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Phenotyping Severe Asthma in Children Andrew Bush MD FRCP FRCPCH Imperial College & Royal Brompton Hospital [email protected]

Phenotyping Children  Why do it? • School age children: principles

• School age children: phenotypes • Summary and Conclusions

What is a phenotype? • A phenotype is here defined as a feature or cluster of features which differentiates a separate group from a defined population at a given time • Some useful action must result! – Understanding of mechanisms of disease – Results in a change of treatment – Helps with monitoring disease

How Phenotype? • Investigator prejudice – Eosinophilic, neutrophilic, mixed, paucicellular

• Self-fulfilling

Self-fulfilling: Infant Wheezing Phenotypes • Never (51%) • Transient (20%) – Wheeze 0-3, not at age 6

• Persistent (14%) – Wheeze 0-3 still present age 6

• Late onset (15%) – Wheeze after age 3

How Phenotype? • Investigator prejudice – Eosinophilic, neutrophilic, mixed, paucicellular

• Self-fulfilling

• Mathematical techniques – PCA, latent class analysis – Systems biology

Data driven: Infant Wheezing Phenotypes

Atopy: a dichotomous variable? Patients and Methods • Birth cohort study age 5 years – Questionnaire n = 815 – SPT n = 717 – Specific IgE n = 478

Main Results • CR 26.1%, CRC 12-1% • Increased risk with greater sensitisation

• Outcomes – Current rhinitis (CR) – Current rhinoconhunctivitis (CRC)

Allergy 2007; 62: 1379-86

Conclusions • Atopy is not ‘all-or-none’

Grass IgE and current rhinitis

Mite IgE and perennial rhinitis

Grass IgE and rhinoconjunctivitis

Grass IgE and seasonal rhinitis

There is a dose effect for specific IgE and atopic manifestations

16S rRNA: The Sterile Airway? • 5054 16S rRNA from 43 subjects, > 70% bacterial species • Bronchial tree NOT sterile– 2000 sequences cm2 sampled • Proteobacteria more abundant in asthmatic children, prevotella in controls (same as adults)

• There are more bugs in the lung than the gut! – –

Think gastric acid! The gut is BETTER protected!

PLoS One 2010; 51: e8578

Phenotyping Children • Why do it?  School age children: principles

• School age children: phenotypes • Summary and Conclusions

Inflammometry: not for mild asthma Mild

Severe

Standard strategy

Sputum strategy Standard strategy

Sputum strategy

ERJ 2006; 27: 483-94

New terminology and definitions Problematic Severe Asthma

NB: is it asthma at all? NB: is it ‘asthma plus’

Stage 1 assessment

Difficult asthma •Remediable factors identified •Therapy adherence addressed

Genuine severe, therapy resistant asthma

Lancet 2008; 372: 1019-21

Problematic Severe Asthma • Difficult asthma = – becomes easier when the basics are got right (adherence, environment, etc.) – NOT candidates for novel therapies

• Severe, therapy-resistant asthma = – treatment still extremely difficult despite getting the basics right – Would be potentially suitable for cytokine specific therapies

‘Difficult’ vs. ‘Severe, Therapy resistant’ Asthma • Psycho-social issues re-addressed – Anecdotally, more likely to ‘open up’ – 74% referrals were after home discussions

• Adherence

• Smoking • Allergens Arch Dis Child 2009; 94: 780-4

Inflammatory pattern? Phenotype Discordance? Steroid Responsiveness? What is target lung function (PAL)? Next Step: FOB Assess symptoms, use of rescue medication

Four weeks later: Decision time





Assess symptoms, use of rescue medication



Spirometry & reversibility



Spirometry & reversibility



Induced sputum, FeNO



Induced sputum, FeNO



FOB, BAL, biopsy



Develop treatment plan

Intramuscular triamcinolone 

Mucosal and Luminal Cytology

No correlation between the two: which matters? Lex et al, BlueJ 2006; 174: 1286-91

Stability of Inflammatory Phenotypes over Time • Sputum obtained from 40 subjects with severe asthma, > twice over a one year period • Age range 8.4-17.6 years – 17 children (42%) showed a change in phenotype (between eosinophilic, neutrophilic and mixed)

• What is a real change in phenotype?

• How often should phenotypes be re-assessed? Fleming L, MD(Res) 2010

Phenotyping Children • Why do it? • School children: principles

 School age children: phenotypes • Summary and Conclusions

RBH Paediatric Severe Asthma: Demographics (1) • N=71 (35 male), group mean age 11.9, range 4.5 - 17-5 • FP equivalent dose 1000 mcg (5003000); n=21, oral steroids

• Admissions median 2, 0-21 (12 ventilated)

Cladosporidium Alternaria Egg Milk Peanut Trees Aspergilus HDM Dog Cat Grasses 0

10

20

30

% positive %positive

SPTs

40

50

60

RBH Paediatric Severe Asthma: Demographics (2) • FEV1 = 76% (33125) • BDR = 14% (12106)

• ACT (25): – >20, 3% – 16-19, 25% – < 15, 72%

Number of subjects

• FeNO50 = 52ppb (5-171), NR 30%

• These are not the same thing! Lancet 1999; 353: 364-9

Eosinophilic/Exacerbating • CAMP: 30% never exacerbated – N Engl J Med 2000;343:1054–1063

• Genetics different: CD14, CD16 – Am J Respir Crit Care Med. 2006; 173: 617-22

• Specific mucin glycan phenotype (O-secretor) – Am J Respir Crit Care Med 2011; 183; 189-94

• Eosinophilic, discordant phenotype

Lessons from TENOR • Previous exacerbation STRONGLY predictive of future exacerbation – Independent of asthma control or duration – Use of controllers – Allergic triggers

• Also predictive are: – Allergic triggers – NOT ‘All or none’ – Non-white race – Poorly controlled asthma (impairment domain)

The exacerbating child: What actions to take? • We (as yet) cannot modulate viral infections! – Are they taking low dose ICS (care with escalation)? – Has baseline control been optimised? – Has baseline lung function been optimised? – What are their allergic triggers? – Has allergen exposure been reduced? – (Has eosinophilic airway inflammation been controlled?)

Phenotyping Children • Why do it? • School age children : principles

• School age children : phenotypes  Summary and Conclusions

Summary and Conclusions • Phenotyping has to be useful if it is to be justifiable – Understanding mechanisms – Guiding treatment

• Get the basics right first • Childhood and adult disease differs

• Be sure you are clear what is meant by ‘severe asthma’ in a given study • We need international collaborations

We have a long way to go!