Thorax 1998;53:315–321 315 Brittle Thorax: first published as 10.1136/thx.53.4.315 on 1 April 1998. Downloaded from

Jon G Ayres, Jon F Miles, Peter J Barnes

The term “brittle asthma” was first used in uliser, and maintenance or courses of oral 1977 to describe patients with asthma who .9 However, it became apparent maintained a wide variation in peak expiratory that this definition of asthma based on PEF flow (PEF) despite high doses of inhaled variability required scrutiny if it was to be used steroids.1 It was coined at a time when patterns as a tool for epidemiological studies into severe of PEF variability were beginning to be asthma. The definition itself lacked precision described with respect to clinical patterns of since the phrase “considerable medical disease, such as the morning dip in PEF12and therapy” did not specify precise doses of treat- the “double dip” pattern of morning and ment such as inhaled steroid dose or use of evening dips3 seen in patients with less well nebulised bronchodilators. In addition, there controlled asthma. The brittle asthmatic PEF was no clear idea of the duration of observation pattern of variability was identified as a necessary before the label “brittle asthma” separate group, being described as chaotic could be applied. Further doubts were cast on showing no such obvious repeating pattern. a predominantly PEF based definition of brittle The significance of the brittle pattern was not asthma when the reliability of PEF meter read- completely clear at that time, although the ings came under question. Recent evidence inference was that these patients had more indicates that several makes of hand held severe asthma that was, by definition, more dif- mechanical PEF meters show non-linear inac- ficult to control. Three papers published curacy in their readings such that they tend to shortly afterwards showed that this chaotic underestimate low and high PEF readings pattern of PEF could lead to death from an 4–6 whereas the mid range readings are acute severe attack and the authors raised the overestimated.10 11 As a result, a prospective possibility that these patients tended to be evaluation of more than 10 000 patient days of poorly compliant with treatment. Nevertheless, PEF data from patients with severe asthma was not all non-compliant patients showed this undertaken, correcting for PEF meter inaccu- chaotic pattern, so clearly other factors were racy. A specified dose of inhaled important. However, it is not clear how these therapy was used—namely, more than 1.5 mg patients would fit into a classification of severe per day beclomethasone or budesonide or asthma which would include all those patients http://thorax.bmj.com/ more than 0.75 mg inhaled fluticasone propi- at risk of death or repeated hospital admissions. Some physicians are unhappy with brittle onate daily—and a definite period (150 con- asthma being classified as a separate asthma secutive days) over which such variability occurred was employed to overcome the phenotype, regarding these patients as simply 12 the severe end of the spectrum. However, it is transient PEF variability seen after acute our belief that definition of diVering asthma exacerbations or allergen exposures. Although phenotypes is important, so what follows it is our impression that a period of three represents our view that brittle asthma should months may be an acceptable period over be considered as a specific asthma phenotype. which to assess variability in the clinical on September 25, 2021 by guest. Protected copyright. We suggest how further study of patients of this context, this tighter case definition is needed type may help in unravelling the pathogenesis for epidemiological work and was used in a and treatment of at risk asthma. series of studies which explored aetiological/ risk factors for brittle asthma. However, this definition does not take into Definitions account those patients who are subject to sud- After Turner-Warwick’s initial definition of den severe life threatening attacks often on a brittle asthma, the term began to become used background of apparently good asthma con- in diVerent ways by diVerent physicians and in trol. Premenstrual asthma may be one such the first British Thoracic Society Asthma example as some women develop a marked Guidelines7 the term was used solely to drop in PEF in the few days before describe those patients with sudden, severe, life menstruation.13 Sometimes these premenstrual Heartlands Research threatening attacks, usually out of the blue. exacerbations are so severe that they necessi- Institute, Birmingham However, studies of asthma deaths have tate ventilation. To allow for this the following Heartlands Hospital, consistently identified PEF variability as a risk classification of brittle asthma is suggested: Birmingham B9 5SS, factor for death.4–6 8 More recently a definition Type 1 brittle asthma: characterised by a UK of brittle asthma based on PEF variability, maintained wide PEF variability (>40% diur- J G Ayres J F Miles amount of treatment, and repeated attacks has nal variation for >50% of the time over a period been proposed.9 Brittle asthma was defined as a of at least 150 days) despite considerable National Heart and diurnal PEF variability (amplitude % maxi- medical therapy including a dose of inhaled Lung Institute, London mum) of >40% for more than 50% of the time steroids of at least 1500 µg of beclomethasone SW3 6LY, UK (for example, 16 days a month) despite (or equivalent) (fig 1, lower plot). P J Barnes maximal medical treatment—namely, high Type 2 brittle asthma: characterised by sudden Correspondence to: doses of inhaled corticosteroids with repeated acute attacks occurring in less than three hours Professor J G Ayres. doses of inhaled bronchodilator, often by neb- without an obvious trigger on a background of 316 Ayres, Miles, Barnes

600 asthma are admitted for but at erratic and unpredictable intervals, Thorax: first published as 10.1136/thx.53.4.315 on 1 April 1998. Downloaded from 500 although in general their use of health care resources is less than that of the type 1 patients. 400 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 300 2 brittle asthma are likely to need ventilation for shorter or longer periods than ventilated 200 patients who do not have brittle asthma. It has, however, been shown that patients ventilated Peak expiratory flow (l/s) 100 for acute severe asthma whose asthma attack came on suddenly (less than three hours) are 0 12 3 4 567 more likely to be men and to have severe acidosis due to extreme hypercarbia, but are Days more likely to be ventilated for a relatively short Figure 1 Peak flow chart in a patient with type 1 brittle asthma before (C) and after (x) period of time.16 These patients would appear treatment with continuous subcutaneous terbutaline. to be similar to the patient with type 2 brittle apparent normal airway function or well asthma. In the same study patients who were controlled asthma. ventilated after a period of unstable asthma These definitions may not include all were likely to be ventilated for longer periods, patients who suVer repeated severe attacks and less likely to be so acidotic, and much more who might be labelled as having brittle asthma, likely to be female, perhaps similar to the but when beginning to try to disentangle these patients with type 1 brittle asthma. Rapid onset severe patients an initial definition has to be attacks have also been shown to be associated attempted. Future work may show that these with a predominance of submucosal neu- definitions may not stand up to critical analysis trophils compared with those with slower onset and alternatives might be found. For instance, attacks where eosinophils predominate,17 al- attention could be given to assessment of 100 though this may reflect the kinetics of granulo- and 50 day periods of peak flow variability as cyte infiltration. It is of interest that the type 2 criteria for inclusion as a definition. However, attacks, being both rapid in onset and in recov- as they stand they do provide a basis for ery, are similar in that way to the attacks research in this area. suVered by the patients involved in the Barcelona soya bean induced asthma outbreaks18 which could lend support to the Epidemiology hypothesis that allergic triggers are important http://thorax.bmj.com/ Little is known about the incidence or in type 2 brittle asthma. prevalence of brittle asthma, partly because of the problems with definition discussed above. MORBIDITY There is no doubt that it is rare but it is not Type 1 brittle asthma is a cause of significant possible to estimate the prevalence from any of morbidity with frequent accident and emer- the studies of “near miss” asthma. The West gency attendances and is a condition for which Midlands Brittle Asthma Register has identi- large amounts of medication are prescribed. fied 76 patients with type 1 or 2 brittle asthma Patients with type 1 disease are very likely to be

within an approximate asthma population of using maintenance oral steroids (40% in the on September 25, 2021 by guest. Protected copyright. 300 000. A conservative estimate of the Birmingham series) and to suVer the eVects of numbers not yet identified by the register such therapy—for example, osteoporosis and would be around 150, giving an overall preva- weight gain. They also suVer almost uniformly lence for brittle asthma of 0.05% of all from oesophageal reflux19 which may be due in asthmatic patients. The type 1 patient is more part to their treatment with high doses of bron- likely to be female (2.5F:1M), most being aged 14 chodilators and consequent oesophageal between 18 and 55 years, whereas in patients smooth muscle relaxation. Preliminary find- with type 2 brittle asthma there appears to be ings suggest that these patients do, however, no sex diVerence. There is little information have reduced values of both total lung capacity available regarding peak flow variability prior 15 and functional residual capacity at around 80% to death from asthma in children. predicted compared with control patients without brittle asthma,20 which would support MORTALITY the idea that these patients generate more Patients with wide variations in PEF have an negative intrapleural pressures resulting in increased risk of dying from acute asthma as reflux. discussed above,4–6 8 but what proportion of patients with brittle asthma die from their con- Risk factors dition is not known. There are very few data available on risk factors for type 1 brittle asthma, and it is not possible HOSPITAL ADMISSIONS to extract specific risk factors from the studies Hospital admissions are frequent in patients of asthma deaths with respect specifically to with type 1 brittle asthma, not only for acute those patients with variable PEF prior to death. severe attacks but also for assessment and sta- In the Birmingham case control study of type 1 bilisation and consequent substantial prescrip- brittle asthma14 atopy, psychosocial factors, and tion of medication. Patients with type 2 brittle food intolerance appeared to be important Brittle asthma 317

associations. We believe that patients with type prescriptions to death and near death in 1 brittle asthma can spiral down into a brittle asthma there was a significant association state by combinations of various initiating and between a history of asthma symptoms after Thorax: first published as 10.1136/thx.53.4.315 on 1 April 1998. Downloaded from exacerbating factors, although it is as yet eating certain foods and the risk of death or unclear why a particular individual becomes near death.28 “brittle”. For patients with type 2 disease there are no published data on risk factors. PSYCHOSOCIAL FACTORS A case-control study of patients with severe ATOPY asthma, many of whom had type 1 brittle Over 90% of patients with type 1 brittle asthma asthma, showed an increase in psychosocial are atopic as defined by at least one positive morbidity with increases in both General (>4 mm diameter weal) skin prick test greater Health Questionnaire (GHQ60) and life events than the response to a negative control.14 The scores.29 A subsequent study of patients with degree of positivity—that is, the cumulative type 1 brittle asthma, also of case-control size of the weals to those allergens tested—was design, has confirmed the finding of increased more than twice that of a control group psychosocial morbidity30 with significantly matched for age, sex, and dose of inhaled ster- greater GHQ60 scores and poorer quality of oid. In particular, responses were greater for life scores (Living with Asthma horse, cat, wheat, and chocolate. The reaction questionnaire31). This study also demonstrated to Dermatophagoides pteronyssinus was not abnormal coping strategies for managing dete- statistically diVerent between the two groups, riorating asthma in these patients. They delay although RAST test responses to Derp1were going for medical help, self-treating by increas- greater in the type 1 patients. It is diYcult to be ing â agonist use and trying to avoid either sure what this finding indicates, particularly as starting or increasing oral steroids if at all pos- there was no diVerence between the two groups sible. A study of group support in eight type 1 in terms of total IgE14 regarded by some as the patients showed significant reductions in bench mark for atopy.21 These findings would, medication use, particularly oral steroid, with a however, be compatible with the hypothesis tendency to improvement in quality of life that type 1 brittle asthma is associated with scores over a six month period, although these increased sensitisation to common allergens. improvements were of modest degree.32 However, there is also increasing evidence that It is diYcult to be certain whether brittle viral infections22 and asthma medication, in asthma is associated with personality disorder 23 particular â2 agonists, may increase IgE or whether the threat of severe asthma induces synthesis. However, the causes of increased psychological instability. Certainly these pa- atopy in patients with brittle asthma remain to tients often cope badly with deteriorating

be explained. asthma and show clear evidence of panic in http://thorax.bmj.com/ Some patients with type 2 brittle asthma may their responses. be triggered by exposure to aeroallergens such as fungal spores. Alternaria spores have been POOR PERCEPTION identified as a cause of sudden and severe There is evidence that patients who have had asthma attacks in some patients24 although near fatal asthma attacks have a reduced positivity to Alternaria was rare in the Birming- perception of worsening airway function33 34 ham study of type 1 brittle asthma.14 and this might be a relevant factor in both type 1 and type 2 brittle asthma.35 Whether

RELATIVE IMMUNOGLOBULIN DEFICIENCY impaired perception of asthma is inherited or on September 25, 2021 by guest. Protected copyright. In a study of patients with severe asthma, most acquired is not yet certain. Patients with previ- of whom had type 1 brittle asthma, mean ous episodes of near fatal asthma also have a circulating IgG and IgA levels were lower, a reduced hypoxic drive, even when their lung finding which seemed to be unrelated to the function is normal, suggesting that during an current dose of oral steroid taken by each acute exacerbation they may not have a normal patient.25 This might suggest an impairment of ventilatory response.36 37 local immunity which increases susceptibility of these patients to respiratory infections. Pre- BETA-AGONISTS liminary findings from a double blind placebo The role of â agonists as a causal factor in controlled study of immunoglobulin replace- death from asthma has been much discussed ment in these patients showed no benefit over a and remains controversial.37–43 three month treatment period,26 although the Although normally prescribed doses of

dose of immunoglobulin used was lower than inhaled â2 agonists are likely to be safe, some that normally employed in the treatment of patients with type 1 brittle asthma take combined humoral immunodeficiency states. excessive doses, particularly with home neb- ulisers, when doses of more than 30 mg of FOOD INTOLERANCE salbutamol daily are often used. There is some

Two thirds of patients with type 1 brittle evidence that high concentrations of â2 agonists asthma report at least one foodstuV which result in impaired glucocorticoid actions in makes their asthma worse (Ayres, unpublished vitro.44 If extrapolated to the clinical situation,

observations), with 20% reporting allergic this suggests that high doses of â2 agonists may reactions to peanuts, an allergy known to be induce steroid resistance and worsen control of occasionally fatal.27 Equivalent data for patients asthma; this could be relevant to patients with with type 2 disease are not yet available. How- type 1 brittle asthma and would appear to ever, in the Saskatchewan study relating support the original epidemiological data. 318 Ayres, Miles, Barnes

However, more recent studies from New bronchoconstriction, but also by the activation Zealand45 46 suggest that the associations from of a local or axon reflex via the release of bron- earlier work were largely due to residual choconstrictor and inflammatory peptides Thorax: first published as 10.1136/thx.53.4.315 on 1 April 1998. Downloaded from confounding by severity. This would also help from airway sensory nerves,57 substance P,58 to explain the apparent paradox of patients and other tachykinins.59 with type 1 brittle asthma being eVectively The association between food allergy and treated by continuous subcutaneous terbuta- brittle asthma may suggest that an anaphylactic line (see section on “Treatment” below). reaction could occur in the airways, and a major component of this response might be Possible underlying mechanisms airway oedema. The therapeutic consequences INVESTIGATION of this might be important as adrenaline, Any attempts to elucidate possible mechanisms through its á-adrenoceptor anti-oedema ac- in brittle asthma are hampered by the diYcul- tion, might be expected to be more eVective

ties in establishing clear cut definitions, as dis- than a â2 agonist in relieving airway obstruc- cussed above. Furthermore, these patients are tion. diYcult to investigate because of the potential Another airway component that may con- danger of invasive investigations. Even the tribute to airway narrowing in brittle asthma is measurement of bronchial reactivity may be the airway vasculature through acute vasodila- contraindicated in such patients. Many pa- tation or venous congestion in the bronchial tients find that more than one forced expiratory circulation resulting in airway narrowing.60 manoeuvre is enough to cause significant worsening of their condition without adding a STEROID RESPONSIVENESS further bronchoconstricting stimulus. Al- Patients with type 1 brittle asthma are usually though fibreoptic bronchoscopy has proved treated with high doses of inhaled and/or oral extremely valuable in elucidating the inflam- steroids, yet their asthma often remains poorly matory mechanisms of asthma,47–49 it is not controlled which suggests that there may be a known whether these techniques may be degree of resistance to the anti-inflammatory applied safely to patients with brittle asthma. It eVects of steroids. True steroid resistance in is likely, therefore, that advances in knowledge asthma is very rare61 but relative resistance to on mechanisms are more likely to occur the anti-asthma eVect of steroids is more com- through other investigative means. mon. In severe asthma, where there is an Non-invasive methods such as exhaled nitric intense inflammatory response, there may be oxide (NO)50 or measures of inflammatory excessive activation of AP-1 and other tran- 51 mediators such as urinary leukotriene E4, scription factors that bind to, and therefore plasma cytokines such as interleukin 5,52 and consume, glucocorticoid receptors.62 This 53 eosinophil cationic protein may also shed could then reduce the response to inhaled and http://thorax.bmj.com/ light on the degree and nature of the oral steroids, resulting in a secondary steroid inflammatory process in brittle asthma. Induc- resistance. Whether this is a factor in brittle tion of sputum using hypertonic saline54–56 asthma is not yet clear, but recent studies in might in theory be useful but is likely to cause patients with steroid resistant asthma have severe bronchoconstriction in this group of demonstrated a marked inflammatory response patients. in the airways despite the fact that these It remains, however, of particular im- patients have been treated with steroids.48 49 portance to determine whether the inflamma-

tory pattern is the same in brittle asthma as in Treatment on September 25, 2021 by guest. Protected copyright. the other types of asthma, whether the expres- COMPLIANCE sion of cytokines and inflammatory enzymes is Patients with brittle asthma are, by definition, similar, and whether there are structural extremely diYcult to manage. Many of them abnormalities, including innervation, that dif- have fallen out with their doctor who, perhaps fer from the findings in mild asthmatic patients. understandably, has run out of therapeutic options and often patience. The standard man- ACUTE AIRWAY NARROWING agement guidelines such as the BTS The mechanisms of the sudden severe airway guidelines7 are inapplicable to these patients narrowing that characterises brittle asthma are once they have become brittle. They are taking unclear. It is likely that airway smooth muscle large doses of inhaled steroids and the only way contraction is an important component, al- to increase the dose when the condition wors- though this is not readily reversed by doses of ens is to resort to oral steroids which many

â2 agonists which suggests that oedema of the resist because of side eVects. Many patients

airways due to plasma exudation from leaky also use very large doses of â2 agonists, taken post-capillary venules may play a part. As either as a metered dose inhaler (often more discussed earlier, patients who die from asthma than one canister per week) or through a neb-

attacks of sudden onset have airways character- uliser, often using more than 30 mg of â2 ago- ised by infiltration of neutrophils rather than nist daily. It is therefore essential that the phy- eosinophils17 which suggests either that neu- sician realises that what the patient wishes to trophils appear earlier than eosinophils in any say and do concerning management assumes a given asthma attack or that this is a character- greater importance than in “ordinary” asthma. istic of patients with attacks of precipitous Non-compliance (or non-adherence) has onset. been much studied in mild to moderate Irritants might induce rapid airway narrow- asthma, and is recognised to result from ing via activation of a cholinergic reflex interaction of many factors, particularly Brittle asthma 319

psychosocial factors.63 The same is true of eVective is far from certain and deserves patients with brittle asthma who often try quite further investigation. However, the fact that Thorax: first published as 10.1136/thx.53.4.315 on 1 April 1998. Downloaded from bizarre management tricks to avoid having to inhaled â2 agonists cause measurable and start or increase a dose of oral steroids. If the reproducible further bronchodilation in pa- physician is prepared to barter with the brittle tients on CSIT68 suggests that there may be a asthmatic patient, then advances can be made, separate population of â receptors which are albeit slowly. Large improvements in control not accessible by the infused route. There is are unlikely in one step and many patients have evidence from animal studies that two such over-ambitious hopes of how much their populations exist in the major airways.69 doctor can do. When these are not achieved There are problems with CSIT which, in patients can regress psychologically, thinking some patients, prove too much to continue the themselves or the medical care a failure. If this treatment. The main problem is the develop- overambition can be restrained and more ment of subcutaneous nodules or inflamma- achievable and realistic targets set, then success tory lesions. The more indolent form show an can be achieved. Small successes, if perceived eosinophilic infiltrate on biopsy specimens.70 as such by the patient, can prove psychologi- These usually settle down once that area of skin cally very helpful in the short term. is avoided, but often leave a fibrotic nodule. More recently a more aggressive type of lesion ALLERGEN AVOIDANCE Control of allergen exposure may be of help in has been demonstrated which sometimes leads these patients although there is only anecdotal on to frank abscess formation, the pus from evidence that this is eVective. The logistics of which is usually sterile. The formulation of the allergen control are great, not only in terms of drug has not changed nor have the preserva- practicality but also cost. Many patients with tives, so the reason for these changes is not type 1 brittle asthma have animals at home and clear, but preliminary findings suggest that removal of what is often their best companion sensitivity to latex in the rubber tip of the 71 will be met with resistance. Unpublished data syringe plunger is not involved. Although the from the Birmingham group show that patients use of nebuliser solution rather than the inject- with brittle asthma are exposed to much higher able form of terbutaline may help, in some the levels of pet allergens (but not house dust mite) skin changes are so severe that administration than other asthmatics, but whether this will has to be changed to continuous intravenous result in removal of pets and important reduc- infusion via an indwelling line. Muscle cramps tions in allergen exposure in this severe group are common and sometimes may be severe, remains in doubt. with an increase in the plasma levels of creati- nine phosphokinase72 although levels of the

STEROIDS myocardial fraction are normal. Some patients http://thorax.bmj.com/ These patients by definition are using high complain of an eVect on memory and ability to doses of inhaled and/or oral steroids, and the concentrate but these have not been formally possibility of steroid resistance in at least some studied. Occasionally menorrhagia is seen9 but of these patients has been raised, as discussed this is not usually severe. above. Whether alternative immunomodula- tory treatment such as methotrexate or cy- LONG ACTING INHALED AGONISTS closporin A will be eVective is not yet certain. â2 In view of the marked fluctuations in PEF and

the eYcacy of subcutaneous â agonist infu- on September 25, 2021 by guest. Protected copyright. SUBCUTANEOUS â2 AGONISTS 2 Patients with type 1 brittle asthma can be sions, it might be expected that long acting treated with a long term continuous subcuta- inhaled â2 agonists would be eVective in stabil- ising the airways. However, in our experience neous infusion of â2 agonist, usually terbutaline (CSIT), at doses of 3–12 mg/day.64 65 Using a salmeterol has proved to be disappointing in two day single blind period of subcutaneous these patients for reasons that are not yet clear. saline before increasing through the doses of Whether formoterol, which is a full agonist, terbutaline, about 50% of patients with type 1 may be more useful than salmeterol, a partial brittle asthma showed considerable improve- agonist, remains to be determined. There is an ments in symptoms, variation in PEF (fig 1), anecdotal report of a patient showing sympto- and use of other asthma medication including matic and lung function improvement with oral steroids, about 25% showed some im- formoterol, but not to salmeterol.73 provement in symptoms but less improvement in PEF, while the remainder did not seem to respond.10 Chronic steroid dependent asthmat- ADRENALINE ics without a wide variability in PEF did not Adrenaline may have theoretical advantages respond. Although mean blood levels of terbu- over selective â2 agonists, because of its action taline achieved by this technique are around as an á-adrenoceptor against reducing airway 150 nmol/l,66 similar to those seen in patients oedema as discussed in the section on acute who have taken deliberate overdoses of airway narrowing above. Preloaded syringes terbutaline,67 changes in serum potassium or (Epi-Pen; Ana Pen) may be useful as an emer- glucose levels are rare (unpublished data) gency treatment, particularly for patients with which suggests tolerance to the side eVects of type 2 brittle asthma with their unexpected and this form of treatment. rapidly progressive attacks. It is not yet certain The reason why subcutaneous â agonists whether inhaled adrenaline may be more eVec-

rather than high dose nebulised â agonists are tive than a selective â2 agonist inhaler. 320 Ayres, Miles, Barnes

NOVEL THERAPIES 4 Bateman JRM, Clarke SW. Sudden death in asthma. Thorax 1979;34:40–43. New therapeutic approaches are urgently 5 Westerman DE, Benatar SR, Portgieter PD, et al. Identifica- needed in the management of brittle asthma. tion of high risk asthmatic patients. Am J Med 1979;66: Thorax: first published as 10.1136/thx.53.4.315 on 1 April 1998. Downloaded from 565–72. The logical development of such treatments 6 Hetzel MR, Clark TJH, Branthwaite MA. Asthma: analysis will depend partly on our increased under- of deaths and ventilatory arrests in hospital. BMJ 1978;408:808–11. standing of the mechanisms involved. In type 1 7 British Thoracic Society, British Paediatric Association, brittle asthma an alternative to steroids appears Royal College of Physicians of London et al, Guidelines on the management of asthma. Thorax 1993;48(Suppl):S1– to be indicated. Whether novel anti- 24. inflammatory treatments such as type IV phos- 8 Boulet L-P, Deschesnes F, Turcotte H, et al. Near fatal phodiesterase inhibitors or cytokine inhibitors asthma: clinical and physiologic features, perception of bronchoconstriction and psychologic profile. J Allergy Clin will prove to be useful is not yet certain. The Immunol 1991;88:838–46. sudden and reversible airway narrowing in 9 O’Driscoll BRC, RuZes SP, Ayres JG, et al. Long term treatment of severe asthma with subcutaneous terbutaline. brittle asthma may be due to non- Br J Dis Chest 1988;82:360–5. inflammatory mechanisms and alternative 10 Miller MR, Dickinson SA, Hitchings DJ. The accuracy of portable peak flow meters. Thorax 1992;47:904–9. treatments such as tachykinin antagonists or 11 Gardner RM, Crapo RO, Jackson BR, et al. Evaluation of opioids may prove to be useful in the future. accuracy and reproducibility of peak flow meters at 1400 m. Chest 1992;101:948–52. Anti-leukotrienes (leukotriene receptor an- 12 Newman Taylor AJ, Davies RJ, Hendrick DJ, et al. tagonists or 5-lipoxygenase inhibitors) may Recurrent nocturnal asthmatic reactions to bronchial provocation tests. Clin Allergy 1979;9:213–9. have a place in the management of some 13 Beynon HLC, Garbett ND, Barnes PJ. Severe premenstrual patients with type 1 brittle asthma. Some exacerbations of asthma: the eVect of intramuscular progesterone. Lancet 1988;ii:370–2. patients with more severe asthma appear to 14 Miles JF, Cayton RM, TunnicliVe WS, . Increased 74 et al respond to this group of drugs which would atopic sensitization in brittle asthma. Clin Exp Allergy merit a trial in patients with brittle asthma. 1995;25:1074–82. 15 Carswell F. Thirty deaths from asthma. Arch Dis Child Psychogenic mechanisms are clearly impor- 1985;60:25–8. tant in some patients with brittle asthma, yet 16 Wasserfallen JB, Schaller MD, Feihl F, et al. Sudden asphyxic asthma: a distinct entity? Am Rev Respir Dis 1990; little attention has been paid to the influence of 142:108–11. psychological factors on airway responses and 17 Sur S, Crotty TB, Kephart GM, et al. Sudden onset fatal asthma: a distinct entity with few eosinophils and relatively whether these could be modified by some more neutrophils in the airway submucosa. Am Rev Respir forms of psychological treatment such as Dis 1993;148:713–9. 18 Picado C. Barcelona’s asthma epidemics: clinical aspects conditioning. Group therapy may have a role in and intriguing findings. Thorax 1992;47:197–200. some circumstances but attention to coping 19 Miles JF, Noble K, Matthews HR, et al. Gastro-oesophageal reflux in patients with brittle asthma. Respir Med (submit- with deteriorating asthma may help to reduce ted for publication). the amount of treatment used and may have an 20 Miles JF, Sapiano S, Cayton RM, et al. Lung function tests in patients with brittle asthma. Am J Respir Crit Care Med impact on hospital admissions. 1995;151:A676. 21 Morton NE. Major loci for atopy? Clin Exp Allergy 1992;22: 1041–3. Summary 22 Lemanske Jr RF, Dick EC, Swenson CA, et al. Rhinovirus http://thorax.bmj.com/ We believe that the asthma phenotypes we have upper respiratory infection increases airway hyperractivity defined as types 1 and 2 brittle asthma appear and late asthmatic reactions. J Clin Invest 1989;83:1–10. 23 Coqueret O, Dugas B, Mencia-Huerta JM, et al. Regulation to be defined subgroups of asthma. For exam- of IgE production from human mononuclear cells by ple, we have characterised patients with type 1 â-adrenoceptor agonists. Clin Exp Allergy 1995;25:304–11. 24 O’Holloren MJ, Yunginger JW, OVord KP, et al. Exposure to brittle asthma, as defined in this review, on the aeroallergens as a possible precipitating factor in respira- basis of peak flow variability and treatment and tory arrest in young patients with asthma. N Engl J Med 1991;324:359–63. these patients remain a separate group when 25 Ayres JG, Thompson RA. IgG sub-class deficiency in brittle assessed by other means such as psychosocial asthma and in patients with recurrent infective exacerba- tions of asthma. Respir Med 1997;91:464–9. factors, immunoglobulin levels, and atopy. The 26 Shaheen MZ, Barker R, Drayson M, et al. Randomised on September 25, 2021 by guest. Protected copyright. question remains as to whether they are truly double-blind cross over trial of immunoglobulin replace- ment therapy in patients with severe asthma. Thorax 1992; separate groups with entirely diVerent pathoge- 47:254. netic influences or whether they simply repre- 27 Loza C, BrostoV J. Peanut allergy. Clin Exp Allergy 1995;25: 493–502. sent the severe end of the spectrum. 28 Ernst P, Habbick B, Suissa S, et al. 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