Workshop: «Difficult-to-treat»-asthma in children
Urs Frey, MD PhDUniversity Children’s Hospital Basel, Switzerland
Seite 2Eur Respir J. 2014 Feb;43(2):343-73
Special aspects in childhood asthma
• Lung development, side effects of treatment on development
• Age dependent phenotypes → focus on schoolage
• Differences in drug response, phenotyp-specific treatment
• Different differential diagnosis
• Different degrees of co-operation, therapy adherence, understanding of disease
• Less published evidence
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Content
• Definition (difficult asthma vs. severe therapy resistant asthma)
• Phenotypes and endotypes
• Related biomarkers of severe asthma
• Related diagnostics
• Stability of phenotypes and monitoring of severe asthma
• Therapy of childhood severe asthma
• Summary, clinical diagnostic algorithm
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Definition: Severe asthma (>6 yrs)
Despite Medication despite high doses ICS+ LABA + LTRA + low dose Theophylline (or failed trials of these add-on therapies, or >50% OCS) for the previous year
Poor symptom control or– Uncontrolled: ACQ consistently >1.5, ACT<19 (not well controlled by NAEPP/GINA)– Controlled: that worsens on tapering these high doses
Frequent severe exacerbations or– 2 or more bursts of systemic CS (>3days) in the previous years
Serious exacerbations or– One PICU visit or mechanical ventilation in the last year– At least one hospitalisation
Airflow limitation– FEV1 < 80% after SABA withhold (in the face of FEV1/FVC)
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ICS (mg) age 6-12 age>12
Beclomethason 800 dp 1200Budenoside 800 1200Ciclosonide 320 640Flunisolide 1250 2000Mometasone 500 880Triamcinolone 1200 2000
Definition: Severe asthma (>6 yrs)
Despite Medication despite high doses ICS+ LABA + LTRA + low dose Theophylline (or failed trials of these add-on therapies, or >50% OCS) for the previous year
Poor symptom control or– Uncontrolled: ACQ consistently >1.5, ACT<19 (not well controlled by NAEPP/GINA)– Controlled: that worsens on tapering these high doses
Frequent severe exacerbations or– 2 or more bursts of systemic CS (>3days) in the previous years
Serious exacerbations or– One PICU visit or mechanical ventilation in the last year– At least one hospitalisation
Airflow limitation– FEV1 < 80% after SABA withhold (in the face of FEV1/FVC)
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Diagnostics of problematic severe asthma
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Entry label:problematic severe
asthma
Consider otherdiagnosis
VCD, GoeR, CF, PCD, CLD, Malformations, others
Assessco-morbidities
Obesity, rhino-sinusitis, OSAS, GER, dysfunctional
breathing, food allergy
Difficult asthmaTherapy resistant severe asthma
define phenotype based on:therapy adherence, environmental triggers (allergens, ETS, pollutants), psycho-social
factors
Bush, Frey& Teague Eur Resp Monograph 2011: 51; 59-81
• Dysfunctional breathing• Vocal cord dysfunction• Bronchiolitis, CLD• Reflux, Microaspiration• Cystic fibrosis• Immune deficiencies• Primary ciliary dyskinesia• Airway Malformation/• Compression• Tumors• Congenital heat disease • Interstitial lung disease
• Obesity• Psychosocial factors• Dysfunctional
breathing• Smoking• Hormonal factors• GOe-Reflux• Drugs: NSAID
Phenotypes of severe childhood asthma (>6 yrs)
Cluster analysis based on clinical characteristics and lung function (SARP)
Adults Children
Mild early onset atopic asthma Early onset atopic asthma (Lufu=n)
Moderate early onset atopic asthma Early onset atopic asthma (Lufu=reduced)
Severe early onset atopic asthma
Obese (female) late onset (red. FEV 1) Early onset asthma (Lufu=markedly reduced)
Late onset, less atopic, less reversible Late onset asthma (Lufu=n) obstruction
Seite 8Fitzpatrick et al. SARP JACI 2011: 127; 362-89.N=161
Endotypes of severe childhood asthmaInflammatory patterns
- Eosinophilia /neutrophilia/mixed cellularity changing over time
- Evidence of TH1 versus TH2 pattern controversal =ǂ= Eosinophilia
- High FeNO
- Role of Vit D deficiency?
- Role of specific cytokines and chemokines: IL6, GRO, RANTES,IL12,IF,IL10, IL33
- Reduced I interferon- and type III interferon- induction by rhinoviruses
- Impaired alveolar macrophage phagocytosis
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ERS/ATSDiagnostics
FeNO (DD: CF, PCD)IgE, IgG,M,ABlood eosinophilsSkin Prick
BAL, induced sputum not generally recommended
Endotypes of severe childhood asthma Structural features and remodelling
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• Epithelial damage
• Increased areas of mucus glands
• Higher number of fibroblasts and collagen deposition
• Reticular basement membrane thickening in difficult asthma (Eos)
• Evidence of angiogenesis
• Particularly severe asthma with persistent obstructive pattern
shows increased smooth muscle
• Airway smooth muscle content related to Vit D levels
Payne DN et al. AJRCCM 2003; 167: 78-82Benayoun et al. AJRCCM 2003; 167: 1360-68Barbato A et al. AJRCCM 2006; 174: 975-81
ERS/ATSdiagnostics
Chest X RayHR-CT not generally recommendedBiopsy not generally recommended
Alternative diagnosis?
Saglani et al. AJRCCM 2005; 171; 722-27Tillie-Leblond Allergy 2008; 63: 553-41Gupta et al. AJRCCM 2011:184:1342-49
Endotypes of severe childhood asthmaFunctional abnormalities
- Variable versus persistent airway obstruction
- Missing response to bronchodilators (FEV1 < -1.96 Z-s)
- Missing response to corticosteroids
- No clear relation to BHR
- Reduced fluctuations in lung function
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ERS/ATSDiagnostics
Lung functionBronchodilator responseSteroid responseBHR not generally recommendedPEF/FEV1 monitoring
Testing steroid response in childrenwith difficult asthma (DA)
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• 89 severe asthmatic children (mean age 11.6 SD 2.8 yrs)• 40 mg/day OCS for 14 days or 80 mg triamcinolone i.m.• Assess clinical and functional improvement
• Symptoms• FEV1• BDR• FeNO
• Full response: 11% all parameters• Partial response: 80% 1-3 parameters• No response: 9% none
Bossley CJ et al. Eur Resp J 2009; 34: 1052-59.
Diagnostics of problematic severe asthma
Seite 13Bush, Frey& Teague Eur Resp Monograph 2011: 51; 59-81
Difficult asthma
Regular asthma treatment:optimise concomitant factors
Therapy resistant severe asthma
Specify mechanism:
• Airway Inflammation (discordance, pattern, distribution)
• Steroid responsiveness
• Lung mechanics, BR (Persistent flow limitation)
(Phenotype specific) treatment
Diagnostic tests:
• Bronchoscopy, BAL, Biopsy, induced Sputum, FENO, IgE, SkinPrick
• Steroid trial
• Lung function, BDR PEF/FEV1 monitoring
Monitoring adherence, a key factor of the therapy of problematic severe asthma
Important role of nurse led home visits
Improvement of adherence, parental coping
Medication changed, inhaler technique changed
Alterations of home environment (obvious allergic triggers)
Psychosocial counseling
Smoking cessation
Seite 14Bracken et al. Arch Dis Child 2009: 94: 780-84.Sales et al. J. Ped. Psychol 2008; 33: 208-19.
ERS/ATS
All recommended
Stability of Phenotype: Monitoring of severe asthma in children
Seite 15Sears MR et al. N Engl J Med 2003;349:1414-22
Persistence of symptomsTracking of lung function over time
Changing Inflammatory pattern
Fleming et al. Thorax 2012: 67; 675-81.Fleming et al. AJRCCM 2013: 188: 401-402.
Monitoring severe asthma in children
Seite 16Bush, Frey& Teague Eur Resp Monograph 2011: 51; 59-81
Difficult asthma
Regular asthma treatment:optimise concomitant factors
Therapy resistant severe asthma
(Phenotype specific) treatment
Monitoring : Control, exacerbation risk, functional development, guide therapy
Controlled severe asthma
Adapt treatment
NO RESPONSERESPONSE
Monitoring severe asthma in children
Guidance of therapy– FEV1 or PEF unknown (improves adherence?)– BHR unknown– Sputum Eosinophils not stable
– FeNO only trend benefit (mainly data from non severe asthma)
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Flemming et al. Thorax 2012 67: 675-81.Flemming et al AJRCCM 2013; 188: 400-2.
ERS/ATS(treatment guidance)
• Symptoms, QoL, Lufu
• FeNO not recommended• Induced sputum not recommended
Zacharasiewicz et al. AJRCCM 2005; 177:1077-82Pinijenburg et al. AJRCCM 2005: 172:831-36De Jongste et al. AJURCCM 2009 15:179(2): 93-7Szefler. et al Lancet. 2008 ;372(9643):1065-72
Monitoring of functional loss over time-Lung function
Severe asthma therapy beyond Guidelines
• Does the child need ‘beyond guidelines therapy’ at all?
• Environmental tobacco exposure reduction and allergy avoidance
• Standard therapy at unusual doses?
• Beyond guideline therapies:– Evidence for Omalizumab (anti-Ig-E)– Other therapies low evidence – Phenotype specific
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Phenotype specific treatment in children
Severe allergic asthma – High eosinophils, high IgE
Eosinophilic asthma– High IgE, recurrent exacerbations
Neutrophilic asthma (rare, consider DD)– Chronic airflow obstruction– Bacterial infections
Chronic airflow obstruction– Remodelling of airway walls
Recurrent exacerbations– Sputum Eos, reduced ICS response
Corticosteroid insensitivity– Sputum neutrophils high– Reduced ICS response
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ERS/ATS (some)
Anti Ig-E (Omalizumab)
ERS/ATS (very low)
Anti-LTB4Macrolides
ERS/ATS (low)
Anti Ig-E (Omalizumab)
ERS/ATS (very low)
TheophillineMacrolides
Summary
Algorithm Severe asthma in children
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• Childhood severe asthma more unstable phenotype• Different from adults• Effect on development• Close monitoring and repetitive re-evaluation• Important role of leading doctors and nurses team
Bush, Frey& Teague Eur Resp Monograph, 2011:51; 59-81
Reserve slides
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ICS dose/day
0 1 2 3 4 5
0
500
1000
1500
2000
2500
Bud
eson
ide
Equi
vale
nt (µ
g)
Years post stage 1
n=31
n=24 n=17n=18
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DA STRA
FEV1% predicted
0 1 2 3 4 5
60
70
80
90
100
110
Years post stage 1
FEV1
% p
redi
cted
n=30n=22 n=14 n=7
Sharples J et al. Eur Respir J. 2012; 40: 264-7
Difficult asthma
ICS daily dose
Years post stage 1
Bud
eson
ide
Equi
vale
nt (µ
g)
0 1 2 3 4 5
0
500
1000
1500
2000
2500
n=46n=36 n=35
n=21
FEV1% predicted
0 1 2 3 4 5
60
70
80
90
100
110
FEV1
% p
redi
cted
Years post stage 1
n=45
n=35 n=30 n=21
STRA
Diagnostics: assess lung function
ERS 2013 - Severe asthma in children - Frey Seite 23
Difficult asthmatics showed:
Higher FEV1% predicted
Less bronchodilator reversibility
Lower FENO
Bronchodilator reversibility
BD
R %
DA STRA0
50
100
150 p=0.021
FENO50
FEN
O50
(ppb
)
DA STRA0
50
100
150
200 p=0.013
FEV1%
FEV1
% p
redi
cted
DA STRA0
50
100
150 p=0.0017
DA: Difficult asthmaSTRA: Severe therapy resistant asthma
CAVE: children with severe asthmacan have normal lung function
Bracken et al. Arch Dis Child 2009; 94: 780-4Slide with permission from Prof A. Bush
Severe asthma therapy beyond guidelines:Anti-IgE: Omalizumab
• After all efforts to reduce burden of allergen exposure
• Good short term safety• Consider local and systemic allergic reactions• Thrombocytopenia
• Effect on symptoms and QoL, little effect on Lufu
• Dosing according to Ig-E levels and weight, 2-4 weekly max 16 wks
• Mainly relevant for school age
• Further studies are needed for aspects of long term safety
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NEJM 2011; 364: 1005-15Chest 2011; 139: 28-35
ERS/ATS
recommended
Allergy 2005; 60: 309-16Clin Pediatr 2009; 48: 859-65JACI 2009; 124: 1210-6
Severe asthma therapy beyond guidelines:Antifungals (Itraconazole) in SAFS
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Recommendation in adults (very low evidence)
Only in ABPA with recurrent exacerbationsDo not use if no ABPA, but just sensitisation
No evidence in children: (isolated case reports)
Current recommendations adapted from adult criteria but no IgE Criteria
ERS/ATS (very low)
• Antifungals only used in special situations
• In specialised centres
• Side effects• Hepatotoxicity
Others: no to low evidence in children
Macrolide antibiotics – little published evidence– Good safety profile– Known immun-modulatory properties– ‘Neutrophilic’ asthma?– DD: Atypical infections?
Immunosuppressives– Methotrexate – small open trials – Cyclosporin – one case series– Azathioprine – no published evidence
Immunoglobulin infusions– No trial data
Subcutaneous terbutaline infusion– No systematic evidence
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Severe asthma therapy beyond guidelines:Macrolides and LTRAs as ICS sparing agents
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Tim
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inad
equa
te a
sthm
a co
ntro
laf
ter s
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ntia
l bud
enos
ide
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Strunk et al. JACI 2008; 122: 1138-44.
Large confidence intervals
(N= 55 randomised school children with moderate to severe asthma)