Thorax 1998;53:315321

315

Brittle asthma
Jon G Ayres, Jon F Miles, Peter J Barnes

The term brittle asthma was first used in

1977 to describe patients with asthma who
maintained a wide variation in peak expiratory
flow (PEF) despite high doses of inhaled
steroids.1 It was coined at a time when patterns
of PEF variability were beginning to be
described with respect to clinical patterns of
disease, such as the morning dip in PEF1 2 and
the double dip pattern of morning and
evening dips3 seen in patients with less well
controlled asthma. The brittle asthmatic PEF
pattern of variability was identified as a
separate group, being described as chaotic
showing no such obvious repeating pattern.
The significance of the brittle pattern was not
completely clear at that time, although the
inference was that these patients had more
severe asthma that was, by definition, more difficult to control. Three papers published
shortly afterwards showed that this chaotic
pattern of PEF could lead to death from an
acute severe attack46 and the authors raised the
possibility that these patients tended to be
poorly compliant with treatment. Nevertheless,
not all non-compliant patients showed this
chaotic pattern, so clearly other factors were
important. However, it is not clear how these
patients would fit into a classification of severe
asthma which would include all those patients
at risk of death or repeated hospital admissions.
Some physicians are unhappy with brittle
asthma being classified as a separate asthma
phenotype, regarding these patients as simply
the severe end of the spectrum. However, it is
our belief that definition of diVering asthma
phenotypes is important, so what follows
represents our view that brittle asthma should
be considered as a specific asthma phenotype.
We suggest how further study of patients of this
type may help in unravelling the pathogenesis
and treatment of at risk asthma.

Heartlands Research
Institute, Birmingham
Heartlands Hospital,
Birmingham B9 5SS,
UK
J G Ayres
J F Miles
National Heart and
Lung Institute, London
SW3 6LY, UK
P J Barnes
Correspondence to:
Professor J G Ayres.

Definitions
After Turner-Warwicks initial definition of
brittle asthma, the term began to become used
in diVerent ways by diVerent physicians and in
the first British Thoracic Society Asthma
Guidelines7 the term was used solely to
describe those patients with sudden, severe, life
threatening attacks, usually out of the blue.
However, studies of asthma deaths have
consistently identified PEF variability as a risk
factor for death.46 8 More recently a definition
of brittle asthma based on PEF variability,
amount of treatment, and repeated attacks has
been proposed.9 Brittle asthma was defined as a
diurnal PEF variability (amplitude % maximum) of >40% for more than 50% of the time
(for example, 16 days a month) despite
maximal medical treatmentnamely, high
doses of inhaled corticosteroids with repeated
doses of inhaled bronchodilator, often by neb-

uliser, and maintenance or courses of oral

corticosteroids.9 However, it became apparent
that this definition of asthma based on PEF
variability required scrutiny if it was to be used
as a tool for epidemiological studies into severe
asthma. The definition itself lacked precision
since the phrase considerable medical
therapy did not specify precise doses of treatment such as inhaled steroid dose or use of
nebulised bronchodilators. In addition, there
was no clear idea of the duration of observation
necessary before the label brittle asthma
could be applied. Further doubts were cast on
a predominantly PEF based definition of brittle
asthma when the reliability of PEF meter readings came under question. Recent evidence
indicates that several makes of hand held
mechanical PEF meters show non-linear inaccuracy in their readings such that they tend to
underestimate low and high PEF readings
whereas the mid range readings are
overestimated.10 11 As a result, a prospective
evaluation of more than 10 000 patient days of
PEF data from patients with severe asthma was
undertaken, correcting for PEF meter inaccuracy. A specified dose of inhaled corticosteroid
therapy was usednamely, more than 1.5 mg
per day beclomethasone or budesonide or
more than 0.75 mg inhaled fluticasone propionate dailyand a definite period (150 consecutive days) over which such variability
occurred was employed to overcome the
transient PEF variability12 seen after acute
exacerbations or allergen exposures. Although
it is our impression that a period of three
months may be an acceptable period over
which to assess variability in the clinical
context, this tighter case definition is needed
for epidemiological work and was used in a
series of studies which explored aetiological/
risk factors for brittle asthma.
However, this definition does not take into
account those patients who are subject to sudden severe life threatening attacks often on a
background of apparently good asthma control. Premenstrual asthma may be one such
example as some women develop a marked
drop in PEF in the few days before
menstruation.13 Sometimes these premenstrual
exacerbations are so severe that they necessitate ventilation. To allow for this the following
classification of brittle asthma is suggested:
Type 1 brittle asthma: characterised by a
maintained wide PEF variability (>40% diurnal variation for >50% of the time over a period
of at least 150 days) despite considerable
medical therapy including a dose of inhaled
steroids of at least 1500 g of beclomethasone
(or equivalent) (fig 1, lower plot).
Type 2 brittle asthma: characterised by sudden
acute attacks occurring in less than three hours
without an obvious trigger on a background of

316

Ayres, Miles, Barnes

Peak expiratory flow (l/s)

600
500
400
300
200
100
0

Days
Figure 1 Peak flow chart in a patient with type 1 brittle asthma before (C) and after (x)
treatment with continuous subcutaneous terbutaline.

apparent normal airway function or well

controlled asthma.
These definitions may not include all
patients who suVer repeated severe attacks and
who might be labelled as having brittle asthma,
but when beginning to try to disentangle these
severe patients an initial definition has to be
attempted. Future work may show that these
definitions may not stand up to critical analysis
and alternatives might be found. For instance,
attention could be given to assessment of 100
and 50 day periods of peak flow variability as
criteria for inclusion as a definition. However,
as they stand they do provide a basis for
research in this area.
Epidemiology
Little is known about the incidence or
prevalence of brittle asthma, partly because of
the problems with definition discussed above.
There is no doubt that it is rare but it is not
possible to estimate the prevalence from any of
the studies of near miss asthma. The West
Midlands Brittle Asthma Register has identified 76 patients with type 1 or 2 brittle asthma
within an approximate asthma population of
300 000. A conservative estimate of the
numbers not yet identified by the register
would be around 150, giving an overall prevalence for brittle asthma of 0.05% of all
asthmatic patients. The type 1 patient is more
likely to be female (2.5F:1M), most being aged
between 18 and 55 years,14 whereas in patients
with type 2 brittle asthma there appears to be
no sex diVerence. There is little information
available regarding peak flow variability prior
to death from asthma in children.15
MORTALITY

Patients with wide variations in PEF have an

increased risk of dying from acute asthma as
discussed above,46 8 but what proportion of
patients with brittle asthma die from their condition is not known.
HOSPITAL ADMISSIONS

Hospital admissions are frequent in patients

with type 1 brittle asthma, not only for acute
severe attacks but also for assessment and stabilisation and consequent substantial prescription of medication. Patients with type 2 brittle

asthma are admitted for acute severe asthma

but at erratic and unpredictable intervals,
although in general their use of health care
resources is less than that of the type 1 patients.
Both types of patient may require ventilation in
acute attacks, although there is no information
as to whether patients with either type 1 or type
2 brittle asthma are likely to need ventilation
for shorter or longer periods than ventilated
patients who do not have brittle asthma. It has,
however, been shown that patients ventilated
for acute severe asthma whose asthma attack
came on suddenly (less than three hours) are
more likely to be men and to have severe
acidosis due to extreme hypercarbia, but are
more likely to be ventilated for a relatively short
period of time.16 These patients would appear
to be similar to the patient with type 2 brittle
asthma. In the same study patients who were
ventilated after a period of unstable asthma
were likely to be ventilated for longer periods,
less likely to be so acidotic, and much more
likely to be female, perhaps similar to the
patients with type 1 brittle asthma. Rapid onset
attacks have also been shown to be associated
with a predominance of submucosal neutrophils compared with those with slower onset
attacks where eosinophils predominate,17 although this may reflect the kinetics of granulocyte infiltration. It is of interest that the type 2
attacks, being both rapid in onset and in recovery, are similar in that way to the attacks
suVered by the patients involved in the
Barcelona soya bean induced asthma
outbreaks18 which could lend support to the
hypothesis that allergic triggers are important
in type 2 brittle asthma.
MORBIDITY

Type 1 brittle asthma is a cause of significant

morbidity with frequent accident and emergency attendances and is a condition for which
large amounts of medication are prescribed.
Patients with type 1 disease are very likely to be
using maintenance oral steroids (40% in the
Birmingham series) and to suVer the eVects of
such therapyfor example, osteoporosis and
weight gain. They also suVer almost uniformly
from oesophageal reflux19 which may be due in
part to their treatment with high doses of bronchodilators and consequent oesophageal
smooth muscle relaxation. Preliminary findings suggest that these patients do, however,
have reduced values of both total lung capacity
and functional residual capacity at around 80%
predicted compared with control patients
without brittle asthma,20 which would support
the idea that these patients generate more
negative intrapleural pressures resulting in
reflux.
Risk factors
There are very few data available on risk factors
for type 1 brittle asthma, and it is not possible
to extract specific risk factors from the studies
of asthma deaths with respect specifically to
those patients with variable PEF prior to death.
In the Birmingham case control study of type 1
brittle asthma14 atopy, psychosocial factors, and
food intolerance appeared to be important

317

Brittle asthma

associations. We believe that patients with type

1 brittle asthma can spiral down into a brittle
state by combinations of various initiating and
exacerbating factors, although it is as yet
unclear why a particular individual becomes
brittle. For patients with type 2 disease there
are no published data on risk factors.
ATOPY

Over 90% of patients with type 1 brittle asthma

are atopic as defined by at least one positive
(>4 mm diameter weal) skin prick test greater
than the response to a negative control.14 The
degree of positivitythat is, the cumulative
size of the weals to those allergens testedwas
more than twice that of a control group
matched for age, sex, and dose of inhaled steroid. In particular, responses were greater for
horse, cat, wheat, and chocolate. The reaction
to Dermatophagoides pteronyssinus was not
statistically diVerent between the two groups,
although RAST test responses to Der p 1 were
greater in the type 1 patients. It is diYcult to be
sure what this finding indicates, particularly as
there was no diVerence between the two groups
in terms of total IgE14 regarded by some as the
bench mark for atopy.21 These findings would,
however, be compatible with the hypothesis
that type 1 brittle asthma is associated with
increased sensitisation to common allergens.
However, there is also increasing evidence that
viral infections22 and asthma medication, in
particular 2 agonists,23 may increase IgE
synthesis. However, the causes of increased
atopy in patients with brittle asthma remain to
be explained.
Some patients with type 2 brittle asthma may
be triggered by exposure to aeroallergens such
as fungal spores. Alternaria spores have been
identified as a cause of sudden and severe
asthma attacks in some patients24 although
positivity to Alternaria was rare in the Birmingham study of type 1 brittle asthma.14
RELATIVE IMMUNOGLOBULIN DEFICIENCY

In a study of patients with severe asthma, most

of whom had type 1 brittle asthma, mean
circulating IgG and IgA levels were lower, a
finding which seemed to be unrelated to the
current dose of oral steroid taken by each
patient.25 This might suggest an impairment of
local immunity which increases susceptibility
of these patients to respiratory infections. Preliminary findings from a double blind placebo
controlled study of immunoglobulin replacement in these patients showed no benefit over a
three month treatment period,26 although the
dose of immunoglobulin used was lower than
that normally employed in the treatment of
combined humoral immunodeficiency states.
FOOD INTOLERANCE

Two thirds of patients with type 1 brittle

asthma report at least one foodstuV which
makes their asthma worse (Ayres, unpublished
observations), with 20% reporting allergic
reactions to peanuts, an allergy known to be
occasionally fatal.27 Equivalent data for patients
with type 2 disease are not yet available. However, in the Saskatchewan study relating

prescriptions to death and near death in

asthma there was a significant association
between a history of asthma symptoms after
eating certain foods and the risk of death or
near death.28
PSYCHOSOCIAL FACTORS

A case-control study of patients with severe

asthma, many of whom had type 1 brittle
asthma, showed an increase in psychosocial
morbidity with increases in both General
Health Questionnaire (GHQ60) and life events
scores.29 A subsequent study of patients with
type 1 brittle asthma, also of case-control
design, has confirmed the finding of increased
psychosocial morbidity30 with significantly
greater GHQ60 scores and poorer quality of
life
scores
(Living
with
Asthma
questionnaire31). This study also demonstrated
abnormal coping strategies for managing deteriorating asthma in these patients. They delay
going for medical help, self-treating by increasing agonist use and trying to avoid either
starting or increasing oral steroids if at all possible. A study of group support in eight type 1
patients showed significant reductions in
medication use, particularly oral steroid, with a
tendency to improvement in quality of life
scores over a six month period, although these
improvements were of modest degree.32
It is diYcult to be certain whether brittle
asthma is associated with personality disorder
or whether the threat of severe asthma induces
psychological instability. Certainly these patients often cope badly with deteriorating
asthma and show clear evidence of panic in
their responses.
POOR PERCEPTION

There is evidence that patients who have had

near fatal asthma attacks have a reduced
perception of worsening airway function33 34
and this might be a relevant factor in both type
1 and type 2 brittle asthma.35 Whether
impaired perception of asthma is inherited or
acquired is not yet certain. Patients with previous episodes of near fatal asthma also have a
reduced hypoxic drive, even when their lung
function is normal, suggesting that during an
acute exacerbation they may not have a normal
ventilatory response.36 37
BETA-AGONISTS

The role of agonists as a causal factor in

death from asthma has been much discussed
and remains controversial.3743
Although normally prescribed doses of
inhaled 2 agonists are likely to be safe, some
patients with type 1 brittle asthma take
excessive doses, particularly with home nebulisers, when doses of more than 30 mg of
salbutamol daily are often used. There is some
evidence that high concentrations of 2 agonists
result in impaired glucocorticoid actions in
vitro.44 If extrapolated to the clinical situation,
this suggests that high doses of 2 agonists may
induce steroid resistance and worsen control of
asthma; this could be relevant to patients with
type 1 brittle asthma and would appear to
support the original epidemiological data.

318

Ayres, Miles, Barnes

However, more recent studies from New

Zealand45 46 suggest that the associations from
earlier work were largely due to residual
confounding by severity. This would also help
to explain the apparent paradox of patients
with type 1 brittle asthma being eVectively
treated by continuous subcutaneous terbutaline (see section on Treatment below).
Possible underlying mechanisms
INVESTIGATION

Any attempts to elucidate possible mechanisms

in brittle asthma are hampered by the diYculties in establishing clear cut definitions, as discussed above. Furthermore, these patients are
diYcult to investigate because of the potential
danger of invasive investigations. Even the
measurement of bronchial reactivity may be
contraindicated in such patients. Many patients find that more than one forced expiratory
manoeuvre is enough to cause significant
worsening of their condition without adding a
further bronchoconstricting stimulus. Although fibreoptic bronchoscopy has proved
extremely valuable in elucidating the inflammatory mechanisms of asthma,4749 it is not
known whether these techniques may be
applied safely to patients with brittle asthma. It
is likely, therefore, that advances in knowledge
on mechanisms are more likely to occur
through other investigative means.
Non-invasive methods such as exhaled nitric
oxide (NO)50 or measures of inflammatory
mediators such as urinary leukotriene E4,51
plasma cytokines such as interleukin 5,52 and
eosinophil cationic protein53 may also shed
light on the degree and nature of the
inflammatory process in brittle asthma. Induction of sputum using hypertonic saline5456
might in theory be useful but is likely to cause
severe bronchoconstriction in this group of
patients.
It remains, however, of particular importance to determine whether the inflammatory pattern is the same in brittle asthma as in
the other types of asthma, whether the expression of cytokines and inflammatory enzymes is
similar, and whether there are structural
abnormalities, including innervation, that differ from the findings in mild asthmatic patients.
ACUTE AIRWAY NARROWING

The mechanisms of the sudden severe airway

narrowing that characterises brittle asthma are
unclear. It is likely that airway smooth muscle
contraction is an important component, although this is not readily reversed by doses of
2 agonists which suggests that oedema of the
airways due to plasma exudation from leaky
post-capillary venules may play a part. As
discussed earlier, patients who die from asthma
attacks of sudden onset have airways characterised by infiltration of neutrophils rather than
eosinophils17 which suggests either that neutrophils appear earlier than eosinophils in any
given asthma attack or that this is a characteristic of patients with attacks of precipitous
onset.
Irritants might induce rapid airway narrowing via activation of a cholinergic reflex

bronchoconstriction, but also by the activation

of a local or axon reflex via the release of bronchoconstrictor and inflammatory peptides
from airway sensory nerves,57 substance P,58
and other tachykinins.59
The association between food allergy and
brittle asthma may suggest that an anaphylactic
reaction could occur in the airways, and a
major component of this response might be
airway oedema. The therapeutic consequences
of this might be important as adrenaline,
through its -adrenoceptor anti-oedema action, might be expected to be more eVective
than a 2 agonist in relieving airway obstruction.
Another airway component that may contribute to airway narrowing in brittle asthma is
the airway vasculature through acute vasodilatation or venous congestion in the bronchial
circulation resulting in airway narrowing.60
STEROID RESPONSIVENESS

Patients with type 1 brittle asthma are usually

treated with high doses of inhaled and/or oral
steroids, yet their asthma often remains poorly
controlled which suggests that there may be a
degree of resistance to the anti-inflammatory
eVects of steroids. True steroid resistance in
asthma is very rare61 but relative resistance to
the anti-asthma eVect of steroids is more common. In severe asthma, where there is an
intense inflammatory response, there may be
excessive activation of AP-1 and other transcription factors that bind to, and therefore
consume, glucocorticoid receptors.62 This
could then reduce the response to inhaled and
oral steroids, resulting in a secondary steroid
resistance. Whether this is a factor in brittle
asthma is not yet clear, but recent studies in
patients with steroid resistant asthma have
demonstrated a marked inflammatory response
in the airways despite the fact that these
patients have been treated with steroids.48 49
Treatment
COMPLIANCE

Patients with brittle asthma are, by definition,

extremely diYcult to manage. Many of them
have fallen out with their doctor who, perhaps
understandably, has run out of therapeutic
options and often patience. The standard management guidelines such as the BTS
guidelines7 are inapplicable to these patients
once they have become brittle. They are taking
large doses of inhaled steroids and the only way
to increase the dose when the condition worsens is to resort to oral steroids which many
resist because of side eVects. Many patients
also use very large doses of 2 agonists, taken
either as a metered dose inhaler (often more
than one canister per week) or through a nebuliser, often using more than 30 mg of 2 agonist daily. It is therefore essential that the physician realises that what the patient wishes to
say and do concerning management assumes a
greater importance than in ordinary asthma.
Non-compliance (or non-adherence) has
been much studied in mild to moderate
asthma, and is recognised to result from
interaction of many factors, particularly

319

Brittle asthma

psychosocial factors.63 The same is true of

patients with brittle asthma who often try quite
bizarre management tricks to avoid having to
start or increase a dose of oral steroids. If the
physician is prepared to barter with the brittle
asthmatic patient, then advances can be made,
albeit slowly. Large improvements in control
are unlikely in one step and many patients have
over-ambitious hopes of how much their
doctor can do. When these are not achieved
patients can regress psychologically, thinking
themselves or the medical care a failure. If this
overambition can be restrained and more
achievable and realistic targets set, then success
can be achieved. Small successes, if perceived
as such by the patient, can prove psychologically very helpful in the short term.
ALLERGEN AVOIDANCE

Control of allergen exposure may be of help in

these patients although there is only anecdotal
evidence that this is eVective. The logistics of
allergen control are great, not only in terms of
practicality but also cost. Many patients with
type 1 brittle asthma have animals at home and
removal of what is often their best companion
will be met with resistance. Unpublished data
from the Birmingham group show that patients
with brittle asthma are exposed to much higher
levels of pet allergens (but not house dust mite)
than other asthmatics, but whether this will
result in removal of pets and important reductions in allergen exposure in this severe group
remains in doubt.
STEROIDS

These patients by definition are using high

doses of inhaled and/or oral steroids, and the
possibility of steroid resistance in at least some
of these patients has been raised, as discussed
above. Whether alternative immunomodulatory treatment such as methotrexate or cyclosporin A will be eVective is not yet certain.
SUBCUTANEOUS 2 AGONISTS

Patients with type 1 brittle asthma can be

treated with a long term continuous subcutaneous infusion of 2 agonist, usually terbutaline
(CSIT), at doses of 312 mg/day.64 65 Using a
two day single blind period of subcutaneous
saline before increasing through the doses of
terbutaline, about 50% of patients with type 1
brittle asthma showed considerable improvements in symptoms, variation in PEF (fig 1),
and use of other asthma medication including
oral steroids, about 25% showed some improvement in symptoms but less improvement
in PEF, while the remainder did not seem to
respond.10 Chronic steroid dependent asthmatics without a wide variability in PEF did not
respond. Although mean blood levels of terbutaline achieved by this technique are around
150 nmol/l,66 similar to those seen in patients
who have taken deliberate overdoses of
terbutaline,67 changes in serum potassium or
glucose levels are rare (unpublished data)
which suggests tolerance to the side eVects of
this form of treatment.
The reason why subcutaneous agonists
rather than high dose nebulised agonists are

eVective is far from certain and deserves

further investigation. However, the fact that
inhaled 2 agonists cause measurable and
reproducible further bronchodilation in patients on CSIT68 suggests that there may be a
separate population of receptors which are
not accessible by the infused route. There is
evidence from animal studies that two such
populations exist in the major airways.69
There are problems with CSIT which, in
some patients, prove too much to continue the
treatment. The main problem is the development of subcutaneous nodules or inflammatory lesions. The more indolent form show an
eosinophilic infiltrate on biopsy specimens.70
These usually settle down once that area of skin
is avoided, but often leave a fibrotic nodule.
More recently a more aggressive type of lesion
has been demonstrated which sometimes leads
on to frank abscess formation, the pus from
which is usually sterile. The formulation of the
drug has not changed nor have the preservatives, so the reason for these changes is not
clear, but preliminary findings suggest that
sensitivity to latex in the rubber tip of the
syringe plunger is not involved.71 Although the
use of nebuliser solution rather than the injectable form of terbutaline may help, in some the
skin changes are so severe that administration
has to be changed to continuous intravenous
infusion via an indwelling line. Muscle cramps
are common and sometimes may be severe,
with an increase in the plasma levels of creatinine phosphokinase72 although levels of the
myocardial fraction are normal. Some patients
complain of an eVect on memory and ability to
concentrate but these have not been formally
studied. Occasionally menorrhagia is seen9 but
this is not usually severe.
LONG ACTING INHALED 2 AGONISTS

In view of the marked fluctuations in PEF and

the eYcacy of subcutaneous 2 agonist infusions, it might be expected that long acting
inhaled 2 agonists would be eVective in stabilising the airways. However, in our experience
salmeterol has proved to be disappointing in
these patients for reasons that are not yet clear.
Whether formoterol, which is a full agonist,
may be more useful than salmeterol, a partial
agonist, remains to be determined. There is an
anecdotal report of a patient showing symptomatic and lung function improvement with
formoterol, but not to salmeterol.73
ADRENALINE

Adrenaline may have theoretical advantages

over selective 2 agonists, because of its action
as an -adrenoceptor against reducing airway
oedema as discussed in the section on acute
airway narrowing above. Preloaded syringes
(Epi-Pen; Ana Pen) may be useful as an emergency treatment, particularly for patients with
type 2 brittle asthma with their unexpected and
rapidly progressive attacks. It is not yet certain
whether inhaled adrenaline may be more eVective than a selective 2 agonist inhaler.

320

Ayres, Miles, Barnes

NOVEL THERAPIES

New therapeutic approaches are urgently

needed in the management of brittle asthma.
The logical development of such treatments
will depend partly on our increased understanding of the mechanisms involved. In type 1
brittle asthma an alternative to steroids appears
to be indicated. Whether novel antiinflammatory treatments such as type IV phosphodiesterase inhibitors or cytokine inhibitors
will prove to be useful is not yet certain. The
sudden and reversible airway narrowing in
brittle asthma may be due to noninflammatory mechanisms and alternative
treatments such as tachykinin antagonists or
opioids may prove to be useful in the future.
Anti-leukotrienes (leukotriene receptor antagonists or 5-lipoxygenase inhibitors) may
have a place in the management of some
patients with type 1 brittle asthma. Some
patients with more severe asthma appear to
respond to this group of drugs74 which would
merit a trial in patients with brittle asthma.
Psychogenic mechanisms are clearly important in some patients with brittle asthma, yet
little attention has been paid to the influence of
psychological factors on airway responses and
whether these could be modified by some
forms of psychological treatment such as
conditioning. Group therapy may have a role in
some circumstances but attention to coping
with deteriorating asthma may help to reduce
the amount of treatment used and may have an
impact on hospital admissions.
Summary
We believe that the asthma phenotypes we have
defined as types 1 and 2 brittle asthma appear
to be defined subgroups of asthma. For example, we have characterised patients with type 1
brittle asthma, as defined in this review, on the
basis of peak flow variability and treatment and
these patients remain a separate group when
assessed by other means such as psychosocial
factors, immunoglobulin levels, and atopy. The
question remains as to whether they are truly
separate groups with entirely diVerent pathogenetic influences or whether they simply represent the severe end of the spectrum.
Our suggested classification into types 1 and
2 forms a useful start for studies of this condition, although prospective evaluation of patients with severe asthma is the only way of
substantiating the validity of these definitions
which will then enable investigation of possible
mechanisms. However, these patients are rare
and in order to study them as a group a
national register would need to be set up along
the lines of the West Midlands Brittle Asthma
Register, perhaps recruiting all at risk
patients and then using this resource as a
means of exploring the diVerent asthma
phenotypes within this broad grouping, including brittle asthma.
1 Turner Warwick M. On observing patterns of airflow
obstruction in chronic asthma. Br J Dis Chest 1977;71:73
86.
2 Clark TJH, Hetzel MR. Diurnal variation of asthma. Br J
Dis Chest 1977;71:8792.
3 Connolly CK. Diurnal rhythms in airway obstruction. Br J
Dis Chest 1979;73:35766.

4 Bateman JRM, Clarke SW. Sudden death in asthma. Thorax

1979;34:4043.
5 Westerman DE, Benatar SR, Portgieter PD, et al. Identification of high risk asthmatic patients. Am J Med 1979;66:
56572.
6 Hetzel MR, Clark TJH, Branthwaite MA. Asthma: analysis
of deaths and ventilatory arrests in hospital. BMJ
1978;408:80811.
7 British Thoracic Society, British Paediatric Association,
Royal College of Physicians of London et al, Guidelines on
the management of asthma. Thorax 1993;48(Suppl):S1
24.
8 Boulet L-P, Deschesnes F, Turcotte H, et al. Near fatal
asthma: clinical and physiologic features, perception of
bronchoconstriction and psychologic profile. J Allergy Clin
Immunol 1991;88:83846.
9 ODriscoll BRC, RuZes SP, Ayres JG, et al. Long term
treatment of severe asthma with subcutaneous terbutaline.
Br J Dis Chest 1988;82:3605.
10 Miller MR, Dickinson SA, Hitchings DJ. The accuracy of
portable peak flow meters. Thorax 1992;47:9049.
11 Gardner RM, Crapo RO, Jackson BR, et al. Evaluation of
accuracy and reproducibility of peak flow meters at 1400
m. Chest 1992;101:94852.
12 Newman Taylor AJ, Davies RJ, Hendrick DJ, et al.
Recurrent nocturnal asthmatic reactions to bronchial
provocation tests. Clin Allergy 1979;9:2139.
13 Beynon HLC, Garbett ND, Barnes PJ. Severe premenstrual
exacerbations of asthma: the eVect of intramuscular
progesterone. Lancet 1988;ii:3702.
14 Miles JF, Cayton RM, TunnicliVe WS, et al. Increased
atopic sensitization in brittle asthma. Clin Exp Allergy
1995;25:107482.
15 Carswell F. Thirty deaths from asthma. Arch Dis Child
1985;60:258.
16 Wasserfallen JB, Schaller MD, Feihl F, et al. Sudden
asphyxic asthma: a distinct entity? Am Rev Respir Dis 1990;
142:10811.
17 Sur S, Crotty TB, Kephart GM, et al. Sudden onset fatal
asthma: a distinct entity with few eosinophils and relatively
more neutrophils in the airway submucosa. Am Rev Respir
Dis 1993;148:7139.
18 Picado C. Barcelonas asthma epidemics: clinical aspects
and intriguing findings. Thorax 1992;47:197200.
19 Miles JF, Noble K, Matthews HR, et al. Gastro-oesophageal
reflux in patients with brittle asthma. Respir Med (submitted for publication).
20 Miles JF, Sapiano S, Cayton RM, et al. Lung function tests
in patients with brittle asthma. Am J Respir Crit Care Med
1995;151:A676.
21 Morton NE. Major loci for atopy? Clin Exp Allergy 1992;22:
10413.
22 Lemanske Jr RF, Dick EC, Swenson CA, et al. Rhinovirus
upper respiratory infection increases airway hyperractivity
and late asthmatic reactions. J Clin Invest 1989;83:110.
23 Coqueret O, Dugas B, Mencia-Huerta JM, et al. Regulation
of IgE production from human mononuclear cells by
-adrenoceptor agonists. Clin Exp Allergy 1995;25:30411.
24 OHolloren MJ, Yunginger JW, OVord KP, et al. Exposure to
aeroallergens as a possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med
1991;324:35963.
25 Ayres JG, Thompson RA. IgG sub-class deficiency in brittle
asthma and in patients with recurrent infective exacerbations of asthma. Respir Med 1997;91:4649.
26 Shaheen MZ, Barker R, Drayson M, et al. Randomised
double-blind cross over trial of immunoglobulin replacement therapy in patients with severe asthma. Thorax 1992;
47:254.
27 Loza C, BrostoV J. Peanut allergy. Clin Exp Allergy 1995;25:
493502.
28 Ernst P, Habbick B, Suissa S, et al. Is the association
between inhaled beta-agonist use and life-threatening
asthma because of confounding severity? Am Rev Respir Dis
1993;148:759.
29 Garden GMF, Ayres JG. The psychiatric and social aspects
of brittle asthma. Thorax 1993;48:5015.
30 Miles JF, Garden GM, TunnicliVe W, et al. Psychological
morbidity and coping skills in patients with brittle and
non-brittle asthma: a case-control study. Clin Exp Allergy
1997;27:11519.
31 Hyland ME, Finnis S, Irvine SH. A scale for measuring
quality of life in adult asthma suVerers. J Psychosom Res
1991;35:99110.
32 Miles JF, Garden G, Ayres JG. Group therapy in the
management of chronic severe asthma. Thorax 1993;48:
1065.
33 Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and
perception of dyspnoea in patients with a history of
near-fatal asthma. N Engl J Med 1994;330:131924.
34 Barnes PJ. Poorly perceived asthma. Thorax 1992;47:4089.
35 Barnes PJ. Blunted perception and death from asthma. N
Engl J Med 1994;330:13834.
36 Town GI, Allan C. Ventilatory responses to hypoxia and
hypercapnia in asthmatics with previous respiratory failure.
Aust NZ J Med 1989;19:42630.
37 Johnson AJ, Somner AR, Stableforth DE, et al. Circumstances of death from asthma. BMJ 1984;288:18702.
38 Inman WHW, Adelstein AM. Rise and fall of asthma
mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1969;ii:27985.
39 Sears MR, Beaglehole R. Asthma morbidity and mortality
in New Zealand. J Allergy Clin Immunol 1987;80:3838.

321

Brittle asthma
40 Speizer FE, Doll R, Heaf P. Observations on recent increase
in mortality from asthma. BMJ 1968;1:3359.
41 Crane J, Flatt A, Jackson R, et al. Prescribed fenoterol and
death from asthma in New Zealand. Lancet 1989;i:91722.
42 Pearce N, Beasley R, Crane J, et al. EVect of the New Zealand asthma mortality epidemic. Lancet 1995;345:414.
43 Sears MR, Taylor DR, Print DG, et al. Regular inhaled beta
agonist treatment in bronchial asthma. Lancet 1990;336:
19916.
44 Peters MJ, Adcock IM, Brown CR, et al. Beta-adrenoceptor
agonists interfere with glucocorticoid receptor DNA binding in rat lung. Eur J Pharmacol 1995;289:27581.
45 Garrett JE, Kolbe J, Rea HH, et al. Risk of severe life threatening asthma (SLTA) and type of prescribed -agonist: an
example of confounding by severity. Aust NZ Med J 1994;
24:433.
46 Garrett J, Kolbe J, Richards G, et al. Major reduction in
asthma morbidity and continued reduction in asthma
mortality in New Zealand: what lessons have been learned?
Thorax 1995;50:30311.
47 Djukanovic R, Roche UR, Wilson JW, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990;142:43457.
48 Matusiewicz SP, Brown PH, Wallace WAH, et al. Bronchial
mucosal inflammation in patients with corticosteroid sensitive (CS) and corticosteroid resistant (CR) chronic asthma.
Thorax 1993;48:10601.
49 Leung DYM, Martin RJ, Szefler SJ, et al. Dysregulation of
interleukin 4, interleukin 5, and interferon gamma gene
expression in steroid resistant asthma. J Exp Med
1995;181:3340.
50 Barnes PJ, Kharitonov SA. Exhaled nitric oxide: a new lung
function test. Thorax 1996;51:2337.
51 Taylor GW, Taylor IK, Black P, et al. Urinary leukotriene E4
following allergen challenge and in patients with acute
asthma and allergic rhinitis. Lancet 1989;i:5848.
52 Corrigan CJ, Haczku A, Gemou-Engesaeth V, et al. CD4
T-lymphocyte activation in asthma is accompanied by
increased serum concentration of interleukin-5. Am Rev
Respir Dis 1993;147:5407.
53 Wever AM, Wever-Hess J, Hensgens HES, et al. Serum eosinophil cationic protein (ECP) in chronic asthma. Relationship to spirometry, flow-volume curves, PC20 and exacerbations. Respir Med 1994;88:61321.
54 Pin I, Gibson PG, Kolendowicz R, et al. Use of induced
sputum cell counts to investigate airway inflammation in
asthma. Thorax 1992;47:259.
55 Virchow JC, Hulscher U, Virchow C. Sputum ECP levels
correlate with parameters of airflow obstruction. Am Rev
Respir Dis 1992;146:6046.
56 Keatings VM, Collins PD, Scott DM, et al. Levels of
interleukin-8 but not tumour necrosis factor-beta induced
sputum discriminates between asthma and chronic obstructive pulmonary disease. Am J Resp Crit Care Med
1996;153:5304.

57 Barnes PJ. Sensory nerves, neuropeptides and asthma. Ann

N Y Acad Sci 1991;629:35970.
58 Lilly CM, Bai TR, Shore SA, et al. Neuropeptide contents of
lungs from asthmatic and non asthmatic subjects. Am J
Respir Crit Care Med 1995;151:54853.
59 Adcock IM, Peters M, Gelder C, et al. Increased tachykinin
receptor gene expression in asthmatic lung and its modulation by steroids. J Mol Endocrinol 1993;11:17.
60 Kuwano K, Boskev CH, Par PD, et al. Small airways dimensions in asthma and chronic obstructive pulmonary
disease. Am Rev Respir Dis 1993;148:12205.
61 Barnes PJ, Adcock IM. Steroid resistant asthma. Q J Med
1995;88:45568.
62 Adcock IM, Lane SJ, Brown CA, et al. Abnormal glucocorticoid receptor/AP1 interaction in steroid resistant asthma.
J Exp Med 1995;182:19518.
63 Bosley CM, Fosbury JA, Cochrane GM. The psychological
factors associated with poor compliance with treatment in
asthma. Eur Respir J 1995;8:899904.
64 Ayres JG. Subcutaneous terbutaline in the management of
brittle asthma. Br J Hosp Med 1992;47:56971.
65 Ayres JG, Fish DR, Wheeler DC, et al. Subcutaneous terbutaline and control of brittle asthma or appreciable morning
dipping. BMJ 1984;288:17156.
66 Sykes AP, Higgins AH, Ayres JG. Continuous subcutaneous
terbutaline is eVective in the treatment of brittle asthma by
achieving high serum terbutaline levels. Thorax 1987;42:
231.
67 Jarvie DR, Thompson AM, Dyson EH. Laboratory and
clinical features of self-poisoning with salbutamol and
terbutaline. Clin Chem Acta 1987;305:4858.
68 Sykes AP, Ayres JG. Further bronchodilatation from low
dose inhaled beta 2-agonists in patients receiving infused
terbutaline. Thorax 1991;46:319.
69 Wong LB, Miller IF, Yeates DB. Regulation of ciliary beat
frequency by autonomic mechanisms in vitro. J Appl
Physiol 1988;65:1895901.
70 Lewis LD, ODriscoll BRC, Hartley RB, et al. An unusual
local reaction to continuous subcutaneous infused terbutaline in unstable asthmatics. Br J Dis Chest 1987;81:18993.
71 TunnicliVe WS, Duncanson RC, Fletcher TJ, et al. Site
problems in type 1 brittle asthmatics using continuous subcutaneous infusions of terbutaline (CSIT) Thorax 1995;50:
(Suppl 2):A74.
72 Sykes AP, Lawson N, Finnegan JA, et al. Creatinine kinase
activity in patients with brittle asthma treated with
longterm subcutaneous terbutaline. Thorax 1991;46:580
3.
73 Ulrik CS, Kok-Jensen A. DiVerent bronchodilating eVect of
salmeterol and formoterol in an adult asthmatic. Eur Respir
J 1994;7:10035.
74 Israel E, Rubin P, Kemp JP, et al. The eVect of inhibition of
5-lipoxygenase, Zileuton, in mild-to-moderate asthma. Ann
Intern Med 1993;119:105966.