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

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 Outcomes –Current rhinitis (CR) –Current rhinoconhunctivitis (CRC) Main Results CR 26.1%, CRC 12-1% Increased risk with greater sensitisation Conclusions Atopy is not ‘all-or-none’ Allergy 2007; 62:

There is a dose effect for specific IgE and atopic manifestations Grass IgE and rhinoconjunctivitis Grass IgE and seasonal rhinitis Grass IgE and current rhinitis Mite IgE and perennial rhinitis

16S rRNA: The Sterile Airway? S rRNA from 43 subjects, > 70% bacterial species Bronchial tree NOT sterile– 2000 sequences cm 2 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 ERJ 2006; 27: Mild Severe Standard strategy Sputum strategy Sputum strategy Standard strategy

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:

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

Next Step: FOB Assess symptoms, use of rescue medication Spirometry & reversibility Induced sputum, FeNO FOB, BAL, biopsy Intramuscular triamcinolone Four weeks later: Decision time Assess symptoms, use of rescue medication Spirometry & reversibility Induced sputum, FeNO Develop treatment plan Inflammatory pattern? Phenotype Discordance? Steroid Responsiveness? What is target lung function (PAL)?

Mucosal and Luminal Cytology Lex et al, BlueJ 2006; 174: No correlation between the two: which matters?

Stability of Inflammatory Phenotypes over Time Sputum obtained from 40 subjects with severe asthma, > twice over a one year period Age range 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 FP equivalent dose 1000 mcg ( ); n=21, oral steroids Admissions median 2, 0-21 (12 ventilated) SPTs

RBH Paediatric Severe Asthma: Demographics (2) FEV 1 = 76% ( ) BDR = 14% ( ) FeNO 50 = 52ppb (5-171), NR <25ppb ACT (25): –>20, 3% –16-19, 25% –< 15, 72% FEV 1 % predicted

Serum Total IgE G median 550 iu G mean 401 iu Serum IgE Frequency (%) normal Ineligible for Anti IgE

Airway Phenotype (post-steroids) BAL: –14/68 eosinophilic –19/68 neutrophilic –11/68 mixed cellularity –24/68 paucicellular EBB –19/68 eosinophilic –19/68 neutrophilic –17/68 mixed cellularity –13/68 paucicellular ERJ 2009; 34:

ENFUMOSA 163 severe asthmatics, 158 mild (low dose ICS) –Median ICS 1773 –One third oral pred –Median pred 19 mg Female preponderance (4.4:1 vs. 1.6:1 mild) Severe asthma (hatched) –Less atopic –More PMNLs SPTs Induced Sputum Eur Respir J 2003; 22: 470-7

Adult and Paediatric Differences? Nearly 50% SA now have COPD! Stronger signal than smoking

Next Step: FOB Assess symptoms, use of rescue medication Spirometry & reversibility Induced sputum, FeNO FOB, BAL, biopsy Intramuscular triamcinolone Four weeks later: Decision time Assess symptoms, use of rescue medication Spirometry & reversibility Induced sputum, FeNO Develop treatment plan Inflammatory pattern? Phenotype Discordance? Steroid Responsiveness? What is target lung function (PAL)?

Discordant Phenotypes Individual variability in clinical, physiological & pathological parameters Am J Respir Crit Care Med 2008; 178:

Inflammometry and Treatment? Pauci-inflammatory –Reduce or do not escalate anti-inflammatory therapy Persistently eosinophilic –Omalizumab –Theophyllines –Steroid sparing agents (MTX, CyA) Neutrophilic –Macrolides –Anti-LTB4 –Theophyllines Mixed –???

Persistent Airflow Limitation Post-steroid trial, post acute BDR FEV 1 < Z-scores –What dose, route of administration and duration of steroids –What dose of bronchodilator? No good paediatric evidence BUT, no point flogging a dead horse!

CAMP: Accelerated Airway Obstruction MILD ASTHMATICS, BUT: –c25% had airway ‘failure to thrive’ –Independent of treatment (ICS, nedocromil, placebo) BlueJ 2004; 170:

Re-analysis of START trial Does early intervention with ICS prevent exacerbations (initial question) –Lancet 2003; 361: Once daily BUD 200mcg (children) or 400mcg (adults) vi Turbohaler™ vs. lactose placebo 7241 patients aged 5-66 years from 32 countries 1363/6767 received one course prednisolone –Placebo, n=818/3368 –BUD, n=545/3399 What was the effect on ΔFEV 1 (new, post hoc question)

Results:

Corticosteroid response ResponseNumber (%) Symptom (ACT ≥ 20/25 or 50% increase) 23/47 (49%) Lung Function (FEV 1 ≥ 80% or 15% increase) 29/52 (56%) FeNO (FeNO 50 < 24) 22/52 (42%) Sputum (Eo < 2.5%) 22/42 (52%)

Proposed criteria for corticosteroid response Complete response: normalisation/ improvement in all parameters (symptoms, FEV 1, FeNO, sputum); 8/52 (15%) Partial: response in one or more of the parameters; 36/52 (69%) Non: response in none of the parameters; 8/52 (15%)

Other criteria for steroid response? Clinical response; ACT and FEV 1 normal or improved –15/50 (30%) Inflammatory response; Normal sputum cytology, or if no sputum available, FeNO normal –26/52 (50%)

Exacerbations vs. Baseline control Exacerbation of Asthma –Linear decline, then linear recovery of PEFR –No increase in variability –Usually viral –Usually difficult to prevent Loss of Asthma control –Wide diurnal variability –Morning dips –BDR > 30% These are not the same thing! Lancet 1999; 353: BUD

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: Specific mucin glycan phenotype (O-secretor) –Am J Respir Crit Care Med 2011; 183; 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!