Postgrad Med J 1996; 72: 12-18 © The Fellowship of Postgraduate Medicine, 1996

Classic diseases revisited

Asthma

Peter MA Calverley

SummaryBronchial asthma is now recog-nised to be a major cause of mor-bidity and even mortality in peo-ple of all ages. Two importantideas have changed our approachto asthma management. The firstis understanding that asthma is achronic inflammatory disorderwhich needs regular treatmentwith anti-inflammatory drugssuch as inhaled corticosteroids toprevent further attacks. The sec-ond development is the avail-ability of prescribable peak flowmeters, which allows both confi-dent diagnosis and early predic-tion of relapse. Asthma manage-ment guidelines provide a logicaltreatment framework for mostpatients, but a few difficult casesstill consume large amounts ofmedical time. The commonestproblem is one of compliancewith treatment which may res-pond to patient education,although this is not universally so.Other problems include misdiag-nosis, acid reflux and, rarely, truecorticosteroid-resistant asthma.Several potentially importantnew treatments have beendeveloped. These include longeracting anticholinergic drugs,drugs with bronchodilator andsome anti-inflammatory proper-ties which antagonise or inhibitthe production of leukotrienes,sub-types of phosphodiesteraseinhibitor with anti-inflammatoryproperties and immunosuppres-sive drugs such as cyclosporin.Ultimately these new treatmentsmust be rigorously tested andintegrated into a care plan thatremains centred on patienteducation.

Keywords: asthma, inflammation, com-pliance, British Thoracic Society guidelines

University Department ofMedicineand Aintree Chest Centre, Liverpool,UKPMA Calverley

Correspondence to Professor Peter Calverley,Consultant Physician, Fazakerley Hospital,Longmore Lane, Liverpool, L9 7AL, UK

Accepted 28 June 1995

Bronchial asthma is still a major source of morbidity and occasionally ofmortality throughout the world. Despite 20 years of remarkable therapeuticadvances, it is still increasing in prevalence"l2 and although it is not yet a Health ofthe Nation target, it may soon become one. The development of specific generalpractitioner-based asthma clinics has meant that more patients are seeking advicefrom their family doctors about how best to use present treatments, andinformation on future developments. This article will briefly review the currentapproach to asthma management in the out-patient clinic and consider thepotential of newer therapies to modify patient care. Like most tales of medicalprogress, this one contains several false starts and blind alleys, as well as roadslikely to lead to patient benefit.

Key concepts in asthma

Two different, but complementary changes in our approach to asthma haveimproved the management of this disease. These changes are, the recognitionthat asthma is an inflammatory disease, and the advent of readily available,prescribable, peak flow meters.

How has our approach to asthma management changed?The theoretical basis on which management goals were formerly built hasshifted, and with it some ofthe goals oftreatment. In so far as theory ever dictatedpractice, most physicians used to believe that asthma was a disease in whichairway smooth muscle showed an exaggerated contracile response to exogenousor endogenous stimuli. They supposed that, in many cases, this was the result ofincreased mediator release in the airways; for example, histamine release causedby IgE-mediated immunological responses. Hence, it was thought that bron-chodilator drugs that relax the smooth muscle would functionally antagonisethese effects and, if given regularly throughout the day, would be sufficient tocontrol the disease. Patients with frequent exacerbations, or those with a marked'immunological' response might benefit from regular sodium cromoglycate orcorticosteroids, the former acting by stabilising mast cells and the latter byblocking immunological reactions.

Inflammatory processes in asthma

Our present views on the causes of asthma are very different. Studies on airwaysmooth muscle from patients with asthma undergoing lung resection or dyingfrom their disease3 have shown that the response to chemical and electricalstimuli is almost normal. At the same time, fibre-optic bronchoscopic biopsystudies, electron microscopy, and use of sophisticated molecular probes4-6 havesubstantiated what authors claimed many years earlier7: that asthma is a chronicinflammatory disorder ofthe airways. Such studies have largely been confined tomild asthma, but a consistent picture of increased mast cell numbers, epithelialdisruption and eosinophilic infiltration of both the epithelium and sub-mucosahas been seen (figure 1). Two particularly important findings are that thesub-epithelial basement membrane is thickened, and that a particular subset ofTlymphocytes (TH2 cells), which orchestrate the inflammatory response, arefound in chronic asthmatics.89 The cellular but not the fibrotic changes can bereversed by regular treatment with inhaled corticosteroids.10 Many convincingand conflicting cascades of mediators have been proposed to explain thecontraction of airway smooth muscle, but it is clear that histamine has only asmall role in this event and that other mediators, particularly the leukotrienes,and possibly prostaglandins, are important. Moreover, some of these mediatorsrecruit other inflammatory cells into the airway and may prolong theinflammatory process, perhaps by increasing leakage of plasma from themicrocirculation.

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Asthma management 13

Key concepts in asthma

* asthma is an inflammatory disorderof the airways

* the characteristic variability inairflow limitation seen in asthma isbest monitored by serial peak flowmeasurement

Box 1

0

0

Figure 1 The airway wall. (1) Damagedepithelium with a permanently thickenedsubepithelial basement membrane. (2) Thick-ened, hypertrophied airway smooth muscle,which occupies most ofthe airway wall, but isfunctionally normal. (3) Parasympatheticnerve fibres, which are mostly efferent,although some are afferent from the epith-elium. They influence the airway smoothmuscle and the microcirculation. Otherneural inputs are less well defined. (4) Themicrocirculation, which is complex, poorlyunderstood and present on both sides of thesmooth muscle layer. Vascular leak may beimportant, as the source of inflammatorycells. (5) T-lymphocytes and eosinophils, thecells which mediate inflammatory damageand mediator release

Home peak flow recording

* needs explanation* following deep inhalation, blow air

out as hard and as fast as possible -record the best of three attempts

* recording of PEF 3-4 times dailyfor two weeks is better than twicedaily for two months

* some patients falsely record theirresults - beware of totally regularrecordings

Box 2

Several conclusions can be drawn from understanding the role ofinflammationin asthma:

* Although regular bronchodilators may block the effects of the disease, theywill not treat the underlying pathology. Only treatment which suppressesinflammation will be likely to reduce bronchial hyperresponsiveness andreduce the frequency and severity of exacerbations.

* Anti-inflammatory therapy will be needed at the point in management whenregular bronchodilators were previously being introduced.

* Blocking one of the steps in the complex web of mediators leading to airwaynarrowing will not necessarily be effective if other pathways are stilloperating.

The distinction between bronchodilator and anti-inflammatory treatment isbecoming increasingly blurred and new terminology is probably needed todescribe new drugs which have both bronchodilator and anti-inflammatoryactions. Although in practice most asthmatic inflammation is corticosteroid-responsive, in some asthmatic patients, corticosteroids do not block mediatorproduction effectively and these individuals are essentially resistant to thistherapy."

Prescribable peak flow meters

The other major change in practice - the advent ofprescribable peak flow meters- has allowed characteristic patterns of variable airflow obstruction to bedocumented and the effects of treatment to be observed (figure 2). Previousreliance on symptoms and sporadic signs contributed to the 'hit and miss' natureof asthma care which made it hard to develop specific patient plans, or monitorprogress. Several studies have shown that the severity of diurnal peak expiratoryflow (PEF) variation is a good surrogate for more complex laboratory tests ofbronchial reactivity.'2 PEF charts are helpful diagnostically, for example, indetecting precipitants or occupational factors and are also a powerful tool inimproving the patients' understanding of their illness.These advances have changed the goals of asthma treatment and how we

monitor whether they are achieved. Ideally, we would like to see the patientasymptomatic without loss of time from work or school, able to sleep, exerciseand grow normally without any fluctuation in PEF, and without side-effects fromtreatment. Such a utopian state is not easily reached and at best will involve someform of regular treatment, adherence to which poses its own problems.

Current approaches to management

Although asthma care is sometimes reduced to a step-wise recipe of drugprescription, this is not the only approach to treatment. It is important todiscover reversible causes or precipitants of attacks. This can be simple, such asreviewing the patient's medication for use of drugs such as P-blockers (even eyedrops) or non-steroidal anti-inflammatory drugs (NSAIDs), or more comp-licated, such as seeking an occupational sensitizer (eg, trimetallic anhydride),which may be worthwhile when symptoms worsen during the working week.Cold, damp air can easily precipate exercise-induced wheezing or cough and thiscan be readily prevented by prior p2-agonist use or, if necessary, by wearing aspecial heat-exchange mask.'3 Avoidance of smokey or dusty atmospheres candecrease cough and wheeze but allergen avoidance is much less effective, as onlytrivial changes in symptoms or bronchial reactivity occur after even the moststringent aero-allergen avoidance regimes.'4 Isolating specific food precipitants(eg, tartrazine dyes in foods) is much more successful. Nonetheless, vacuum-cleaning bedding and use of non-allergic pillows or covers may help someyounger, milder asthmatics. Another important aspect ofmanagement is patienteducation. All patients should have some understanding of the precipitants oftheir symptoms, the expected course of their illness, how it is to be monitored,what their treatment does, and how to recognise an acute attack and takeappropriate action.'5 Explaining this takes time and is probably better done by apractice nurse than by a harassed doctor. Asthma clinics, whether practice- orhospital-based, should have the resources to meet these basic educational aimsand be able to spot the patients who are having compliance problems.

Despite these steps, the mainstay of treatment remains pharmaceutical. Theprincipal classes of drugs, their doses and side-effects are briefly summarised intable 1. The most recent British Thoracic Society guidelines provide a consensusview of current 'best practice' and are outlined in table 2. The universalapplication of this approach would produce considerable improvement in asthmacare and there are signs that some fund-holding practices and purchasing groupsare including adherence to such standards within their hospital contracts.

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Non-pharmacologicaltherapy

* allergen avoidance, eg, pets, specificfoods

* drug withdrawal, eg, P-blockers,NSAIDs

* desensitization - still controversial* avoid non-specific trigger factors,

eg, cold air, smokey rooms

Box3

However, there are still unresolved dilemmas which this view of 'best practice'does not fully address. This is particularly true for the place ofnewer agents suchas long-acting P2-agonists, for example, salmeterol (Serevent). There are alsodifferences in approach between treatment in children and adults and, forexample, continuing uncertainties about the best way to handle the 'wheezy'toddler who may not have asthma but who behaves like or even has the samepathology as that of his wheezy older siblings. Finally, specific advice in theguidelines is lacking on how to deal with the 'non-standard' or difficult patient.Hopefully, these issues will be addressed in the revision of the British AsthmaGuidelines planned for late 1995.

Practical aspects of management

It is a sad fact that many patients only seek medical help when their asthmaexacerbates and they attend the surgery or hospital emergency department fornebulised bronchodilator treatment. Good management should avoid this.Diagnosis relies on the recognition of the significance of chest tightness in themorning, cough at night and after exercise, as well as nocturnal wheeze, sleepdisruption and protracted symptoms after respiratory tract infections. A lowthreshold in instituting home peak flow assessment is necessary. No minimum ormaximum periods over which recording should take place have been agreedupon, but data generated over a two-week period will usually suffice. In addition,evidence of significant diurnal variation and/or PEF improvement in recordingsbefore and after inhaled P2-agonists should be recorded. Referral for hospitalassessment is necessary if in doubt and if significant symptoms still exist. PEFrecording provides objective evidence of good asthma control and response totherapy, and should be routine following exacerbation to confirm clinicalstability.Applying this combination ofguidelines, advice and education requires a team

approach involving both doctors and asthma nurse specialists. Specific self-management plans do appear to reduce morbidity and hospitalisation, and

Table 1 Drug treatment of asthma

Drug Action Dose/route' Side-effects Comment

BronchodilatorsP2-agonists2eg, salbutamol (Ventolin),terbutaline (Bricanyl),salmeterol (Severent)

Anticholinergicseg, ipratropium (Atrovent),oxitropium (Oxivent)

Xanthineseg, theophylline(Uniphyllin)aminophylline(Phyllocontin)

Anti-inflammatory/prophylacticCromoglycate andrelated drugseg, disodium cromoglycate(Intal) ornedocromil sodium (Tilade)

Corticosteroidseg, beclomethasone(Becotide, Becloforte),budesonide (Pulmicort),fluticasone (Flixotide),oral prednisolone

Relax airway smoothmuscle

Relax airway smoothmuscle

Relax airway smoothmuscle; low doses mayhave an anti-inflammatory effect, ofwhich the significance isas yet unclear

Unclear but unlikely toinvolve mast cells

Complex actionsinvolving steroid-responsive genes andtheir productsespecially cytokines

Usually inhaled,sometimes oral; inhaled50 1g pm; 2.5 mgnebulized3; salmeterol50 Lg bid

Inhaled only; 40-80fLgbid/tid (ipratropium);200 jig bid/tid(oxitropium); 500 fignebulized ipratropiumOral or iv 200-400mgusually bid; 250-500mgiv slowly (adults)

Inhaled, 10-20mgqid (disodium cromo-glycate); 4 mgbid/qid (nedocromil)

Inhaled: 200 g -2mgdaily; oral: minimumdose possible

Tremor, tachycardia,transient fall in serumpotassium

Dry mouth, bitter taste;very rarely glaucomawith the nebulizedsolution

Nausea, vomiting,headaches - at toxiclevels cardiacarrhythmias (SVT, VT)and convulsions.Monitor serum levels forsafety

Very few; there can bea bitter taste withnedocromil, which ismasked by a mintflavour

Inhaled: thrush,hoarseness, somepotential for systemicabsorption at very highdose; oral: bone, skin,adrenal, gastric andCushingoid effects -more than 20 recorded

Despite recent anxietiesthey appear safe.Turbuhaler/diskhalerare easy-to-use drypowder devices.Salmeterol is valuable innocturnal asthma.Valuable in COPD andacute asthma but notusually needed inuncomplicated asthma

Declining use, but theycan reduce overnightfalls in PEF

Relatively mildpreventative drugs -may be useful if worriesabout corticosteroidsand especially inchildrenInhaled therapy is nowthe cornerstone ofasthma careFluticasone may bemore potent than theothers but more data isneeded to be sure

'All inhaled therapy requires a check on the ability to use the device properly-change to spacer or dry powder may be needed.2Other effects, eg mast cell inhibition are seen in vivo - significance uncertain. Salmeterol is not anti-inflammatory.3Nebulized treatment is useful acutely but is seldom needed chronically in asthma.COPD: chronic obstructive pulmonary disease

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Asthma management 15

Table 2 Management of chronic asthma 1993

Adults Step Children

Inhaled P2-agonists as required Step 1 Inhaled P2-agonists as required

Inhaled P2-agonists + regular inhaled anti- Step 2 Inhaled P2-agonists + regular inhaled anti-inflammatory agentsinflammatory agents (low-dose beclomethasone (disodium cromoglycate)dipropionate or budesonide, alternatively disodiumcromoglycate or nedocromil sodium)

Inhaled P2-agonists pm + high-dose inhaled Step 3 Inhaled P2-agonists + regular inhaled low-dose (50-200 tgcorticosteroid: beclomethasone dipropionate bid) corticosteroid (budesonide or beclomethasone).or budesonide (800-2000 tg). Alternatives in Consider a 5-day course of soluble prednisolonepatients with problems with high-dose steroids: or temporary increase in inhaled steroids.salmeterol, sustained release theophylline orpossibly disodium cromoglycate or nedocromil

As step 3 + regular bronchodilators (sequential Step 4 Inhaled P2-agonists + high dose inhaled corticosteroidstrial of inhaled, long-acting P2-agonists, 400-800 ig daily (consider a short prednisolone course orsustained release theophylline, inhaled adding salmeterol)ipratropium or oxitropium, long-acting po P2-agonists, high-dose inhaled bronchodilators andcromoglycate/nedocromil sodium)

As step 4 + oral prednisolone Step 5 As step 4 + xanthines or nebulized P2-agonists (step 5a)or oral prednisolone and consider regular ipratropium or scinfusion of a P2-agonists (step 5b)

Asthma self-management* involves education about the nature

ofasthma, what treatment does,how to take it and what to do if itfails

* requires patient co-operation andcommitment

* use pre-set levels ofPEF (usuallymorning levels) to step up (ordown) treatment intensity ormedical attention

Box 4

- Post-bronchodilator

45000 Preonchodlator

350

300

250 i I IIT--F-l II *- ---T-III I- - -i'l ...'-T .N . q' X*, X XtOJX t' _'N t ' N W l C"J ' tIV C- C'"

MI I I

Date

Figure 2 The effect of a bronchodilator on the peak expiratory flow of an asthmatic patient

should be formulated jointly with the patient. Despite this, a few asthmaticpatients remain 'difficult' to control.

Difficult asthma

Some patients with asthma continue to be symptomatic and/or have very variablePEF recordings despite aggressive treatment which may reach steps 4 or 5 of theguidelines. Several factors are worth considering in such patients.

COMPLIANCEStudies ofcompliance with both inhaled and oral treatment have shown just howpoor this can be in up to a third of patients.6'67 The hidden monitoring of inhaleruse, which not only records activations but also the time at which they occur, hasproduced alarming results. The psychology of poor compliance is under-researched but fears about the long-term side-effects of treatment, the socialstigma of inhalers and differences in the aims of treatment between patient anddoctor all probably play important parts.

MISDIAGNOSISHeavy-smoking 'wheezy' bronchitics may resemble patients with adult onsetasthma and indeed, may have some response to bronchodilator treatment.

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However, they are likely to remain symptomatic and be more subject torespiratory tract infection. Likewise, bronchiectasis or even pulmonary oedemacan be associated with wheezing and breathlessness which is not helped by highdoses of inhaled steroids.

ACID REFLUXThe clinical association between acid reflux in the lower oesophagus andwheezing, particularly at night, is a strong one. In at least one study, acidregurgitation has been demonstrated in patients with symptomatic reflux whoshow falls in peak flow during the night.'8

UNSUSPECTED PRECIPITANTSThe role of occupational sensitization has already been discussed but otherfactors may produce a characteristic pattern ofsymptoms. Some women developpre-menstrual wheezing, the mechanism for which remains obscure. In otherpatients, contact with a specific allergen, like animal fur, may lead to attacks onlywhen they visit particular places.

CORTICOSTEROID-RESISTANT ASTHMASome patients appear genuinely resistant to the effects of even high doses ofcorticosteroids. Defects in monocyte function and in the cellular response tonon-specific stimuli have been described.'9 Recent evidence suggests that theremay be a specific genetic defect associated with this failure of the normalmodulation of inflammation, although this appears to be very uncommon. Suchpatients may prove to be the general practitioner's most troublesome asthmaticindividuals.

Future prospects in asthma therapy

As more is being learned about the pathophysiology of asthma, more potentialsites of drug action have suggested themselves. In general, three areas of attackhave been identified. Drugs can act on the smooth muscle cell membrane to blockor enhance receptor activity and hence modify contraction. This is where mostexisting bronchodilator drugs, for example, P2-agonists such as salbutamol(Ventolin) and salmeterol, and antimuscarinic drugs such as ipratropium(Atrovent) and oxitropium (Oxivent), operate. The second option is to interferewith the generation of lipid membrane products, namely leukotrienes, prostag-landins and platelet-activating factor. These compounds can cause smoothmuscle contraction but also have anti-inflammatory properties, resulting inplasma leakage from small vessels and cellular infiltration. Antagonism of thesemediators is a promising area of pharmaceutical research. Finally, the numberand function of inflammatory cells, particularly T lymphocytes, within theairway can be modified. This is thought to be where corticosteroids have theirrole, although other actions have been suggested.

RECEPTOR-MEDIATED BRONCHODILATATIONSeveral different pathways exist within the cell membrane that can initiatesmooth muscle contraction (figures 3 and 4). Calcium channels, both receptoroperated and voltage dependent, seem to be very important in vascular smoothmuscle but attempts at blockade of airway smooth muscle have been disappoin-ting.20 Beta-receptor stimulation produces a cascade of effects as well asrelaxation of the airway smooth muscle but despite the fact that the receptorsystem has now been well worked out, the action of salmeterol and other longacting P2-agonists remains contentious. Muscarinic receptors have beensubclassified, those on the smooth muscle being the M3 subtype. New,long-acting anti-muscarinic drugs like tiotropium bromide, offer some promiseof blocking an alternative pathway to that conventionally affected by 132-agonists,"l however, the role of these drugs is yet to be established. Potassiumchannel blockade, for a time, seemed to be the most promising area of all, with thedevelopment of a drug called cromakalim2' but problems with toxicity led to areformulation which proved ineffective.23 Moreover, systemic effects, particular-ly po)stural hypotension and headache, make clinical potassium channel blockadea remote possibility at present.A related approach, not involving the membrane receptors, is to inhibit the

enzyme phosphodiesterase which is involved in the metabolism of cyclic AMP.Although theophylline-like drugs are no longer believed to act on this enzyme atclinically acceptable concentrations, new, more specific drugs act on enzymesub-types. Thus, 6 mg of the phosphodiesterase 3/4 inhibitor zardaverine wasshown to produce a 12% increase in FEy, in 12 asthmatic patients, but this was

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Asthma management 17

Ca2+ K+ Muscaninc 3-Mmcaetii Membrane.lipid Pre-formed mediator

SMOOTH MUSCLE CONTRACTION Arachidonic acid LysPAF

Figure 3 The smooth muscle cell memb- Histaminerane. The muscarinic receptors are M3 recep- Cathepsintors responding to local acetylcholine release Lipoxygenase ECP

diphosphate Asc+ aPc LT

|eukotroliene Leukobene

LTD4,MLTE4 LTB4contracbon Chemotaxisvessel leak

Figure 4 The inflammatory cell wall. PAF: platelet-activating factor; ADP: adenosinediphosphate; FLAP: 5-lipoxygenase activating protein; ECP: eosinophil cationic protein; LT:leukotriene

still less than the 23% rise in the same patients after 200 tLg salbutamol.4 Otherdrugs with greater efficacy are being studied.

MEMBRANE-GENERATED LIPID PRODUCTSLeukotrienesIt is more than 10 years since the characterisation of the slow-reacting substanceof anaphylaxis as a mixture of leukotrienes made the Nine O'Clock News onBBC1. Only now are the first pharmacological products of this revolution beingtested in patients. Leukotriene receptor antagonists appear to produce both shortterm bronchodilatation and some longer term 'anti-inflammatory' effects,possibly because of reduced small vessel leakiness. Three compounds are worthspecific mention: MK-571 (now withdrawn from development) is a selectiveleukotriene D4 antagonist which produced a 22% increase in FEVy, afterintravenous administration to 12 stable asthmatics.25 Its effects were additive tothose of salbutamol and greatest in the most bronchoconstricted subjects.Similar results have been seen with 40 mg of the oral leukotriene inhibitorzafirlukast (AccolateTM),26 which is to be marketed in the near future. Finally,inhibition of 5-lipoxygenase, a crucial enzyme in leukotriene generation, hasbeen shown to reduce leukotriene E4 excretion and produce a dose-dependentincrease in FEV, in a large (139 patient) parallel-group double-blind study.27

ProstaglandinsIn contrast, drugs modifying prostaglandin production have been disappointingand, in fact, some non-steroidal agents appear to promote bronchospasm bystimulating local prostaglandin activity. Until recently platelet-activating factorantagonism was thought to offer the best hope of blocking asthmaticinflammation and reducing bronchial reactivity28 but studies with two differentclinically potent platelet activating factor antagonists have been very disappoin-ting, with one drug unable to block allergen challenge in human volunteers, andthe other completely ineffective in improving asthma control or reducing therequirement for inhaled steroids in a significant number of asthmatic out-patients.9

CELLULAR MANIPULATIONMost drugs which work in this way have been borrowed from other areas ofmedicine, particularly chemotherapy and rheumatology. Anecdotal reports thatmethotrexate and gold injections improved asthma control led to open studieswhich appeared to support this view. One double-blind steroid-sparing studyusing methotrexate (Maxtrex) raised high hopes30 but these data have not beenconfirmed by others3' and our own experience is that any benefit can usually beobtained at less risk to the patient by modifying other drug treatment. Althoughoral gold is a little more effective, it is nonetheless quite toxic and even the bestclinical studies of gold can be criticized for underuse of inhaled corticosteroids.'2The most promising drug in this field is cyclosporin (Sandimmun) which is

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normally used as an anti-rejection agent in transplant recipients. It is the onlydrug in this category to improve asthma control in otherwise corticosteroid-resistant patients33, possibly because of an effect on T lymphocyte function.However, it is expensive, requires regular monitoring of renal function andcauses hirsutism in many patients. Its use is still strictly experimental but it doesoffer some promise for the future and has given useful confirmation of theimportance of T lymphocytes in the inflammatory processes of chronic asthma.

Conclusion

Improved understanding of the pathological basis of asthma is changingattitudes towards care and modifying treatment goals. Sadly, there is still nocomparable improvement in our understanding of why the disease arises andwhy it is increasing in incidence, although tantalizing hypotheses are sometimessuggested.34 Many exciting new therapies are in development and some willundoubtedly be available on prescription to add to the choice available. Steps toimprove patients' understanding of their illness, deal with their anxieties about itand overcome difficulties with compliance, should always go hand in hand withselection of the appropriate medication from the widening range available.

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