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Brittle Asthma
ERS 2004, Glasgow PG8

Jon Ayres
j.g.ayres@abdn.ac.uk

Department of Environmental & Occupational Medicine University of Aberdeen

Brittle asthma

[ERS 2004 PG8]

Aims of the session Understanding the present definitions of Type 1 and Type 2 brittle asthma Understanding the risk factors for these phenotypes with respect to the potential for intervention Understanding what interventions may be of use.

Asthma Labels & Phenotypes

Difficult Severe Unstable Therapy resistant Chronic persistent Brittle Life threatening
But phenotypic descriptions need to be established Must be appropriate, precise, easily recognisable and have an end in sight.

[Ayres JG J Roy Soc Med 2001;94:115-8]

Is this just severe asthma or is something else going on as well?

COPD Bronchiectasis Vocal cord dysfunction Hyperventilation Obstructive sleep apnoea Upper airway resistance syndrome Asthma plus one or more of the above

Brittle Asthma
Definitions

Brittle asthma?
Repeated hospital admissions Repeated attacks Uncontrolled asthma Rapid onset attacks Chaotic symptoms and peak flows More than one of these Something else

Definitions of Brittle Asthma

Turner Warwick BTS Guidelines

1977

1990

Chaotic peak flow readings with symptoms. No specific mention of amount of treatment

where an asthma attack becomes severe within a few minutes or hours with little instability of asthma in the preceding days.

1995
Not mentioned

Brittle Asthma Definitions

Type 1

Wide swings in peak flow (>40% DV for >50% of the time); repeated attacks

Type 2

Sudden attacks on a background of apparent good asthma control

[Ayres et al Thorax 1998;53:315-21]

Case 1

55 year old woman with repeated attacks of asthma

55 year old woman with repeated attacks of asthma

55 year old woman with repeated attacks of asthma

Defining peak flow variation

At the severe end of the market

at least 3, better 4x daily

Max-min/max % Correction of non-linear scale

Defining peak flow variation

At the severe end of the market

at least 3, better 4x daily

Max-min/max % Correction of non-linear scale

37
Achieved peak flow criterion

22

Raw data

15

Did not achieve peak flow criterion

Defining peak flow variation

At the severe end of the market

at least 3, better 4x daily

Max-min/max % Correction of non-linear scale

37
Achieved peak flow criterion

22 20 10

Raw data

15 2 5

Corrected data

Did not achieve peak flow criterion

Brittle Asthma
Risk factors

Contributory factors for Type 1 brittle asthma

Psycho-social factors long term short term Compliance Atopy + allergen exposure inhaled ingested Peri-menstrual hormonal changes Gastro-oesophageal reflux Genes Obstructive sleep apnoea ?Reduced Ig levels ?Nutrient deficiency

[Ayres et al Thorax 1998;53:315-21]

Case 2

Brittle asthma?
Female aged 19

physiotherapist

Repeated episodes of breathlessness on exertion

Unable to take part in sports

Frequent hospital attendances Woken from sleep on occasions Often rapid to recover Labelled as vocal cord adduction (with psychological overtones)

Peak flow chart

What next?
Admit for observation Measure BHR Reinforce treatment rationale and repeat PFs Exercise test Laryngoscopy FV loop Food challenge

Exercise test

Vocal Cord Dysfunction

Often misdiagnosed as asthma Over half of cases occur in patients with pre-existing asthma Symptoms are throat tightness, voice change & difficulty breathing in Patients are typically female aged 20-40 with family difficulties High frequency of psychiatric disorder including somatisation disorder

Asthma, vocal cords and ventilatory responses

CO2 hypersensitivity? Laryngeal inflammation? Dysautonomia?

VC D H V CATASTROPHISATION
Other Sx

True Asthm a

Case 3

History
Female age 25 Acute onset of breathlessness with wheeze over 3 hours pH 7.35, PO2 18 kPa, PCO2 3.6 kPa, BE 8 Recovered in two hours; sent home. Is this acute severe asthma or hyperventilation?

Subsequent history
Six months later Rapid onset of breathlessness over 1 hour pH 6.96, PO2 18.8, PCO2 12.1 kPa, BE 16 PCO2 normalised at 2 hours One month later another episode; PCO2 3.3 4 months later Respiratory arrest with PCO2 11.6 kPa
Diagnosis Type 2 brittle asthma

Psychological morbidity in Type 1 brittle asthma

Brittle asthma [n=29]
GHQ [mean] <11 Hyland Family Apgar ASC panic/fear 19.5 21 1.3 7.3 4/29

Non-brittle asthma [n=29]

7.2 2 1.0 8.65 11/29

0.0002 0.006 <0.002 0.09 0.04

[Miles et al Clin Exper All 1997;27:1151]

Quality of Life in severe asthma

[Highfield et al 2003]

Type 1 BA Type 2 BA Severe Asthma

No. 44 18 67

GHQ AQLQtotal HADSanx* HADSdep*

24 42 6 6

7 55 2 1

17 41 9 8

*Number above threshold

Compliance/adherence
Admittedly low Often clear decision made rather than forgetfulness Measuring drug levels

Theophyllines Beta-agonists Steroids

Serum Prednisolone levels compared to serum cortisols in patients prescribed oral prednisolone

450

400

350

[Cortisol] nmol/l

300

250

200

150

100

50

0 0 100 200 300 400 500 600 700 800 900 1000

[Prednisolone] nmol/l

Serum Prednisolone levels compared to serum cortisols in patients prescribed oral prednisolone

450

400

350

[Cortisol] nmol/l

300

250

200

150

100

50

0 0 100 200 300 400 500 600 700 800 900 1000

[Prednisolone] nmol/l

Serum Prednisolone levels compared to serum cortisols in patients prescribed oral prednisolone

450

400

350

[Cortisol] nmol/l

300

250

200

150

100

50

0 0 100 200 300 400 500 600 700 800 900 1000

[Prednisolone] nmol/l

Serum Prednisolone levels compared to serum cortisols in patients prescribed oral prednisolone

450

400

350

[Cortisol] nmol/l

300

250

200

150

100

50

0 0 100 200 300 400 500 600 700 800 900 1000

[Prednisolone] nmol/l

Allergen exposure in sensitised individuals by group

Mild
g/g

Severe
g/g

Brittle
g/g

Der p 1 (BR) Can f 1 (LR)

1.74
(0.6-4.94)

12.79
(4.58-35.72)

7.23
(3.08-16.99)

0.83
(0.68-0.99)

15.94
(3.11-81.58)

31.96
(7.28-140.39)

[Tunnicliffe et al Eur Resp J 1999;13:654]

Allergen exposure in those both exposed and sensitised by severity

Der p 1
g/g

Can f 1
g/g

Fel d 1
g/g

Mild (26) Severe (28) p

4 (15%) 14 (50%) 0.007

0 (0%) 13 (46%) <0.0001

1(4%) 7 (25%) 0.029

[Tunnicliffe et al Eur Resp J 1999;13:654]

Contributory factors for Type 1 brittle asthma

Psycho-social factors

long term short term

Compliance Atopy + allergen exposure

inhaled ingested

Gastro-oesophageal reflux Genes Obstructive sleep apnoea ?Reduced Ig levels ?Nutrient deficiency

Peri-menstrual factors
[Ayres et al Thorax 1998;53:315-21]

Brittle Asthma
Management

Long term drug treatment of difficult asthma

Compliance Inhaled steroids
Doses too high?; steroid resistance

High dose bronchodilators

potentiation of allergen; down-regulation of receptors

CSIT
wide PF variation

Steroid sparers
methotrexate, cyclosporin, gold

Immunoglobulin? LTRAs NCEs

e.g. anti-IgE; anti-Il5 etc

Indications for CSIT

Type 1 brittle asthma

Wide variation in peak flow despite maximal medical therapy

Very effective in around 50% Of some benefit in around 25% Not useful in

Type 2 brittle asthma Severe asthma without airflow variability as an N-of-1 double blind placebo controlled trial

Must be introduced as an in-patient

CSIT positive responder

female aged 52

CSIT placebo responder

female aged 30

Run in usual treatment

CSIT patient related problems

Variably reported

Weight gain? Poor concentration Vivid dreams Poorer perception of onset of an acute attack Body Image/Social

2-agonist-related

tremor palpitations anxiety muscle cramps elevated CK

Not a problem : hypokalaemia myocarditis

CSIT patient related problems

Infusion sites
Haematomas Abscesses Nodules (eosinophilic)

Needle allergy
Plaster allergy

CVADs
Infection
Major vein thrombosis

Management

Management of psychological aspects of Type 1 brittle asthma

Holistic approach with target setting Individual cognitive behavioural therapy Anxiety/stress targetting Group therapy Psycho-tropic drugs
Respiratory depressant effects Use higher in studies of asthma deaths

Overall management of Type 1 brittle asthma

Identify causal factors - and deal with them

e.g. allergens, occupation, foods

Direct admission policy if possible Address anxiety/panic/other psycho-social factors MedicAlert bracelet or equivalent Multi-disciplinary approach Ensure treatment is appropriate

mostly at Step 5 of the guidelines

Beware iatrogenic problems

Management of Type 2 brittle asthma

Identify triggers Medicalert Maintenance ICS Sub-cut adrenaline

Brittle asthma mad? bad? dangerous to know?

Byron