro W, Ward R, Parker D, Morgan MDL, Wardlaw
AJ, et al. Sputum eosinophilia and short-term response to
prednisolone in chronic obstructive pulmonary disease: a randomised
controlled trial. Lancet. 2000;356:1480-85 (190).
4. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw
AJ, Pavord ID. Mast-cell infiltration of airway smooth
muscle in asthma. N Engl J Med. 2002 May 30;346(22):1699-705.(607)
5. Green RH, Brightling CE, McKenna S, Hargadon B, Parker
D, Bradding P, Wardlaw AJ, Pavord ID. Asthma
exacerbations and sputum eosinophil counts: a randomised controlled trial.
Lancet. 2002 Nov 30;360(9347):1715-21. (692)
6. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling
CE, Wardlaw AJ, Green RH. Cluster analysis and clinical
asthma phenotypes. Am J Respir Crit Care Med. 2008:178:218-24 (312)
7. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W,
Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord
ID. Mepolizumab and exacerbations of refractory eosinophilic asthma.
N Engl J Med. 2009:360(10):973-84. (452)
Funding: This research has been supported by Asthma UK, the
Medical Research Council, the Wellcome Trust and a number of
pharmaceutical companies, in particular GlaxoSmithKline.
Details of the impact
The main impact of the group's work has been to change the paradigm of
asthma from a hierarchical model in which Th2 mediated eosinophilic
inflammation causes all aspects of the disease, to a more complex model in
which inflammation and lung function abnormalities are relatively
independent of each other. In this model the heterogeneity of asthma,
including different responses to treatment, is explained by the varying
extent to which abnormalities such as lung function, lung damage and
inflammation are expressed in any one individual. This conceptual
framework is in harmony with the increasing emphasis on stratified
medicine in which treatments are targeted at specific disease processes
within a condition rather than necessarily all aspects of the disease. The
group's work therefore has had important consequences for understanding
disease pathogenesis, drug development and patient management.
Pathogenesis
By showing that the lung function abnormalities, inflammatory processes
and lung damage which characterise asthma and COPD can occur
independently, the Leicester team's model emphasises the need to carefully
phenotype patients according to those disease processes if sense is to be
made of genetic data and analysis of diseased tissue.
Drug development
Drug development depends first and foremost on identifying a biological
target which, when blocked by a drug, will ameliorate a disease process.
It is fundamentally important that the target is closely linked to a
specific outcome which is relevant to disease control and can be measured
when evaluating the drug. Drug development in asthma, particularly
involving inhibitors of the Th2 pathway which has been the main focus of
the pharmaceutical industry in recent decades, has been hampered by a
failure to select patients with eosinophilic disease for clinical trials
and the choice of forced expiratory volume in one second (FEV1,)
which is not necessarily affected by inflammation, as the main outcome
measure. Based on its observations the group hypothesised that blocking
the Th2 pathway would have a relatively narrow effect, preventing severe
exacerbations in patients with active Th2 (eosinophilic) inflammation, but
would not have any effect on other aspects of asthma such as variable
airflow obstruction or non-eosinophilic disease.
To support this hypothesis the group undertook a single-centre,
investigator-led study of a biological therapy developed by
GlaxoSmithKline called mepolizumab which neutralises the specific
eosinophil growth factor IL-5 and ameliorates eosinophilic inflammation.
This drug had been studied in unselected asthma patients using lung
function as a primary outcome and had been regarded as ineffective, almost
causing it to be dropped by the company. The Leicester researchers
demonstrated that it was effective at preventing exacerbations in patients
with active eosinophilic inflammation, findings which have been replicated
in a large multi-centre trial (5.4). A phase 3 trial will report in
2014 and the group is confident it will be licensed and will be a
life-changing treatment for tens of thousands of people at risk of dying
from asthma or whose lives are blighted by the side effects of
corticosteroids (5.5, 5.6). The group's work has also
blazed a trail for two more anti-eosinophil therapies which are in late
stages of development and has explained the findings with other anti-Th2
therapies which have also been shown to prevent exacerbations in
eosinophilic patients with relatively little effect on non-eosinophilic
patients or lung function. While the life-changing impacts on patient care
through new drugs are still potential, the research has already had a
significant impact on the business decisions and strategic direction of
drug development companies. It has also already had an impact on patient
care through a change in the way asthma patients are managed: -
Patient management.
Perhaps the most important impact of our observations has been on patient
management. Asthma comprises in large part two components: inflammation
and disordered lung function. Traditionally asthma management has been
based on measuring lung function but not inflammation. In the sub-set of
patients in which lung function and inflammation are most clearly
dissociated (i.e. adult onset, eosinophilic inflammation predominant
asthma and non-eosinophilic asthma), the group has shown that measurement
of inflammation (by analysing sputum), allows targeted use of
corticosteroids leading to both reduced side effects and a lower risk of
exacerbations.
In 2003 the group established a difficult asthma clinic, which more than
1,000 patients have since attended, based on the idea of routinely
measuring airway inflammation. An internal audit showed a 50% reduction in
severe exacerbations; in addition, the group is expecting the Royal
College of Physicians' national audit of asthma deaths, which will report
in 2014, to show that Leicestershire has a very low rate of asthma deaths
in adults — the group is aware of only two over the last decade, neither
of which could easily have been prevented. The importance of measuring
inflammation, particularly in more severe disease, has now been widely
incorporated into asthma guidelines in the UK and internationally (5.1,
5.2, 5.3) and is embedded in the practice of the members of
the British Thoracic Society (BTS) severe asthma network.
Sources to corroborate the impact
- BTS-SIGN Asthma Guidelines Updated 2012: Section 7.3.5 Monitoring
airway response in difficult asthma.
- American Thoracic Society-European Respiratory Society Guidelines on
severe asthma. In press
- Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE,
Bleecker ER, et al. Uniform definition of asthma severity, control, and
exacerbations: document presented for the World Health Organization
Consultation on Severe Asthma. J Allergy Clin Immunol.
2010;126(5):926-38. Epub 2010/10/12
-
Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON,
Ortega H, Chanez P P. Mepolizumab for severe eosinophilic asthma
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet.
2012 Aug 18;380(9842):651-9
- Leicester Mercury: Breakthrough for asthma patients. 17 August 2012.
http://www.leicestermercury.co.uk/Breakthrough-asthma-patients/story-16726460-detail/story.html
- The Telegraph. New asthma drug can cut hospital admissions by half:
study. 17 August 2012.
http://www.telegraph.co.uk/health/healthnews/9480016/New-asthma-drug-can-cut-hospital-admissions-by-half-study.html