Treatment of asthma exacerbations in children

Sejal Saglani Clinical Senior Lecturer Respiratory Paediatrics Imperial College London

Outline
Risk factors for exacerbations Predictors of exacerbations in children
Predictors of severe exacerbations

Treatment
Pre-school wheeze Steroids LTRA Magnesium sulphate

Impact of exacerbations Severe exacerbation accelerated lung function decline 30ml/ year greater decline in FEV1 Significant morbidity
Hospitalisation

Fatal
McDonald V & Gibson PG CEA 2010;42:670-7

Risk factors for asthma deaths in children: 2001-2006 (UK)

Observational case series
Hospital and primary care post mortem reports Asthma severity, admissions, adherence, precipitating factors

20 deaths: 9/20- mild-moderate

10/20 deaths between June and August

Importance of seasonal allergy
Anagnostou K Prim Care Respir J 2012

Risk factors for exacerbation in children

Poor control Exacerbation in previous year Younger age Allergen exposure Season Tobacco smoke exposure Pollution Non-white race

Forno E & Celedon JC Curr Opin Pulm Med 2012

The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study (TENOR) 3 year, multi-centre, observational cohort Total n=4756 n=497; 13-17 years, n=770; 6-12 years Severe or difficult-to-treat asthma

Strongest predictors of exacerbation: recent exacerbation history (12 months previously) uncontrolled asthma
Chipps BE JACI 2012 EPub

Synergistic predictors of exacerbations

Haselkorn T et al JACI 2009;124:921-7

Clinical score to predict exacerbations

Good PPV for no hospitalisation (94-99%), but only 70% ability to predict exacerbation

Forno E Chest 2010;138:1156-65

Exhaled breath IL-5 and asthma control score predict exacerbations

Good PPV low risk of exacerbation predicted Poor NPV Robroeks C et al CEA 2012;42:792-8

No role for FeNO in predicting / preventing exacerbations

90 children aged 6-17 years randomised to FeNO driven control or conventional FeNO + reported symptoms used to change medication in FeNO group 12 month duration No difference in exacerbation rate between the 2 groups
Pike K et al Clin Respir J 2012

No role for sputum eosinophils in predicting / preventing exacerbations

Fleming L et al Thorax 2012;67:193-8

Sputum phenotype variability in children

Not related to FeNO, change in ICS, asthma control, disease severity

Fleming L et al Thorax 2012;67:675-81

Vitamin D & exacerbations CAMP study

VitD level and risk of hospitalisation / emergency visit over 4 years 35% of all children had vitD insuffuciency (<30ng/ml) Low VitD status associated with higher odds for hospitalisation (OR: 1.5) adjusted for age, sex, BMI
Brehm J et al JACI 2010

Vitamin D and exacerbation severity

560 Puerto Rican children aged 6-14 years Vitamin D insufficiency associated with severe exacerbations regardless of race, atopy, disease severity or control

Brehm JM et al AJRCCM 2012;186:140-6

Does vitD supplementation reduce exacerbations?

Majak PJACI 2011;127:1294-6

ERS Task Force definitions of preschool wheeze phenotypes

Brand et al ERJ 2008;32:1096-110

Temporal pattern of wheeze Episodic (viral) wheeze

Definition Wheeze at discrete times Often with evidence of viral cold NO symptoms in between episodes Wheeze with discrete exacerbations AND symptoms between episodes

Multiple-trigger wheeze

NB: Phenotype can be applied at the time of consultation

Viral wheeze & oral steroids initiated at home: no benefit

Oommen Lancet 2003;362:1433-8

Viral wheeze & oral steroids in hospitalised children: no benefit

687 children aged 10 months-6 years Oral prednisolone or placebo for 5 days

Primary outcome:
Duration of hospitalisation

Secondary outcomes:
Symptom severity & duration Use of beta-agonists

No difference between groups

Panickar J NEJM 2009;360:329-38

Intermittent inhaled steroids vs montelukast for viral wheeze

Age 12-59 months > 2 wheezing episodes with RTI in last yr At least 1 episode in last 6/12 At least 1 episode needing oral steroids No controller medication No evidence of persistent symptoms No more than 6 courses pred in past year

Bacharier et al JACI 2008;122:1127-35

Randomisation
Budesonide neb 1mg bd Montelukast 4mg od Placebo
At onset of RTI for 7 days

Primary outcome
episode free days over 12 months

Secondary outcomes
Symptom severity in 14 days from initiation of therapy Total courses of oral steroids Number of wheezing episodes
Bacharier et al JACI 2008;122:1127-35

Results

Bacharier et al JACI 2008;122:1127-35

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Imperial College London

Viral wheeze & parent-administered high dose ICS

129 children aged 1-6 years previous intermittent wheeze 750mcg bd fluticasone / placebo Start at onset of URTI for up to 10 days Primary outcome:
Rescue oral steroids

Secondary outcomes:
Symptoms Use of beta-agonsits Hospitalisations Change in growth & bone mineral density
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Imperial College London

Ducharme F et al NEJM 2009;360:339-53

Intermittent high dose ICS in viral wheeze

Median study duration 40 weeks:

8% of fluticasone group needed rescue steroids 18% of placebo group needed rescue steroids

Fluticasone group:
Smaller gain in height and weight

No group difference in cortisol or bone mineral density

Imperial College London Page 24

Ducharme F et al NEJM 2009;360:339-53

Daily or intermittent budesonide for preschool recurrent wheezing?

278 children Age 12 53 months Positive Asthma Predictive Index Recurrent wheezing episodes >1 exacerbation in past year

Zeiger RS et al NEJM 2011;365:1990-2001

Zeiger RS et al NEJM 2011;365:1990-2001

No difference between intermittent or continuous budesonide regimen

Zeiger RS et al NEJM 2011;365:1990-2001

No significant group differences in adverse effects

Total budesonide exposure lower in intermittent regimen group (45.7mg) compared to daily regimen group (149.9mg)
Zeiger RS et al NEJM 2011;365:1990-2001

Bacterial infections and preschool wheeze

Cohort study children from asthmatic mothers Age 4 weeks 3 years Planned follow-ups and during acute symptoms

Assessment of viral and bacterial infection with and without acute wheeze
Bisgaard H BMJ 2010

Wheezy episodes associated with both bacterial and viral infection - independently

Bisgaard H BMJ 2010

Clarithromycin in acute asthma

Koutsoubari I et al Pediatr Allergy Immunol 2012;23:385-90

Duration of exacerbation reduced in clarithromycin group

Koutsoubari I et al Pediatr Allergy Immunol 2012;23:385-90

Early oral corticosteroids and outcome

Bhogal S Ann Emerg Med 2012;60:84-91

Bhogal S Ann Emerg Med 2012;60:84-91

Single dose dexamethasone or 3 days prednisolone?

Advantages Single oral dose Compliance assured Long half-life: 36-72 hours Disadvatages Only mild moderate exacerbations More potent than prednisolone (6x)

Cross KP Can Fam Phys 2011;57:1134-6

No difference in initial A&E outcomes

Altamimi et al Ped Emerg Med 2006

No difference in 5 day outcomes

Altamimi et al Ped Emerg Med 2006

Oral montelukast for acute asthma: Hospitalisation

Watts K Cochrane Syst Database Rev 2012

IV montelukast: Hospitalisation

MgSO4
Single dose IV MgSO4 effective in children when
Poor initial response to inhaled/nebulised bronchodilators Severe exacerbation High risk of admission

Should be used in A&E to prevent admission No role for inhaled / oral Mg

Non-invasive ventilation
Advantages Trial in status asthmaticus when conventional management fails CPAP or BiPAP May avoid need for intubation & IPPV Disadvantages Cannot be used with altered mental state

Need patient co-operation

Variable tolerability, especially in younger patients

Minimal sedation needed

Levine DA Curr Opin Pediatr 2008;20:261-5

Summary
Prevention and prediction of exacerbations is critical, especially with increasing disease severity - ?vitD supplementation future preventative intervention Important risk factors / predictors Exacerbation in previous year Poor asthma control Synergistic effects of risk factors
Most common infectious precipitants: Viruses (HRV) ?equal role of bacteria in pre-school children Pre-school wheeze Contrasting effects of oral and inhaled steroids intermittent therapy for intermittent symptoms