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Eur Respir J1998; 12: 12091218DOI: 10.1183/09031936.98.12051209Printed in UK - all rights reserved

Copyright ERS Journals Ltd 1998European Respiratory Journal

ISSN 0903 - 1936

REVIEW

Difficult asthma

P.J Barnes*, A.J Woolcock**

aa

Most patients with asthma are easily diagnosed and res-pond to standard treatment with a short-acting inhaled 2-agonist for symptom control and long-term treatment withan inhaled corticosteroid in doses of up to 2,000 g daily.Approximately 5% of patients do not respond to this re-gime and require further investigation to establish the rea-sons for the lack of response. "Difficult asthma" may bedefined as failure to achieve control when maximally rec-

ommended doses of inhaled therapy are prescribed. Al-though difficult asthma is usually severe, as judged by theneed for extensive treatment, it may not necessarily be soas some patients have severe exacerbations but are wellcontrolled most of the time.

There are several factors that may contribute to a poorresponse to conventional therapy. It is important to consid-er these reasons systematically (table 1). Many patientswith severe asthma are undertreated; in a recent survey,over 60% of patients classified as having severe asthmawere not even treated with anti-inflammatory therapy [1].All patients classified as suffering from difficult asthmashould be assessed by a respiratory specialist, preferablyin a specialist clinic devoted to patients with difficult as-

thma. Since patients with difficult asthma account for a

large proportion of the direct and indirect costs of asthma,referral is financially as well as clinically justifiable [2].

Incorrect diagnosis

In some patients, an incorrect diagnosis of asthma re-sults in an apparent failure to respond to conventional anti-asthma therapy. Several diseases may cause wheezing,

including left ventricular failure, chronic obstructive pul-monary disease (COPD) or localized obstruction of a maj-or airway. COPD is usually easy to distinguish from asthma,by its slowly progressive course and association with long-standing cigarette smoking, but sometimes the distinctionfrom late onset asthma, particularly in cigarette smokers,may be difficult. In these patients, a trial of oral cortico-steroids is indicated; this involves administration of oralprednisone/prednisolone (3040 mg in the morning) for14 days. An increase in forced expiratory volume in onesecond (FEV1) or peak expiratory flow (PEF) of >15%indicates asthma. A negative response may indicate COPD,or rarely corticosteroid-resistant asthma (which shows thecharacteristic bronchodilator response of asthma), or sim-

ply a failure to adhere to the course of oral corticosteroids.

Difficult asthma. P.J Barnes, A.J Woolcock. ERS Journals Ltd 1998.ABSTRACT: Asthma is usually easy to manage, but ~5% of patients are not control-led even on high doses of inhaled corticosteroids. It is important to assess thesepatients carefully in order to identify whether there are any correctable factors thatmay contribute to their poor control. It is critical to make a diagnosis of asthma andto exclude other airway diseases, particularly chronic obstructive pulmonary disease(COPD), and vocal cord dysfunction ("pseudo-asthma"). Poor adherence to therapy,particularly inhaled corticosteroids, is a common reason for a poor response. Theremay be unidentified exacerbating factors, including unrecognized allergens, occupa-tional sensitizers, dietary additives, drugs, gastro-oesophageal reflux, upper airwaydisease, or other systemic diseases, that need to be identified and avoided or treated.Psychological factors may be important in some patients, but it is difficult to knowwhether these are causal or secondary to troublesome disease. Some patients haveinstability of their asthma, with resistant nocturnal asthma, premenstrual exacerba-tions or chaotic and unpredictable instability (brittle asthma). A few patients arecompletely resistant to corticosteroids, but more patients are relatively resistant andrequire relatively high doses of corticosteroids to control their symptoms (steroid-dependent). Some patients develop progressive loss of lung function, as in patientswith COPD. Management of patients with difficult asthma should be supervised by arespiratory specialist and should involve careful assessment to confirm a diagnosis ofasthma, identification and treatment of exacerbating factors, particularly allergens,and recording of peak expiratory flow patterns. A period of hospital admission maybe the best way to assess and manage these patients. Treatment involves optimizingcorticosteroids therapy, assessing additional controllers such as long-acting inhaled

or subcutaneous 2-agonists or subcutaneous, theophylline and antileukotrienes. Insome patients, the use of immunosuppressive treatments may reduce steroid require-ments, although these treatments are rarely effective and have side-effects. In thefuture, the nonsteroid anti-inflammatory treatments now in development may be use-ful in these patients.Eur Respir J 1998; 12: 12091218.

*Dept of Thoracic Medicine, National Heartand Lung Institute, Imperial College, Lon-don, UK. **Institute of Respiratory Medi-cine, Royal Prince Alfred Hospital andUniversity of Sydney, Australia.

Correspondence: P.J. BarnesDept of Thoracic MedicineNational Heart and Lung InstituteDovehouse StLondon SW3 6LYUKFax: 44 1713515675

Keywords: Adherencebrittle asthmacorticosteroid-resistancegastro-oesophageal refluxpremenstrual asthmapseudo-asthma

Received: June 19 1998Accepted for publication July 8 1998

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1210 P.J. BARNES, A.J. WOOLCOCK

One study using phenobarbitone as a marker of compli-ance showed that 26% of patients in a corticosteroid trialfailed to take the tablets and could have been classified asnonresponsive [3]. In children, several diseases may pres-ent with wheezing, including cystic fibrosis and acute viralbronchiolitis.

It is important to consider the possibility that other dis-eases are causing wheezing. Because the diagnosis is us-ually obvious if a careful history is taken, and the presenceof reversible airflow limitation confirmed by appropriate in-vestigations.

Vocal cord dysfunction

Vocal cord dysfunction ("pseudo-asthma") is often mis-diagnosed as asthma. It is due to upper airway obstructioncaused by adduction of the anterior two-thirds of the vocalcords, leaving only a 45-mm posterior "chink", resultingin upper airway obstruction [4, 5]. This is likely to be ahysterical conversion syndrome with secondary gain fromthe diagnosis of a chronic disabling disease. In a recentseries of such patients, 32% had coexistent asthma, whichcomplicates the diagnosis [5]. Some of these patients maybe treated with large doses of antiasthma therapy, includ-ing oral corticosteroids and immunosuppressive therapy,

and may even be classified as having corticosteroid-resist-

ant asthma [6, 7]. The wheezing in these patients is neverpresent during sleep and often worsens during examina-tion of the chest.

Forced expiratory tracings often show suboptimal effortwith variable responses, and a flowvolume curve indi-cates reduced inspiratory flow. Despite low recorded val-

ues of FEV1 and PEF, plethysmographic measurements ofairways resistance are usually normal. When forced expi-ration is reduced out of proportion with the increase in air-ways resistance, this may be due to coexistent asthma.Direct examination of the vocal cords by laryngoscopyshows the characteristic adduction of the vocal cords inassociation with wheezing [5, 8]. Some patients who pres-ent with cough and wheeze have an increased reactivity ofthe extrathoracic airway to inhaled histamine measured bya flowvolume loop; some of these patients have asthma(airway hyperresponsiveness) and others do not [9]. Pat-ients with increased extrathoracic sensitivity to histamineare more likely to present as cough than wheeze and haveassociated chronic diseases of the upper respiratory tract,

particularly chronic sinusitis and postnasal drip.Management of vocal cord dysfunction is difficult, and

direct confrontation is not helpful. It is important to with-draw oral and inhaled corticosteroids, but it may be usefulto continue inhaled 2-agonists on an "as-required" basis.Psychiatric assessment is rarely useful, but speech therapycan be helpful in some patients. Hypnotherapy and neuro-feedback training have also been reported to be successfulin some patients [8].

The natural history of this condition is pessimistic, andthe patients frequently revert to antiasthma therapy. In threepatients followed over 10 yrs, the condition persisted intwo patients who continued antiasthma therapy and therewas a response in one patient only after bypassing the

upper airway with tracheostomy [10].

Poor adherence

One of the commonest reasons for a poor response toasthma therapy is the failure to take the prescribed treat-ment correctly [11, 12]. Poor adherence is surprisinglycommon, and a recent study that measured compliance witha computerized timing device in a dry-powder inhaler show-ed that only 18% of patients took inhaled corticosteroidsas prescribed [13]. Another study of an inhaled anticholin-ergic in a clinical trial showed similar poor compliancewhen a computerized timing device was used (15% adher-ence) and demonstrated that canister weighing overestimat-

ed compliance [14]. It is likely that poor compliance withinhaled corticosteroids results from a lack of immediatebeneficial effect on asthma symptoms and an unwarrantedfear of side-effects. Many patients with poorly controlledasthma who are admitted to hospital show rapid improve-ment when the previously prescribed medication is givenunder supervised conditions. Monitoring of compliance isdifficult in clinical practice as monitoring has demonstrat-ed that many patients "dump" the doses before attendingthe outpatient clinic when the inhaler will be weighed or thenumber of activations recorded [13, 14]. Over the long-term, monitoring of the number of prescriptions filled maybe a useful way of assessing the amount of medicationused and is facilitated by computerized recording of pre-

scriptions in some countries.

Table 1. Difficult asthma

Wrong diagnosisCOPDLeft ventricular failureLocalized obstructionCystic fibrosis

Vocal cord dysfunctionPoor adherence to therapyUnidentified exacerbating factors

Unidentified allergensOccupation exposureUpper airway disease

RhinitisSinusitisObstructive sleep apnoea

Gastro-oesophageal refluxSystemic diseases

ThyrotoxicosisCarcinoid syndromeChurg-Strauss syndrome and other vasculitides

Drugs-blockersNonsteroidal anti-inflammatory drugsACE inhibitors?

Chronic infectionsMycoplasmaChlamydia

Psychological factorsUnstable asthma

Nocturnal asthmaPremenstrual asthmaBrittle asthma

Type IType II

Corticosteroid-resistant asthmaCorticosteroid-dependent asthmaIrreversible obstruction*

COPD: chronic obstructive pulmonary disease; ACE: angi-otensin-converting enzyme.

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DIFFICULTASTHMA 1211

Adherence may be better with tablets than with inhal-ers, and one study showed a significantly better compli-ance with oral theophylline than with inhaled corticosteroids[15]. However, more studies are needed to determine thefactors that contribute to poor compliance. Adolescent pa-tients are particularly poor at complying with regular ther-

apy, as they are resentful about the need for therapy andmay be unduly concerned about side-effects. Compliancemay be improved by education, although this has yet to bedemonstrated convincingly in controlled studies. Combi-nation therapy with an inhaled 2-agonist and corticoster-oid may improve compliance as the bronchodilator effectof the inhaled 2-agonist may increase the overall compli-ance. Indeed, a fixed combination inhaler of terbutalineand budesonide gave a better control of asthma than eithertreatment alone [16], and may be a useful strategy for somepatients, particularly when fixed combinations of a long-acting 2-agonist and a corticosteroid (salmeterol + fluti-casone or formoterol + budesonide) become available. Forpatients who are noncompliant with oral corticosteroids, it

may be necessary to use an intramuscular preparation suchas triamcinolone acetonide, which may improve control insome patients with severe life-threatening asthma [17].

Unidentified exacerbating factors

Asthma may remain difficult to control if exacerbatingfactors persist, and it is important to identify and eliminatethese whenever possible.

Unidentified allergens

Inhaled allergens are important in driving asthmatic in-

flammation, and exposure to high levels of allergen maybe an important factor in patients with severe asthma thatis not readily controlled. It is important to introduce strictallergen-avoidance procedures for such patients. The mostcommon domestic allergens are house dust mite and cats,but exposure to other allergens, including cockroaches, do-mestic pets and mould spores should be considered. Somesevere exacerbations of asthma may be precipitated byaeroallergens such as mould spores [18].

Some patients have been described with severe asthmathat appears to be due to an allergic reaction to the skinfungal infection trychophyton and responds to eradicationof the infection with antifungal agents [19]. These patientshave negative skin reactions to common aeroallegens and

would be classified as having nonatopic asthma. Whetherthis phenomenon applies to other fungal infections has notyet been established.

Occupational exposure

There are many chemical sensitizers to which patientsare exposed at work [20], and it is important to consider anoccupational history, particularly when asthma improves atweekends and on holiday. It is particularly important tomake the diagnosis of occupational asthma early so thatappropriate avoidance measures can be instituted. Expo-sure to the causative agent for more than 6 months may beassociated with the persistence of asthma, even when

avoidance is complete.

Dietary factors

Patients commonly believe that dietary constituents mayworsen asthma, but there is little objective evidence thatchronic asthma is worsened by allergic responses to nor-mal dietary components. Food additives, such as sodiummetabisulphite and tartrazine, may cause wheezing and shouldbe avoided [21]. Dietary salicylates may worsen asthma incertain patients and salicylate-free diets may result in im-provement in asthma. Monosodium glutamate, a previous-ly frequent additive in Chinese meals, has been associatedwith wheezing, but this is very uncommon [22]. Dietaryfactors may cause an acute anaphylactic response, whichmay be mistaken for brittle asthma (see below).

Drugs

Asthma may be exacerbated by ingestion of certaindrugs, including nonsteroidal anti-inflammatory drugsand -blockers [23].

Aspirin-sensitive asthma (ASA) is relatively common

in some areas, such as Eastern Europe and Japan, but israre in Western Europe, USA and Australasia, so may beoverlooked. ASA is often preceded by rhinitis and nasalpolyps. Attacks are precipitated by aspirin and other non-steroidal anti-inflammatory drugs, and may be severe [24].There is evidence for increased production of cysteinyl-leukotrienes [25] and overexpression of leukotriene (LT)C4synthase, predominantly in eosinophils in bronchial bi-opsies [26]. ASA is more frequently associated with a ge-netic polymorphism in the promoter sequence of LTC4synthase that is associated with increased enzyme expres-sion [27]. ASA is effectively blocked with antileukotrienes[28, 29] and these drugs may be the optimal treatment forthese patients [30].

-Blockers are well recognized to precipitate exacerba-

tions of asthma that may occasionally be fatal, but patientswith asthma are still given -blockers inadvertently. Theworsening of asthma is due to blockage of2-adrenocep-tors, but even 1-selective blockers, such as atenolol, bis-oprolol and metoprolol, are dangerous, since they are notcompletely selective. -Blocker eye-drops, such as tim-olol, used for the treatment of glaucoma, are also danger-ous since some patients may be extremely sensitive tothese drugs. The mechanism of-blocker induced asthmais not completely understood, but may in part be due toincreased cholinergic bronchoconstriction and may be re-versed with anticholinergic drugs [31]. All -blockers shouldbe avoided in asthmatic patients and alternative therapies,such as calcium antagonists and -blockers used to treatischaemic heart disease and hypertension.

There is no evidence that the well recognized cough as-sociated with angiotensin-converting enzyme (ACE) in-hibitors, such as captopril and enalapril, is more commonin patients with asthma. It is not certain whether ACE in-hibitors may worsen asthma. A retrospective cohort studysuggested that bronchospasm was twice as common inpatients treated with ACE inhibitors compared to the ref-erence group treated with lipid lowering drugs [32]. Therewas some evidence that bronchoconstriction was morecommon in patients with cough. In a controlled trial in as-thmatic and hypertensive patients (with and without cough),there was no change in lung function following adminis-tration of captopril and no increase in reactivity to hista-

mine or bradykinin [33], and similar findings were obtained

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in a group of asthmatic patients given ACE inhibitors for 3weeks, although one subject (out of 21) developed in-creased wheezing [34]. This suggests that ACE inhibitorsare unlikely to worsen asthma in the majority of patients,although there may be occasional patients in whom thisoccurs. When there is a possibility that asthma has been

worsened or precipitated by an ACE inhibitor, the drugshould be withdrawn and an alternative agent selected.

Gastro-oesophageal reflux

Gastro-oesophageal reflux is more common in patientswith asthma than in the general population, with an esti-mated prevalence of 3480% [35, 36]. It has been esti-mated that approximately one-third of patients who sufferfrom gastro-oesophageal reflux-related asthma may havesilent reflux [35]. Reflux may be due to transient relaxa-tion of the gastro-oesophageal sphincter, as a result ofbronchodilator therapy, flattening of the diaphragm due to

air trapping and raised intra-abdominal pressures [37, 38].Gastro-oesophageal reflux may cause unexplained cough,but may also lead to exacerbation of asthma and may in-crease asthma symptoms [39]. This may be due to activa-tion of an oesophageal vagal reflex via cholinergic pathwaysor to reflux of stomach contents with microaspiration.Continuous monitoring of pH suggests that the reflex the-ory is more likely as patients with asthma usually haveacidification of the distal, rather than the proximal, oeso-phagus, whereas patients with noncardiac chest pain usu-ally have proximal reflux [40]. There may be improvementwith anticholinergic therapy [41]. However, in a study offour patients in whom simultaneous measurements of oes-ophageal and tracheal pH were made, episodes of airwaynarrowing correlated with lowering of tracheal pH, indi-cating microaspiration [42].

If oesophageal reflux is suspected, measures should betaken to reduce reflux and a trial of therapy with the pro-ton pump inhibitors (omeprazole, lansoprozole, pantopraz-ole) should be undertaken. Patients with gastro-oesophagealreflux may require higher than conventional doses for aprolonged period. However, response to this therapy isusually disappointing, suggesting that gastro-oesophagealreflux is unlikely to be an important mechanism of wors-ening of asthma, even when marked reflux has been dem-onstrated [43].

Upper airway disease

The role of upper airway inflammation in exacerbatingasthma is often overlooked. Allergic rhinitis is common inpatients with asthma and may contribute to poor control.Treatment of allergic rhinitis with nasal corticosteroids im-proves airway hyperresponsiveness, indicating a link bet-ween upper and lower airway inflammation [44]. Treatmentof symptomatic rhinitis should always be considered whenasthma remains poorly controlled.

Sinus disease may also predispose persons to poor as-thma control. Surgical treatment of sinus disease may im-prove asthma control [45].

The mechanisms whereby upper airway disease can wor-sen asthma are poorly understood. Naso-bronchial neural

reflexes have been described, but it is unlikely that they

contribute to long-standing worsening of asthma control.Experimental sinusitis in rabbits leads to an increased air-way hyperresponsiveness that is not seen when the ani-mals are kept "nose down", suggesting that post-nasal dripmay be important [46], possibly in delivering cytokines tothe lower airways. Another possible explanation is that in-

flammatory mediators in post-nasal drip result in extratho-racic hyperresponsiveness, resulting in cough [9].

Obstructive sleep apnoea and snoring also appear toaggravate asthma so that it is more difficult to control,possibly because of increased inhaled allergens or de-creased humidity of inspired air when the upper airwaysare bypassed. In such patients, treatment with nasal posi-tive pressure at night can improve control [47].

Other diseases

Surprisingly few concomitant diseases worsen asthmacontrol, presumably because asthma is localized to the air-ways.

Thyrotoxicosis causes worsening of asthma, althoughthe mechanisms are uncertain. Since hyperthyroidism is as-sociated with an increased sympathetic drive, this mightbe expected to reduce asthma symptoms. Asthma im-proves with treatment of thyrotoxicosis [48]. The worsen-ing of asthma may be related to an interaction betweenthyroid hormone receptors and glucocorticoid receptors,resulting in reduced effects of corticosteroids.

Carcinoid syndrome with hepatic metastases is a veryrare cause of worsening of asthma, due to the release ofbronchoconstrictor peptides, such as bombesin and kinins,from the hepatic secondaries [49].

ChurgStrauss syndrome is a rare vasculitic syndromein which asthma is associated with systemic vasculitis and

eosinophilia [50]. Asthma may be severe and difficult tocontrol with inhaled corticosteroids. A very high eosi-nophil count and features of vasculitis, such as peripheralneuropathies, renal dysfunction and cardiac arrhythmia,should be warning signs. Recently, patients with ChurgStrauss syndrome associated with the introduction of zaf-irlukast have been reported, but these cases appear to berelated to a reduction in systemic corticosteroids after theintroduction of the antileukotriene [51].

Respiratory tract infections

Several studies have highlighted the importance of vir-us infections in precipitating acute severe exacerbations of

asthma [52]. There is some evidence that Mycoplasmapneumoniae may be found in patients with more severeasthma and could act as a perpetuating mechanism [53].Treatment with clarithromycin resulted in an improvementin asthma symptoms and airway wall inflammation. Inchildren, persisting infection with Chlamydia pneumoniaehas been associated with more frequent exacerbations ofasthma [54] and might be another infection that worsensasthma. Chronic chlamydia infection has been reported insome patients with severe corticosteroid-dependent asth-ma with improvement after treatment with clarithromycinor azithromycin [55]. Treatment with macrolide antibio-tics may therefore have some potential in the managementof patients with difficult asthma and needs to be evaluated

in controlled trials.

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Psychological factors

In many patients with difficult asthma psychological fac-tors may play a role [56]. It is difficult to separate whetherhaving difficult and, in some cases, life-threatening as-thma makes patients psychologically unstable, or whether

psychiatric abnormalities worsen asthma control. In a sur-vey of patients with near-fatal asthma, over 50% werefound to have significant psychological abnormalities [57].

Stress is a well-known asthma trigger, but there is noevidence that stress itself causes asthma. The marked pla-cebo response seen in some patients indicates that psycho-logical factors have a profound effect on asthma, and it islikely that they contribute to poor control of the disease insome patients. Psychological factors may be associatedwith poor adherence with asthma therapy, although thereare no obvious personality traits that have been identifiedin poor compliers. Depression, anxiety and problems withinterpersonal relationships reduce adherence with therapy[58]. Many patients with brittle asthma have psychologi-

cal problems, but this may result from the unpredictablenature of severe exacerbations.

Unstable asthma

In some patients, asthma may be difficult to control des-pite adequate therapy.

Nocturnal asthma

Nocturnal asthma is the commonest pattern of instabil-ity and is usually an indicator of suboptimal treatment.Sometimes, nocturnal asthma persists despite treatment withmaximal doses of inhaled corticosteroids and long-actinginhaled 2-agonists or slow-release theophylline. Some-times, these patients respond well to a subcutaneous infu-sion of a short acting 2-agonist (salbutamol, terbutaline)overnight.

Premenstrual asthma

Premenstrual worsening of asthma may occur in somefemales. Although premenstrual exacerbation of asthma maybe mild and may respond to an increased dose of inhaledcorticosteroids, it may be particularly severe in some pa-tients and appears to be corticosteroid resistant. Occasionalpatients will require hospital admission and even ventila-tion every month [59]. The characteristic pattern is ofincreased asthma symptoms and a fall in PEF 25 daysbefore the menstrual period, with improvement once men-struation begins. There is no association with symptomsof premenstrual tension, and it is unclear why this patternis only seen in a proportion of females. Airway hyperre-sponsiveness increases premenstrually, and it is assumedthat this increase is greater in females who are sympto-matic [60].

The mechanisms of premenstrual symptoms are uncer-tain. The timing of the asthma exacerbation coincideswith a fall in progesterone secretion and a rise in the oes-trogen:progesterone ratio. This suggests that progesterone

normally exerts a protective, possibly anti-inflammatory,

effect in these patients. Progesterone receptors, like gluco-corticoid receptors, directly interact with the transcriptionfactor nuclear factor-B (NF-B) [61]. NK-B appears tobe a key transcription factor that orchestrates asthmaticinflammation, and therefore, a fall in progesterone wouldtend to increase asthmatic inflammation. Why this should

only produce worsening of asthma in a proportion of fe-males is unclear, but it may be related to their sensitivityto corticosteroids. Premenstrual asthma is poorly respon-sive to increased inhaled or oral corticosteroids, indicatinga degree of corticosteroid resistance in these patients. Sinceglucocorticoids also block NF-B, this may indicate thatthere is excessive NF-B formation in these patients. An-other possibility is that there is an abnormality in -receptor function. There is a premenstrual reduction in2-receptor density on circulating lymphocytes, suggestingthat the bronchodilator response to inhaled 2-agonists maybe impaired in patients with premenstrual asthma [62].

Management of premenstrual asthma symptoms maybe difficult. As discussed above, these patients are poorly

responsive to glucocorticoids. Progesterone appears to beeffective, but only when large doses are given parenterally[59]. Oral progesterone appears to be ineffective, and it isrecommended that patients are treated with a intramuscu-lar progestogen (such as DepoProvera) during the weekbefore menstruation. Unfortunately, this may lead to fluidretention and depression in some patients. Gonadotro-phin-releasing hormone analogues, such as goserelin orbuserelin, which increase progesterone concentrations, arean alternative approach. Occasionally, premenstrual asth-ma is so severe that it can only be controlled by surgicalremoval of the ovaries.

Brittle asthma

Brittle asthma refers to unstable asthma that is unpre-dictable, and often no consistent trigger factors can be id-entified. Brittle asthma is rare and may occur in only 0.05%of all asthmatics, although these patients present consider-able management problems. There are two patterns of brittleasthma [63]. Type I: persistent and chaotic variability inPEF (usually >40% diurnal variation in PEF for >50% oftime) despite considerable medical therapy, and type II:sporadic sudden falls in PEF on a background of normalor near normal lung function and well-controlled asthma.

In type I brittle asthma there are usually no identifiabletrigger factors that are related to the falls in PEF. Many ofthe patients have psychological problems and there maybe problems of adherence with therapy.

In type II brittle asthma, there may be rapid and un-expected falls in PEF with severe exacerbations that mayrequire ventilation. Some of these patients may have aproblem with perception of disease severity. In patientswho had suffered sudden onset near-fatal asthma attacks,there was impaired perception of airway narrowing and areduced ventilatory response to hypoxia [64, 65]. Thissuggests that such patients may not be aware of the sever-ity of attacks and therefore delay taking appropriate pre-ventive or reliever therapy [66]. Patients with type IIbrittle asthma often respond poorly to nebulized broncho-dilators, suggesting that there may be a component of air-way narrowing that is not due to airway smooth musclecontraction. It is possible that this may be explained by an

acute oedematous swelling of the airway. There is some

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evidence that patients with type II brittle asthma have a highincidence of food allergy [67] and reported food allergy isa risk factor in death and near death from asthma [68]. It ispossible that type II brittle asthma may therefore representan airway anaphylactic response that is triggered by food.

Management of type I brittle asthma is difficult, as

these patients often fail to respond to conventional ther-apy. Patients with type I brittle asthma who have persistentvariability in PEF often fail to respond to inhaled long-act-ing 2-agonists or repeated nebulized 2-agonists and anti-cholinergics. Subcutaneous infusions of 2-agonists (sal-butamol or terbutaline) may be very helpful in some pat-ients, particularly in controlling nocturnal symptoms [69].The 2-agonist is usually given via an insulin infusionpump, and the lowest dose that controls symptoms is se-lected (usually terbutaline 312 mg in 24 h). Side-effectsmay be a problem. The most troublesome adverse effect ismuscle cramps, associated with elevated levels of total ser-um creatinine kinase, which are often dose limiting [70].

Treatment of type II brittle asthma is even more diffi-

cult, as these patients often have normal or near normal lungfunction for most of the time. It is not certain whether vig-orous preventive therapy is effective in these patients. Thepossibility of food allergy should be considered. In a pre-liminary report, food intolerance was identified by double-blind challenge in 6/8 patients with brittle asthma whowent on to improve with an exclusion diet [71]. Treatmentof acute exacerbations should involve immediate adminis-tration of a bronchodilator. Because of the rapidity of theattacks, bronchodilator therapy is best given by injection,and because of the possibility that anaphylaxis is involved,adrenaline (epinephrine) is the bronchodilator of choice.Patients should always carry preloaded adrenaline syringes(e.g. Epi-pen, Mini-jet) and relatives or close associates

should be instructed in giving these injections. Patients shouldalso carry some type of warning, such as a Medic-Alertbracelet.

Corticosteroid-resistant asthma

Response to glucocorticoids is the hallmark of asthma,but there are some patients in whom corticosteroids areineffective. True corticosteroid-resistant asthma is veryuncommon and may occur in only 1 in 1,000 to 1 in10,000 asthmatic patients [72, 73]. It is important to est-ablish the diagnosis carefully with a formal trial of corti-costeroids. This is recommended to be oral prednisolone3040 mg daily in a single morning dose for 2 weeks. Thisshould be preceded by a 2-week period of monitoring,ideally with placebo tablets. Corticosteroid resistance isdiagnosed if the increase in FEV1 or mean PEF is 15% and spontaneous variability inPEF [73]. Bronchial biopsy studies have demonstrated thatthese patients, like corticosteroid-sensitive asthmatic patients,also have an eosinophilic infiltration and express similarT-helper (Th)2 cytokines [74].

The molecular mechanisms of corticosteroid-resistant as-thma have recently been established, and the mechanismsmay differ from patient to patient [75, 76]. The majority ofpatients have normal plasma cortisol concentrations and do

not suffer from adrenal insufficiency, suggesting that the

metabolic and endocrine functions of endogenous gluco-corticoids are unimpaired. The defect appears to be in theanti-inflammatory action of corticosteroids and, whereasthere are usually no abnormalities in binding of gluco-corticoids to glucocorticoid receptors, there is an impairedinteraction between glucocorticoid receptors and deoxyri-

bonucleic acid (DNA), which appears to be secondary toan abnormality between the glucocorticoid receptor andthe transcription factor activator protein-1 (AP-1) [77, 78].Indeed, there is an increased basal and stimulated activa-tion of AP-1 in these patients, suggesting that this tran-scription factor may consume glucocorticoid receptors viaa direct proteinprotein interaction, thus reducing the anti-inflammatory effect of glucocorticoids. There is increasedactivation of AP-1 by cytokines, and this appears to be dueto excessive activation of the key enzyme Jun kinase [79].

Management of these patients is problematic in view oftheir failure to respond to corticosteroids [75, 80]. Indeed,treatment with glucocorticoids should be discontinued, asthese patients do develop systemic side-effects to corticos-

teroids (presumably mediated via the normally function-ing endocrine and metabolic pathways) [81]. Long-actinginhaled 2-agonists may be useful in these patients. Theo-retically, immunosuppressants, such as methotrexate andcyclosporin A, may be useful in these patients, but in ourexperience, they appear to provide little benefit and oftenhave unacceptable side-effects.

Corticosteroid-dependent asthma

Corticosteroid-dependent asthma is defined as asthmathat can only be controlled with oral corticosteroids. Bydefinition, it is severe, but is differentiated from corticos-teroid-resistant asthma by the fact that there is a responseto corticosteroids, although only when high doses are given.Lowering the maintenance dose of inhaled corticosteroidsresults in worsening asthma control. This suggests thatthese patients are relatively resistant to the anti-inflamma-tory effects of corticosteroids and may be part of a contin-uum, with corticosteroid-resistant asthma at one extreme.

The mechanisms of relative corticosteroid resistance arenot yet certain, as these patients are difficult to investigatewith invasive techniques. Patients with steroid-dependentasthma showed activated eosinophils, T-lymphocytes andinterleukin (IL)-5 immunoreactivity in their bronchialbiopsies, although to a greater extent than in mild asthma[82, 83]. Recent studies with bronchial biopsy, broncho-alveolar lavage and induced sputum have shown that in-flammation persists, despite high doses of corticosteroids,and there is an increase in neutrophils in the airways ofthese patients [84, 85], but whether this contributes to thepathophysiology or whether it reflects high dose steroidtreatment (as corticosteroids increase neutrophil survival)is not yet certain. It is possible that these patients developcorticosteroid resistance secondary to asthmatic inflamma-tion. The pro-inflammatory cytokines, IL-1 and tumournecrosis factor (TNF)-, activate the transcription factorsAP-1 and NF-B, which then bind to glucocorticoid re-ceptors, thus reducing the number of receptors availablefor activation by glucocorticoids. It is possible to demon-strate this mechanism of resistance both in vitro and invivo [86, 87]. Treatment with very high doses of corticos-teroids might overcome this resistance, and once the pro-

inflammatory transcription factors have been blocked, the

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glucocorticoid receptors will be available, restoring gluco-corticoid sensitivity. In treating severe asthma, it is rat-ional to start with high doses of corticosteroids (inductionphase), with reduction to lower doses to maintain control(maintenance phase). Pulse therapy with high doses ofcorticosteroids (such as systemic methylprednisolone) may

therefore be considered in these patients in order to re-establish corticosteroid sensitivity.

Another possible mechanism for corticosteroid resistancemay be the effect of high doses of inhaled 2-agonists. Invitro high concentrations of2-agonists may interfere withthe actions of glucocorticoids by activating the cyclic ade-nosine monophosphate response element binding (CREB)protein transcription factor, which interacts directly withthe glucocorticoid receptor, in the same manner as AP-1and NF-B. This interaction had been demonstrated inlung tissue, T-lymphocytes, and epithelial cells [88, 89],and predicts that high doses of inhaled 2-agonists resultin relative corticosteroid resistance. When patients treatedwith very high doses of inhaled 2-agonists are weaned to

low doses, there is evidence for a reduced requirement fororal corticosteroids [90, 91], and this strategy should beconsidered in all patients thought, or known, to be takinglarge doses of2-agonists.

Irreversible obstruction

Although asthma is a reversible disease, progressiveairflow obstruction is seen in some patients [92, 93]. Theannual rate of decline in lung function is increased in asth-matic patients to the same degree as in cigarette smokers[94]. This irreversible narrowing of the airways only ap-pears to occur in some patients and usually in those withmost severe disease, but at the moment, there is no way of

predicting which patients will show the greatest decline.The nature of the airway obstruction in these patients isnot yet known, but is presumed to be due to structuralchanges in the airways, such as fibrosis and thickeningof airway smooth muscle, which are a consequence ofuncontrolled chronic airway inflammation. However, sub-epithelial fibrosis is found even in patients with mild epi-sodic asthma and does not appear to be increased even incorticosteroid-dependent asthmatic patients [95]. High-resolution computed tomography scans have demonstrat-ed an increase in emphysema and bronchiectasis in patientswith more severe asthma, particularly when it is nonaller-gic [96]. It is possible that some of the proteolytic en-zymes released from inflammatory cells in the airways of

asthmatic patients, such as matrix metalloproteinases, mayaccount for these structural changes. Structural changesare presumed to be irreversible using currently availabletherapies, and this emphasizes the need for early and ef-fective control of the inflammatory process. There is in-creasing evidence that the early use of inhaled corticosteroidsmay prevent irreversible changes in airway function [97100], but more controlled studies are needed.

Some patients will have both asthma and COPD as bothdiseases are common and may have a common underlyingpredisposition. The asthmatic component of the diseaseis revealed using a formal trial of oral corticosteroids.Management of such patients may involve treatment withbronchodilators (combination of inhaled 2-agonists andanticholinergic) and the use of corticosteroids.

The practical approach to the management of difficultasthma

When confronted with a patient in whom asthma ap-pears to be difficult to control with inhaled 2-agonists andhigh-dose inhaled corticosteroids, it is important to adopt

a logical approach (table 2): 1) It is critical to establish thediagnosis of asthma, and in particular to exclude COPDand vocal cord dysfunction, using appropriate physiologi-cal tests and a formal trial of corticosteroids if necessary.2) It is important to then establish whether the patient iscompliant with therapy by direct questioning and by mon-itoring inhaler and tablet usage, by direct counting or fromfilled prescriptions. It is also important to check correctusage of inhalers. It may be necessary to admit patients tohospital to determine whether supervised therapy resultsin better control. 3) Exacerbating factors should be vigor-ously sought by careful questioning and appropriate in-vestigation. These should then be corrected, where possi-ble, with careful monitoring of asthma. Allergen avoidance

may be particularly important in some patients. 4) Unsta-ble as-thma should be carefully assessed with peak flowmonitoring and appropriate therapy instituted. The corticos-teroid requirement of patients with severe asthma shouldbe de-termined. 5) A period of hospital admission is desir-able, as it is then possible to administer medication undersup-ervised conditions, and it is possible to make a morede-tailed assessment of the patient, which may includeanalysis of induced sputum, fibreoptic bronchial biopsy, ahigh-resolution computed tomography scan and detailedlung function tests.

Treatment

If patients are not controlled on short-acting inhaled 2-agonists and high doses of inhaled corticosteroids, controlmay be improved by adding a long-acting inhaled 2-ago-nist (salmeterol or formoterol), theophylline or an antileu-kotriene [101104]. In patients with difficult asthma who

Table 2. Important questions in management of difficultasthma

Does the patient have asthma?Steroid trial if doubts about COPDLung function at time of symptomsBronchial biopsy

Are adequate doses of steroids reaching the airways?ComplianceInhaler technique

Have all provoking stimuli been removed from the dailyenvironment of the patient?

Domestic allergensOccupational sensitizers

Have all potential aggravating factors been removed?Gastro-oesophageal refluxUpper airway diseaseObstructive sleep apnoeaDrugs: -blockers, nonsteroidal anti-inflammatory drugs,

ACE inhibitors?High doses of inhaled -agonists?

Has the patient followed a strict management plan aimed atreducing the severity for disease for at least 6 months?

COPD: chronic obstructive pulmonary disease; ACE: angi-

otensin-converting enzyme.

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require maintenance oral corticosteroids, the lowest possi-ble dose should be used. Various steroid-sparing treatmentshave been investigated in an attempt to reduce the dose oforal steroids [105], and these include methotrexate, gold,cyclosporin A, intravenous gamma-globulin and colchi-cine. None of these treatments is very effective, and they

all have a high prevalence of side-effects. Recent studiesindicate that some of the patients with difficult asthmahave persistent inflammation in the airway, despite the useof oral corticosteroids. For these patients, more specificanti-inflammatory therapies (such as interleukin-5 antago-nists or chemokine receptor (CCR3) antagonists) may beuseful in the future [106]. Other patients with difficultasthma appear to have no active inflammation (as meas-ured in biopsies or induced sputum), and their persistentabnormality may be due to an abnormal behaviour of air-way smooth muscle that will require a different form oftreatment (such as selective potassium channel openers ordrugs that interfere with abnormally active signal transduc-tion pathways).

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