Severe Asthma in Children

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Severe Asthma in Children

• Andrew Bush MD FRCP FRCPCH
• Imperial School of Medicine
• Royal Brompton Hospital

email a.bush_at_imperial.ac.uk
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Preliminary Steps

• Is it asthma at all?
• Is it a steroid sensitive asthma?
• Are they taking the treatment?
• CAN they take the treatment?
• Dysfunctional breathing?

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Asthma The Basics

• Most children with asthma are easily treated
• Most respond to modest ICS doses, and get no
  benefit from high doses
• High dose ICS may be harmful
• What makes this childs asthma different and
  difficult to treat?

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Definitions

• Difficult to treat asthma becomes easy when the
  basics are got right (adherence, environment,
  etc.)
• Really severe asthma treatment still extremely
  difficult despite getting the basics right

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Treatment of Difficult Asthma

• Is the diagnosis correct?
• Is the drug delivery device appropriate?
• Are there important environmental issues?
• Are there important psychological issues
• What is the pathological phenotype?

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Endobronchial Foreign Body

• Very sudden onset of symptoms
• Ask specifically about the possibility of choking
  or aspiration
• Listen for abnormal signs asymetric, fixed
  monophonic wheeze Signs MAY be bilateral, or
  absent
• CXR may be normal
• Bronchoscope on history alone record is 25 years
  undiagnosed!

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Treatment of Difficult Asthma

• Is the diagnosis correct?
• Is the drug delivery device appropriate?
• Are there important environmental issues?
• Are there important psychological issues
• What is the pathological phenotype?

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Is the drug going to the right place?
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Correct use of the nebuliser a tight fitting
mask is essential
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Treatment of Difficult Asthma

• Is the diagnosis correct?
• Is the drug delivery device appropriate?
• Are there important environmental issues?
• Are there important psychological issues
• What is the pathological phenotype?

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Steroid Resistance 2ry to Environmental Smoke
exposure?

• I never smoke in front of the children, Dr!
• Their dad smokes, but only outside!

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Cigarette smoke induced, 2ry steroid resistance

• FP 1000 mcg/day vs. placebo
• Steroid naïve asthmatics
• COPD excluded BDR, positive Mch
• Lower sputum eosins (3.8 0.7-5.5 vs. 0.3
  0.0-0.9) in smokers
• PEFR, BHR, sputum induction

Thorax 2002 57 226-30
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Steroid Resistance 2ry to Allergens

• He is no worse when the cat is around, Dr!
• I took the cat away for 2 weeks, and he was no
  better!
• Honey the kids are allergic to the cat we had
  better get rid of the kids!

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Dose-response curves for inhibition of PHA
stimulation. White no IL-2 or 4 Black IL-2
IL-4 IL-2 IL-4 decrease sensitivity to the
anti-proliferative effects of dexamethasone
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Am J Respir Crit Care Med 2007 176 20-6
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Treatment of Difficult Asthma

• Is the diagnosis correct?
• Is the drug delivery device appropriate?
• Are there important environmental issues?
• Are there important psychological issues
• What is the pathological phenotype?

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Flow volume loop Marked attenuation of
inspiratory flow rates
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Treatment of Difficult Asthma

• Is the diagnosis correct?
• Is the drug delivery device appropriate?
• Are there important environmental issues?
• Are there important psychological issues
• What is the pathological phenotype?

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Patterns of Difficulty in Asthma

• Near fatal asthma which may recur despite
  adequate treatment
• Brittle asthma
• Sudden dips on a background of good control
• Persistently labile peak flow
• Persistent symptoms despite high dose therapy

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Components of the Asthma Phenotype

• Bronchial hyper-reactivity
• Airway inflammation
• Best achievable airway calibre target lung
  function

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The Difficult Asthma Protocol

• Visit two FOB
• Assess reversible factors
• Assess symptoms,
• use of rescue medication
• Spirometry, PC20, reversibility
• Induced sputum, eNO
• FOB, BAL, biopsy

Intramuscular Triamcinolone

• Visit one MDT Assessment
• Drug delivery device
• Home visit environment
• School visit bullying?
• Assess compliance
• Psychological assessment

1-2 months
4-6 weeks

• Visit three Decision time
• Assess symptoms, diary card,
• and use of rescue medication
• Spirometry, PC20, reversibility
• Induced sputum, eNO
• Serum cortisol assay

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Visit One Team Assessment

• Home visit
• Environment pets, tobacco exposure
• Use of devices
• Adherence medicines not found, out of date, in
  original wrapping
• GP visit
• Prescriptions dispensed
• School Visit
• School absences
• Bullying
• 50 Need No Further Action

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Endobronchial Biopsy
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• Histology can be very variable
• Normal
• Eosinophilia
• Neutrophilia
• Mixed cellularity

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Phenotype Specific Asthma Treatment

• Steroid sensitive (eosinophilic) inflammation
• Normal lung function, normal sputum FeNO, no
  BHR on Visit 3
• Usually eosinophilic inflammation on visit 2
  biopsy

• Treatment approach
• Wean steroids
• (Cyclosporin A if intolerable side-effects)

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Phenotype Specific Asthma Treatment

• Steroid resistant eosinophilic inflammation (1)
• Symptomatic
• Eosinophilic biopsy on visit 2, no triamcinolone
  response (sputum, FeNO)
• (steroid receptor abnormalities)

• Treatment approach
• Look for causes of steroid resistance
• Cyclosporin A
• Other steroid sparing agent

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Steroid Resistance

• Congenital
• Low receptor numbers
• Normal binding affinity
• Very rare

• Acquired
• Normal or high receptor numbers
• Reduced binding affinity
• Common

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Secondary Steroid ResistanceWhat to Do?

• Eliminate not asthma at all
• CF, foreign body
• Eliminate asthma plus
• Rhinitis, GERD
• Eliminate Difficult Asthma
• Detailed multidisciplinary assessment

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Phenotype Specific Asthma Treatment

• Steroid resistant eosinophilic inflammation (2)
• No symptoms on Visit 3
• Eosinophilic biopsy on visit 2, eosinophilic
  sputum visit 3

• Treatment approach
• Await events
• Eosinophils not always the bad guy

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Is Inflammation Always Bad?
Control
MBP Staining
Asthma in remission
BlueJ 2001 164 2107-13
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Phenotype Specific Asthma Treatment

• Neutrophilic inflammation
• Symptomatic throughout
• Neutrophilic inflammation on visit 2 biopsy
• Persistent sputum neutrophilia, visit 3

• Treatment approach
• Theophyllines (neutrophil apoptosis)
• Macrolides (reduced epithelial IL-8)
• 5-Lipoxygenase inhibitor (LTB4) or LTB4 receptor
  antagonist
• Smoking??

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Phenotype Specific Asthma Treatment

• BHR, no inflammation
• Symptomatic throughout
• Marked PF variability and reversibility
  throughout
• No inflammation on visit 3 sputum visit 2 biopsy
  may be variable

• Treatment approach
• Subcutaneous terbutaline infusion
• (Increase dose of LABs)

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Continuous subcutaneous infusion of terbutaline
- CSIT

• IV preparation (0.5 mg/ml)
• Graseby pump, 90 Thalaset needle
• Dose - 5 mg/day
• smaller child 2.5 mg / day
• maximum 10 mg / day
• Start as in-patient
• Ideally n1 trial, with saline also
• Payne et al, Ped Pulmonol 2002

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Effect of subcutaneous terbutaline on peak flow
Pediatr Pulmonol 2002
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Inflammation in Severe Asthma

• Sputum induction (3.5 saline) in 40 children,
  symptomatic despite gt 1 mg FP/day
• Two excluded as FEV1 lt 65 all given ß-2 agonist
  prior to procedure
• 28/38 (74) sample obtained

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Inflammation in Severe Asthma

• 7/38 symptomatic during induction, only 3 ? FEV1
  gt -20
• Only 9/28 had persistent inflammation
• 6 eosinophilic (eosins gt 2.5)
• 3 non-eosinophilic (neutrophils gt 54)

Conclusion inflammation apparently not that
common
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Phenotype Specific Asthma Treatment

• Fixed airflow obstruction
• Symptomatic throughout
• Obstructive spirometry, no reversibility
  throughout
• No inflammation on visit 2 biopsy

• Treatment approach
• Reduce treatment until evidence of reversibility
  appears
• Uusually able to stop all therapy (Obliterative
  bronchiolitis)

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Obliterative bronchiolitis ?post adenoviral
infection
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Summary and Conclusions

• Do not forget the obvious
• Wrong diagnosis
• Not taking treatment
• Cannot use device
• Ask the key question What makes this asthma
  difficult?
• Consider environmental causes of steroid
  resistance
• Only then think of escalating therapy

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