ERS Annual Congress Barcelona7-11 September 2013
EDUCATIONAL MATERIAL
Morning seminar- MS4
Asthma phenotypes and endotypes
Room 4.1 (CC4)
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Morning Seminar MS4
Tuesday, 10 September 2013 (07.00 – 08.15)
Asthma phenotypes and endotypes
Prof. Christopher John Corrigan Dept Asthma, Allergy and
Respiratory Science 5th Floor, Tower Wing
Guy's Hospital, Great Maze Pond SE1 9RT London
UNITED KINGDOM [email protected]
Dr. Gary P. Anderson Department of Pharmacology
University of Melbourne 3010 VIC Parkville
AUSTRALIA [email protected]
Chair: Dr. Pascal Chanez
7 rue Scudery 13007 Marseille
FRANCE [email protected]
Aims: To appreciate the differences between endotype and phenotype; to understand the difficulties in describing endotypes/phenotypes in patients with severe asthma; and to understand how patient endotyping may enable personalised therapies.
Programme:
Page
7:00 to 7:10 Introduction from the chair
7:10 to 7:35 Defining asthma phenotypes Prof. Christopher John Corrigan
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7:35 to 8:00 Asthma endotypes: the pathway to new effective drugs? Dr. Gary P. Anderson
11
Answers to MCQs
Faculty Disclosure
12
13
8:00 to 8:15 Discussion
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Defining asthma phenotypes
Chris CorriganProfessor of Asthma, Allergy & Respiratory Science
King’s College, University of LondonMRC and Asthma UK Centre in Allergic Mechanisms of
Asthma
Educational grants from GlaxoSmithKline, Novartis, Meda, Chiesi�Research collaborations with Novartis�Consultation fees from Mundipharma
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Socioeconomic consequences of uncontrolled asthma
• UK has the highest incidence of asthma in the world– 12% of children– 6% of adults– Nearly 6 million people
• 600,000 people suffer daily symptoms• There is one unnecessary death every 8 hours• In 2007, 18 million days were lost from work or school• Asthma is a huge financial burden
– £800 million NHS costs– >£2 billion total societal costs
3
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Distribution of asthmatics according to the BTS treatment steps
Neville et al. ERJ 1999; n=15,649
STEP 1β2-agonist
STEP 2β2-agonist
+Low dose
ICS
STEP 3β2-agonist
+Low doseICS + LAB
orHigh dose
ICS
STEP 4β2-agonist
+High dose
ICS+
LAB
STEP 5β2-agonist
+High dose
ICS+
LAB+
Regularoral
steroids
30.2%
51.8%
11.9%
5.3%
0.8%
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Characteristics associated with the “severe asthma” syndrome (1)
• Clinical– Symptoms: wheeze, chest tightness, shortness of breath, cough, waking at night, fear,
anxiety, inability to cope– Variable perception of breathlessness– Severe and/or frequent exacerbations– Age/context of onset (atopic march or later without previous atopic disease)– Female gender?
• Physiological– Airways obstruction with complete or incomplete reversibility to bronchodilator– Small and large airways obstruction– Bronchial hyperresponsiveness
• Triggers– Viral infections– Aspirin/non-steroidal anti-inflammatory drugs– Allergens and other occupational triggers– Psychological– Smoking– Industrial pollutants
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Characteristics associated with the “severe asthma” syndrome (2)
• Co-morbidity– Bronchiectasis/ABPA– Rhinosinusitis/allergic rhinitis
• Airways remodelling– Neovascularisation– Mucous hypertrophy– Smooth muscle hypertrophy/hyperplasia– Lay down of interstitial proteins in the bronchial submucosa
• Inflammation– Site (large/small airways, smooth muscle)– Cellular composition (eosinophils, neutrophils, inconspicuous)
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KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Problem: just because a feature is present, this does not mean that it is
necessarily important.So, what to do?
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Phenotype
• Observable, reproducible characteristics• Typically multiple or grouped• Develop from the interaction of an organism with
its environment• Implications
– Prevention– Aetiology– Pathophysiology– Treatment??
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Approaches to identifying phenotypes of asthma
• Clinical characteristics (age, severity, BMI, reversibility of airways obstruction, etc.)
• Triggers (allergens, aspirin, obesity)• Inflammatory changes in the airways• Problems
– Non-specific– Vague– Arbitrary– Must correspond with a recognisable “patient”
5
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Postulated phenotypes of asthmaMiranda C et al. JACI 004;113:101-108
Haldar P et al. AJRCCM 2008;178:218-224Moore WC et al. AJRCCM 2010;181:315-323
Siroux V et al. ERJ 2011;38:310-317
• Early onset, “allergic”• Poorly reversible, very severe, “neutrophilic”• Late onset, “eosinophilic”• Late onset, symptom dominant, obese, minimal inflammation• Problems:
– No clues about pathophysiology or role of environment– No information on stability– Definitions often based on percentages of cells in induced
sputum– No associated biomarkers– Do not direct a therapy strategy
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
From phenotype to endotype
“Subtypes of a condition linked by a distinct functional or
pathophysiological mechanism”Anderson GP. Lancet 2008;372:1 107-119
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Defining asthma endotypes
• Difficult at present because there are few long term, large scale studies which link the presence of, and changes in phenotypes with the presence of, and changes in pathophysiological features
• Will require consideration of clinical features, pathophysiology, biomarkers, genetics, natural history and stability
6
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Tentative asthma endotypesFrom Lotvall J et al. JACI 2011;127:355-360; Wenzel S. Clin Exp Allergy 2012
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Severe, early onset allergic asthma• Not all severe asthma with an atopic background is early onset• Family history suggest genetic element but common genetic
“signature” not yet defined• Generally reversible airways obstruction• Stability unknown (although probably most severe child allergic
asthma persists into adulthood)• No distinct pathophysiology• Conflicting reports on response to therapy
– Omalizumab never specifically targeted to these patients
• No biomarkers– Specificity of periostin unknown– FeNO: non-specific, also elevated in allergic rhinitis
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Adult onset, persistent eosinophilic asthma
• Adult onset (20-40 yr)• Severe, rhinosinusitis, atopic diseases less prominent• Extensive overlap with aspirin sensitive endotype• Element of corticosteroid resistance; responds to LT antagonists
and anti-Th2 cytokine strategies (anti-IL-4/5/13)• Family history unusual• No genetic signature (LT receptor polymorphisms)• Distinct pathophysiology defined only by elevated percentages of
eosinophils in sputum, and this is not specific for the endotype• Biomarkers: periostin, 15-lipoxyganse, iNOS, eotaxins
7
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Allergic bronchopulmonary mycoses
• Focussed principally on Aspergillus• Natural history unclear: not known if disease progresses because of
fungal sensitisation• Adults• Bronchiectasis• Airways obstruction variable and sometimes minimal• Pathophysiology: persistent fungi in the airways? Epithelial
malfunction? IgE/Th2 response?• Treatment:
– Systemic corticosteroids (why not topical?)– Anti-IgE?– Anti-fungals?
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Symptomatic, obese older female asthmatics
• Very symptomatic compared with degree of airways obstruction
• Atopic disease absent or not prominent• Mid 40s age, peri-menopausal• Pathophysiology not clear: eosinophils or nothing!• Weight loss improved symptoms in most of these
patients but reduced bronchial hyperreactivity only in non-atopic patients
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Other proposed endotypes of asthma
• “Neutrophilic”– Elevated percentages of neutrophils in sputum– High dosage corticosteroid therapy– Smoking– Genetics: IL-1 family markers– Treatment: macrolide antibiotics?
• Smokers’ asthma
8
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
OverviewWenzel S. Clin Exp Allergy 2012
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Conclusions
• Confirming asthma phenotypes and linking them up with endotypes, of possible, is in its early stages and few firm conclusions can be drawn as yet
• Endotype identification will require an integrated, long term approach
• Hopefully it will identify new groups of molecular targets
KING’SCollege
LONDONFounded 1829
Asthma, Allergy & Respiratory Science
Many thanks for your kind attention
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Defining asthma phenotypes
Prof Chris Corrigan
References1. Wenzel, S. "Severe asthma: from characteristics to phenotypes to endotypes." Clinical &
Experimental Allergy 42, no. 5 (2012): 650-658.
Evaluation1. Regarding phenotypes of severe asthma:
a. They are currently clearly definedb. They are by definition dependent on interaction with the environmentc. They typically involve multiple or grouped featuresd. They clearly point to optimal therapeutic strategies
2. Endotypes of asthma are by definition characterised by:a. Similar disease severityb. Similar functional mechanismsc. Similar atopic statusd. Similar pathophysiological mechanisms
3. Tentative current asthma endotypes include:a. Obese maleb. Early onset allergicc. Basophilicd. Neutrophilic
Please go to the end to find the answers
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Asthma endotypes: the pathway to new effective drugs?
Dr. Gary Anderson
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MCQ AnswersPlease find all answers in bold below
Defining asthma phenotypes - Prof Chris Corrigan1. Regarding phenotypes of severe asthma:
a. They are currently clearly definedb. They are by definition dependent on interaction with the environmentc. They typically involve multiple or grouped featuresd. They clearly point to optimal therapeutic strategies
2. Endotypes of asthma are by definition characterised by:a. Similar disease severityb. Similar functional mechanismsc. Similar atopic statusd. Similar pathophysiological mechanisms
3. Tentative current asthma endotypes include:a. Obese maleb. Early onset allergicc. Basophilicd. Neutrophilic
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Faculty Disclosures
Prof. Christopher Corrigan has received educational grants from GlaxoSmithKline, Novartis, Meda, and Chiesi. He also has research collaborations with Novartis and has received consultation fees from Mundipharma
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