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

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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

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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

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Equi

vale

nt (µ

g)

0 1 2 3 4 5

0

500

1000

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n=46n=36 n=35

n=21

FEV1% predicted

0 1 2 3 4 5

60

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FEV1

% p

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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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Strunk et al. JACI 2008; 122: 1138-44.

Large confidence intervals

(N= 55 randomised school children with moderate to severe asthma)