Difficult/Therapy-Resistant Asthma

Copyright #ERSJournals Ltd 1999 EurRespir J 1999;13: 1198– 1208 EuropeanRespiratory Journal Printedin UK– allrights reserved ISSN0903-1936

ERSTASK FORCE

Difficult/therapy-resistantasthma

Theneed for anintegrated approachto define clinicalphenotypes ,evaluate riskfactors, understandpathophys iologyand find noveltherapies

ERSTaskForce on Difficult/ Therapy-ResistantAsthma

:K.F. Chung and P.Godard (co-chairmen),E. Adelroth, J.Ayres,N. Barnes, P.Barnes, E.Bel, P.Burney, P.Chanez, G.Connett, C.Corrigan, J.de Blic,L. Fabbri, S.T. Holgate, P. Ind, G.Joos, H.Kerstjens,P. Leuenberger, C-G.Lofdahl, S.McKenzie, H.Magnussen, D.Postma, M.Saetta, S.Salmeron, M.Silverman and P. Sterk.

CONTENTS Formulatingthe definition ...... 1198 Managementand treatment ...... 1203 Diagnosisof asthma...... 1199 Allergenavoidance...... 1203 Exclusionof other diagnoses...... 1199 Psychosocialfactors...... 1204 Asthmacontrol...... 1199 Specifictherapy...... 1204 Factorscontributing to loss of asthmacontrol.... 1200 Corticosteroids...... 1204 Asthmatherapy...... 1200 Short-acting ß-adrenergicagonists...... 1204 Patientcompliance and supervision...... 1200 Long-acting ß-adrenergicagonists...... 1204 Definitionof difficult/therapy-resistantasthma.... 1201 Theophylline...... 1205 Patterns ofdifficulty in asthma ...... 1201 Leukotrieneinhibitors...... 1205 Evaluationand pathophysiology of diffcult/ Immunosuppressantsand antimetabolites...... 1205 therapy-resistantasthma...... 1201 Areasfor research ...... 1205 Lungmechanics and airway responsiveness...... 1202 Definitionof clinicalphenotype...... 1205 Computedtomography of theairways and lungs. 1202 Factorsassociated with difficulty/ therapy- Airway inflammation...... 1202 resistantasthma...... 1205 Pathology...... 1202 Specificareas for investigation...... 1205 Airway wallremodelling...... 1203 Assessingnew therapies...... 1206 Glucocorticoidresponsiveness...... 1203 Europe-wideresearch group...... 1206

ATaskForce supported by the European Respiratory Formulatingthe definition Societywas setup in 1997 in order to addressthe major issuesrelevant to difficult/ therapy-resistantasthma. Al- Alargenumber of terms are used by clinicians when thoughthe group of patients involved is small in com- referringto asthmaticpatients who have "difficult to treat" parisonto thehigh numbers of patientswith asthma, these disease:difficult acute, difficult chronic, chronic severe, patientsconsume a significantproportion of medical re- acutesevere, therapy-resistant, difficult to control, cortico- sourcesin terms of both time and money [1]. The major steroid-resistantor corticosteroid-dependent, symptomat- issuesfacing the Task Force were howtodefine"difficult ic,life-threatening, and fatal. An encompassing inclusive asthma",how the patient with difficult asthma should be ratherthan exclusive definition was soughtand the use of evaluated,the pathophysiological mechanisms underly- theterm "difficult/ therapy-resistantasthma" was adopted ingdifficult asthma and the treatments available. The toinclude all such cases of asthmaof allage groups. Since TaskForce also concerned itself with defining the areas of wheezingdisorders in preschoolchildren are poorly char- researchnecessary to bring about a greaterunderstanding acterized,this report specifically excludes children below ofthe causes of difficult asthma and novel treatments. theage of 5 yrs.Response to therapy is included in this Thedocument resulting from thisTask Force represents a conceptand will have research implications. It was ac- consensusof differentopinions, which will form thebasis ceptedthat the definition needed to be inclusive, although for furtherresearch. losingsome precision, but it was alsorecognized that its

Thisposition document of the European Respiratory Society was officially adopted by the ERS ExecutiveCommittee.

Thisreport was compiled following the submission of manuscriptsfrom the T askForce membership and a meetingheld at the National Heart& LungInstitute in London, UK inJanuary 1998. The full manuscripts will be publishedin the EuropeanRespiratory Review . Correspondence:K.F. Chung , NationalHeart &LungInstitute , Imperial CollegeSchool of Medicine , DovehouseSt., London SW3 6L Y,UK.Fax:44 1713512126. DIFFICULT/THERAPY-RESISTANTASTHMA 1199 usewas dependentto some extent on theobjective of in- Table 1. –Diagnoses that may masquerade asdifficult/ dividualresearch. For example,a definitionfor epidemio- therapy-resistantasthma logicalpurposes may not be entirelysimilar to one used for In children determiningthe mucosal pathology of thecondition. One Obliterativebronchiolitis furtherdifficulty is the need to assess patients over a period Vocalcord dysfunction oftime, generally 6– 12 months, rather than immediately Bronchomalacia onpresentation, before they can be labelled as having Inhaledforeign bodies difficult/therapy-resistantasthma. Cysticfibrosis Recentaspiration (particularly in handicapped children) Developmentalabnormalities of the upper airway Diagnosisof asthma Immunoglobulindeficiencies Primaryciliary dyskinesia Itis essential to be as certain as possible of aprimary In adults diagnosisof asthma.This diagnosis very much rests on a Cysticfibrosis clinicalhistory and physiological evidence of variableand Bronchiectasis reversibleairways obstruction and on the exclusion of Inhaledforeign body possiblealternative diagnoses that may mimic asthma (see Tracheobronchomalacia Recurrentaspiration below).Often, on presentationto thespecialist, it may not Chronicobstructive pulmonary disease bepossible to obtain contemporary evidence of these Congestivecardiac failure featuresif the patient is already established on anti-asth- Tumoursin or impingingon central airways matherapy, which it is not usually possible to discontinue. Obstructivebronchiolitis At thisstage, the bronchodilatory response to ß-agonist Vocalcord dysfunction therapymay be small and the response to high-dose cor- Bronchialamyloidosis ticosteroidtherapy blunted ( e.g. "steroid-resistant"or "ster- Aspart of the asthmatic diathesis oid-insensitive"asthma). Supportive evidence may only be Allergicbronchopulmonary aspergillosis availablefrom previousrecords of variable and reversible Pulmonaryeosinophilic syndromes ( e.g. Churg–Strauss) airflowobstruction. Both from theclinical and the research viewpoint,certainty in the diagnosis of asthmais essential, butit may not be achievedimmediately in many patients touse reliever short-acting ß-agonistmedication. This con- becauseof the nonspecificity of symptomsand the lack of trolcan be difficultto assess in the absence of antiasthma diagnosticmarkers. therapynowadays because, by thetime of presentationto thespecialist, most patients have been started on some form oftherapy.Patients vary in theirperception of airflow Exclusionof other diagnoses limitationand poor perceivers may be particularlyprone to Manyconditions can induce wheezing associated with severeattacks [3, 4]. Two patterns of symptoms are im- airwaysobstruction and a patientwith a presumeddiag- portantin defining control. The number of acuteexacer- nosisof asthma but not apparently responding to asthma bationsrequiring oral/ systemiccorticosteroid therapy is medicationshould be investigatedfor otherpossible alter- onemarker of asthma control; however, the term "exa- nativeor associated diagnoses (table 1). Asthma may be cerbation"requires refinement and classification. The mistakenfor manysuperficially similar conditions and extentof chronicsymptomatology is theother means of thisleads to manypatients being prescribed inhaled ster- recognizingpoor control. Monitoring of peak expiratory oidtherapy. Although cough and the presence of eosi- flow(PEF) maybe usedto document airway obstruction nophilsin sputummay be considereda variantof asthma, andits diurnal variability. Such measurements, often coughalone in the absence of evidence of intermittent recordedby thepatient at home, are effort-dependent and bronchialobstruction is unlikely to be causedby asthma. requiretotal cooperation. Allergicbronchopulmonary aspergillosis and pulmonary Withinthe definition of asthmacontrol lies the concept eosinophilicsyndromes ( e.g. pulmonaryeosinophilia or ofasthmaseverity ,whichmay be consideredas the amount Churg–Strauss syndrome) may be considered unique ofairwaysobstruction or ofsymptoms or theneed for ß- diseaseswith some of theclinical features of asthmaand agonistreliever therapy. PEF andforced expiratory volume areoften difficult to treat; these are probably best con- inone second (FEV 1)havebeen used to grade the severity sideredoutside the definition of difficult/therapy-resistant ofasthma,with values <60%of predicted graded as severe, asthma.V ocalcord dysfunction characterized by adduc- those60– 80% pred as moderatelysevere and those >80% tionof the vocal cords can masquerade as and may asmild [5]. There have been no studies comparing this coexistwith asthma [2], which could make asthma appear classificationwith other asthma outcome measures but moresevere than it really is. Other respiratory conditions suchmeasurements of airwaysobstruction may be useful suchas chronic bronchitis or bronchiectasis may also co- for asthmaticswith "fixed" airways obstruction. The pres- existwith asthma, but the effect of these on asthma se- enceof persistentairways obstruction does not necessar- verityor controlis not known. ilyreflect loss of control. Asthma-specificmeasures of quality of life and func- Asthmacontrol tionalstatus are another dimension of outcome and a measureof the impact of thedisease on patients in their Asthmacontrol is usually assessed by evaluationof the environments[6]. Finally, the value of usingasthma bio- patient’sperceptionsof theirsymptoms of wheeze, short- markersto assess the amount of airways inflammation nessof breath,cough, and nocturnal awakenings and need andthe relationship of this to asthma control is under 1200 K.F.CHUNG, P .GODARD evaluation.Increasingly, the amount of inhaledanti-infla- analysesof asthmadeaths or near-asthmadeaths indicate mmatorytherapy needed for controlof asthma,rather than thefollowing relative risk factors: female sex, young age thequantification of symptoms or of lung function [7], (<25yrs old), exposure to high levels of allergen ( e.g. whichrequire a periodof follow-up in order to observe soya bean or Alternaria),psychosocialdisturbances, be- responseand optimally titrate symptoms with treatment, ingin an ethnic minority group, concomitant smoking, isbeing used to define asthma severity. The observation havinghad a previouslife-threatening episode, and dis- oftheasthmatic over a periodof 6–12 months,therefore, continuityof physiciancare [20– 23]. In the case of most willallow both diagnosis of asthmaand assessment of its ofthese associations, it is not known whether these are severityand control with therapy. This is applied in the director indirecteffects, but they do provideareas where Task Force’sproposeddefinition of difficultasthma (see therapeuticpossibilities can be investigated.At themore below). mechanisticand research level, potential risk factors that maycontribute to difficult/ therapy-resistantasthma may Factorscontributing to loss of asthma control involve:1) the development of specific inflammatory changesin airways; 2) chronic structural changes; 3) Itis important to distinguish between the factors that certaingenetic polymorphisms, perhaps related to airway eitherpredispose to or cause asthma and those factors inflammation;and 4) specific environmental factors in- which,in a patientalready suffering from asthma,contri- cludingexposure to pollutants and allergens. buteto loss of control and difficult/ therapy-resistantasth- ma.The difficulty in making this distinction is thatsome of thesefactors may be commonto bothcausation and wor- Asthmatherapy sening.This is animportant concept in the light of ongoing Onpresentation to the specialist, patients with difficult studiesexamining both genetic susceptibility to and envir- asthmawill have been established on asthmatherapy for a onmentalfactors in asthma.However, the difficult/ therapy- periodof time, usually inhaled corticosteroid therapy .The resistantasthmatic patient may have a distinctgenotype. dosageof inhaled corticosteroid therapy required above Anumberof medical factors may contribute to poor whichone may consider asthma to bedifficult to manage is controlin asthma (table 2). Gastro-oesophageal reflux is arbitrary,reflectingthe balance between diminishing thera- commonlynoted in asthmatics, with a reportedincidence peuticreturns and increasing risks of unwantedeffects. In ofupto60% in children with moderate-to-severe asthma adults,a totaldaily dosage in excess of 2,000 µg bec- [8,9]. Although a precisemechanistic link between lomethasone,1,600 µgbudesonide,1,000 µgfluticasone gastro-oesophagealreflux and a declinein asthmacontrol orequivalentdoses of other inhaled corticosteroids and, in isnot established, varying degrees of improvement in children,a doseof beclomethasone or budesonide >800 asthmahave been observed when concomitant gastro- µg.day-1 or 400 µg.day-1 offluticasonewould appear to be oesophagealreflux has been treated [10, 11]. Sinusitis/ areasonablethreshold for thedefinition of difficultasthma. rhinitisand asthma are frequently coexisting problems Thesedoses are likely to be ontherelatively "flat" portion [12],and significant improvement in asthmacontrol may ofthe corticosteroid dose– response relationship, above beobtained with targeted treatment for sinusitis/rhinitis whichthe potential for furthertherapeutic effect diminishes [13].Viral and sometimes bacterial infection of the sin- andthe likelihood of systemic side-effects is significant useshave been implicated as exacerbating factors in [24].Often, the patient with difficult asthma is taking asthma,but their importance in initiating difficult asthma dosesof inhaledcorticosteroid therapy higher than these needsto be assessed. and/ororalcorticosteroid therapy. From apracticalstand- Psychosocialfactors, which may be linkedwith or com- point,patients whose asthma is not controlled on high- poundedby poor patient compliance and lack of ap- doseinhaled corticosteroid therapy can be consideredto propriatemedical care [14] have also been implicated in havedifficult/ therapy-resistantasthma. From aclinical retrospectiveanalyses of asthma deaths. High scores of standpoint,the initial aim is to determine whether or not psychiatricmorbidity have been correlated with severe thereare immediately remediable or avoidable factors asthmaand in the families of childrenwho die. contributingto this lack of response. Otherfactors may include exposure to allergens,indoor andoutdoor air pollution, endotoxin and viral respiratory tractinfections [15, 18]. There is some evidence for the Patientcompliance and supervision involvementof chlamydialinfections [19]. Retrospective Sinceresponse to therapy is part of the definition of Table 2. –Factorsthat may contribute to lossof controlin difficult/therapy-resistantasthma, the question of patient asthma adherenceto treatmentmust be considered. Compliance to inhaledcorticosteroid therapy in asthmahas been reported Poorcompliance/ adherenceto therapy Psychosocialand emotional factors tobe 30–70% [25, 26]. How muchthis contributes to poor Inadequatemedical facilities asthmacontrol is not known. This remains an area where Pooraccess to medical facilities moredefinite answers are needed. Adequacy of anti- Inadequatetreatment asthmatreatment (particularly with preventive or anti- Exposureto allergens inflammatorytherapy) relevant to the degree of severity Viralrespiratory tract infections ofasthma is also of importance. The use of electronic Indoor/outdoorpollution monitorson inhalers should ideally form partof the Gastro-oesophagealreflux assessmentof thepatient with difficult asthma, not only Sinorhinitis for regulartherapy but also for asneeded therapy, such as Geneticfactors inhaledshort-acting ß2-agonists. DIFFICULT/THERAPY-RESISTANTASTHMA 1201

Definitionof difficult/ therapy-resistantasthma moreirreversible state, some patients still retain a bron- chodilatorresponse to ß2-agonists.However, it shouldbe Difficult/therapy-resistantasthma is that which is poorly notedthat these categories are not mutually exclusive. controlledin terms of chronic symptoms, episodic exacer- Itis not known whether any of theseclinical phenotypes bations,persistent and variable airways obstruction and a differin terms of their airway pathology. In addition to continuedrequirement for short-acting ß2-agonistsdespite thesepatterns, other subgroups of patientsin whom asthma deliveryof areasonabledose of inhaledcorticosteroids (as maybe difficultto treat include those with aspirin-induced definedabove). Patients may require courses of oral cor- asthma(triad of symptoms: usually of late-onset, not as- ticosteroidsor a regulardose of oral corticosteroids to sociatedwith atopy, rhinosinusitis and nasal polyps, and maintainreasonable control of the disease. Rarely ,control exhibitingsensitivity to aspirin and/ ornonsteroidal anti- ofasthma may be totally uninfluenced by corticosteroid inflammatorydrugs), premenstrual worsening of asthma therapy.Diagnosis on the basis of this definition can be andadult-onset asthma, usually with a nonatopicback- establishedby means of follow-up of and care for the ground.Other clinical patterns may emerge on examina- patientby a respiratoryspecialist for aperiodof $6 tionof largercohorts. monthsduring which time asthma management is carried outaccording to published asthma guidelines [27– 29] and Evaluationand pathophysiology of issuessuch as compliance with treatment, identification ofexacerbatingfactors and exclusion of other diagnoses difficult/therapy-resistantasthma aredealt with (table 1). The diagnosis should thus be Aprotocolfor evaluatingdifficult/ therapy-resistantas- confirmed,features of the difficulty in asthma deter- thmais necessary in order to address and attempt to valid- mined,treatment optimized and its effects observed, and ateissues raised in the proposed definition, to provide data adherenceto treatment and delivery of care optimized. thatcan be comparedbetween centres and to standardize Ideally,this would be achieved by evaluation of the patientcategories for researchpurposes, including thera- patientat the initial visit and again 6– 12 months later . peutictrials. A proposedlist of techniquesfor theinvesti- gationof difficult/therapy-resistantasthma is proposed in Patterns ofdifficulty in asthma table3. Adiscussionof some of theaspects of thisinvesti- gationwith regard to understanding the pathophysiology Somedistinct "patterns" in the patient with difficult andcause of difficult/therapy-resistantasthma follows. asthmahave been described, usually characterized by the temporralsequence of exacerbations and symptoms, the Table 3. –Investigation of difficult/therapy-resistantasth- chronicityand rapidity of onsetof the symptoms and the ma responseto treatment [30]. Such descriptions have been Assessmentof severity obtainedfor themost part from personalobservations in Symptomscore chart and use of ß2-agonistreliever therapy smallgroups of patients and must be verified in largerco- Spirometricmeasurement of lungvolumes and gas transfer horts.It is important to confirm such different patterns, Bronchialresponsiveness to methacholine/ histamine particularlyin patients already established on inhaled Diurnalvariation in peak expiratory flow corticosteroidtherapy. Descriptive patterns of airwayob- Qualityof lifeassessment structioncan be classified, generally supported by re- Determinationof pharmacological responsiveness cordingsof PEF measurements,as follows. 1) Patientswho Assessmentof compliance to therapy and inhaler technique experiencea fatalor near-fatalepisode of asthmathat is Bronchodilatorresponse to ß2-adrenergicagonists associatedwith hypercapnia or necessitates mechanical Responseto prednisolone (corticosteroid-responsivenes s) Radiology ventilation.These episodes may recur despite "adequate" Chestradiograph treatment;therefore, such patients are at risk of death Bariumswallow causedby asthma. Within this group are those that have Computedtomography of sinuses recurrentepisodes of severeasthma necessitating frequent High-resolutioncomputed tomography of the lungs intermittentsystemic corticosteroids. 2) Patients experi- Blood tests encingrecurrent episodes of severeairway narrowing that Fullblood count, including eosinophil count appearrapidly over minutes-to-hours, occurring at any SerumIgG, IgA, IgM and IgG subclasses timeof day, with no obvious triggers and often labelled Serumtotal IgE "brittleasthma" when the onset is particularly rapid [31]. SpecificIgE to selected allergens Thesepatients have either normal lung function between Thyroidfunction tests Other tests episodesthat cannot be prevented by corticosteroidtherapy Biomarkersof inflammation (exhaled nitric oxide, eosinophils orapersistentbackground of widevariability in airways ininduced sputum) obstruction.Some patients with nocturnal or morning Sweattest and genetic assessment of CFTR mutations(if indi- asthmasymptoms show severe morning dips in PEF with cated) markeddiurnal flow variability, sometimes accompanied 24-hoesophageal pH monitoring byalargebronchodilator response. 3) Patients with a per- Examinationof nasopharyngealairways sistentpattern of airway obstruction, with or without Testsof ciliary function episodesof suddendeterioration, and requiring oral cor- Skinprick test to common aeroallergens ticosteroidtreatment, to which they show an incomplete Fibreopticbronchoscopy with bronchial biopsy and bronchoal- veolarlavage response.The terms "corticosteroid-dependence" or "a Psychologicalassessment partialcorticosteroid resistance" are often used. This pat- ternseems to be rare inchildren. The term "fixed" obstruc- Igimmunoglobulin; CFTR: cysticfibrosis transmembrane con- tionis also used occasionally; although this term implies a ductanceregulator. 1202 K.F.CHUNG, P .GODARD

Lungmechanics and airway responsiveness responseto therapy. The use of fibreopticbronchoscopy to obtainmucosal biopsies for histologicalexamination is Lungmechanics and airway responsiveness are major likelyto be safe, although the risks and benefits of this determinantsof the clinical severity and expression of investigationin the patient with difficult asthma have not difficult/therapy-resistantasthma, although these appear to beenwidely assessed [44]. There is already suggestion beofminor importance in the evaluation of patients.One thatdifficult/ therapy-resistantasthma may be subclassi- ofthe pathophysiological features of severe asthma is fiedhistologically. The presence of eosinophils and ac- excessiveairway narrowing, as can be demonstrated by the tivatedT -cellsdespite anti-inflammatory therapy may lossof maximalplateau responses following high doses of indicate"resistance" to the effects of treatment.A recent bronchoconstrictorstimuli [32]. This unlimited airway investigationof patients with difficult asthma on oralcor- narrowingmay be related to an increased amount of ticosteroidtherapy did not reveal significant submucosal airwaysmooth muscle [33, 34], exudative swelling of the eosinophiliabut rather an increase in neutrophil numbers airwaywall [35, 36] and airway– parenchymal interac- [45].Some patients with difficult to treat asthma have tions[37]. A notablefeature of severeasthma is the loss persistentlyelevated levels of exhalednitric oxide despite ofbronchodilatation on deep inspiration, which may be beingon high-dose oral corticosteroid therapy [46]. Use associatedwith airways inflammation [38] and excessive ofbiomarkers of inflammation obtained by means of narrowingduring bronchoconstriction [39]. The loss of noninvasivetechniques will be useful in understanding deepbreath-induced bronchodilatation may contribute to thepathophysiology and also in the management of these theincreased perception of breathlessness in patients with patients. asthma[40]. Loss of mechanicalload may also affect the Sinceinflammatory abnormalities may not only be behaviourof airway smooth muscle by favouring the confinedto the proximal airways, the value of examining developmentof force-maintenance [41]. These observa- transbronchiallung biopsies to assess the distal airways tionsmay form thebasis of therapidity of developmentof andlung parenchyma needs to be ascertained. There are, severeairway narrowing in certain patients and also the however,potential dangers in this procedure. It may chronicshortness of breath observed in some patients excludeother bronchiolar diagnoses. In a smallstudy of withdifficult asthma. It is not known whether the dif- patientswith difficult asthma undergoing steroid therapy, ficult/therapy-resistantasthma patient demonstrates more nocomplications were reportedfollowing transbronchial pronouncedabnormalities of airwaysmooth muscle mass lungbiopsy showing a neutrophilicrather than an eosi- andcontractility or oflossof airway– parenchymal inter- nophilicinfiltrate, similar to changes observed in more dependence. proximalbronchial biopsies [45]. In nocturnal asthma, thereis a morepronounced eosinophilic inflammation in thedistal airways sampled by transbronchial lung biop- Computedtomography of the airways and lungs sies[47]. Use ofvideo-assistedthoracoscopic surgery for obtainingperipheral lung tissue from patientswith dif- Computedtomography has been used to assess poten- ficultasthma should be debated:it may be associated with tialstructural changes in the medium-sized airways. One lesserrisk. However, no consensus can yet be arrivedat earlystudy demonstrated that the severity of asthma, as concerningits potential utility. Examination of peripheral definedby a clinicalscore, was relatedto the degree of lungtissues could advance understanding of the patho- airwaythickening and dilatation [42], whereas another logicalprocess and perhaps help in the staging of the relatedit to the degree of air-trapping, measured on in- chronicityof theprocess, but it should be debated as to spiratoryand expiratory scans [43]. The pathological whethersuch information will benefit patients in terms of correlatesof these changes on computed tomographic theirfuture management. scanninghave not been determined. Whether these air- waywall changes are a reflectionof thickening of the muscleor submucosa or oedema are not known. The Pathology usefulnessof thistechnique in assessing difficult/ therapy- resistantasthma remains undefined. One advantage of Inpatients with mild asthma, patchy loss of the sur- performingthese scans is the exclusion of other patho- faceepithelium, thickening of thereticular basement mem- logiessuch as bronchiectasis, emphysema, obliterative braneand increased cellular infiltrate in the bronchial bronchiolitisand extrinsic allergic alveolitis. Its valuein mucosa,consisting mainly of eosinophils, often mast cells assessingairway wall remodelling is unclear and the andT -lymphocytes,are observed in bronchialbiopsy sec- significanceof radiologicalevidence of airwaywall thick- tions.The severity of asthma, as measured by the ex- eningand dilatation in a patientwith asthma remains pressionof symptoms and degree of airflow limitation, has speculativein the absence of pathologicalcorrelation. beenassociated with the presence of activatedeosinophils andexpression of certain cytokines in the mucosa ( e.g. interleukin(IL)-5, granulocyte-macrophagecolony-stimu- Airwayinflammation latingfactor) in several studies [48– 50]. In more severe asthmaticson chronic oral steroid therapy, marked neu- Sinceso few studieshave evaluated airways inflamma- trophiliain bronchoalveolar lavage fluid and endo- and tionin difficult asthma, the value of this remains unde- transbronchialbiopsies has been observed, whereas mod- terminedfor bothclinical and research purposes. It seems eratelysevere asthmatics not on oral steroids demon- likelythat routine evaluation of thebronchial inflammatory stratedeosinophilia [45]. Neutrophilic inflammation has infiltrateat the cellular and molecular level may provide alsobeen reported during acute exacerbations of asthma, cluesas to the likely clinical course of the disease and andin cases of fatal asthma attacks of sudden onset [51]. DIFFICULT/THERAPY-RESISTANTASTHMA 1203

Immunohistochemicalstudies of fatal asthma as com- theairways submucosa of steroid-resistantasthmatics [59]. paredto mild nonfatal asthma have not provided any clear Corticosteroidsalso do notinhibit ex vivo proliferationof indicationsas to possible contributing factors to the severe theperipheral blood T -cellsof steroid-resistant asthmatics obstruction.Some studies have indicated that the eos- [60].A reductionin the number of glucocorticoid re- inophilicinflammatory response is worse inthe proximal ceptorsavailable for bindingto deoxyribonucleicacid in airways,with a redistributionof T-lymphocytesaway from steroid-resistantasthmatics may be attributedto increased theairway epithelium, and others emphasize the even activationof thetranscription factor, activating protein-1 distributionof inflammation in both small and large [61].The mechanisms underlying corticosteroid-resistant airways[52, 53]. Submucosal vascular congestion may asthmamay shed light on thoseunderlying difficult asth- alsobe animportantfeature. It is not entirely clear whe- ma[62]. Circulating mononuclear cells in patients with theror notthe cellular components of airwayinflamma- spontaneouslydeteriorating asthma show a decreased tionare distinct in difficult asthma. If thereare distinct bindingaffinity of theircorticosteroid receptors, which is clinicalphenotypes of difficult asthma, it behoves us to reversedon treatment with oral corticosteroids. A de- characterizethese subgroups thoroughly before embark- creasedbinding affinity is also observed in patientstaking ingon studies of theairway mucosal pathology. long-termoral corticosteroids, but this is unlikely to be secondaryto the effect of long-term treatment with oral corticosteroids.However, what is needed is a studyof the Airwaywall remodelling mechanismof actionor inactionof corticosteroidsin the airwaysof patients with difficult asthma. Corticosteroid Aproportionof patients with asthma experience a receptorsare expressed at a particularlyhigh level in the relentlessdecline in lung function [54, 55], which may be airwayepithelial cells of nonasthmatics and mild asth- partiallycorticosteroid-resistant. What underlies this matics[63], and these cells may reflect the responsiveness declinein lung function is unclear but it may reflect oftheairways to corticosteroid therapy as the epithelium chronicprogressive airway wall "remodelling". This has isexposed to the highest concentrations of topicalcorti- beendefined as structural changes, with the appearance of costeroids.Further research should determine the factors subepithelialfibrosis and collagen deposition and an whichmodulate corticosteroid-responsiveness in difficult increasein the number of submucosalblood vessels and asthmaand ways of restoring responsiveness. ofairwaysmooth muscle mass [56].The pathogenesis of thisprocess of remodelling as well as its physiological significanceremains to be elucidated,but mayinvolve the expressionof growthfactors and pro-inflammatory cyto- Managementand treatment kinesinfluencing the deposition and breakdown of the collagenmatrix and increasing airway smooth muscle Manyof the aspects of diagnosis and optimization of mass andthe number of submucosalblood vessels. These treatmenthave already been addressed. Attention to these changesmay not be reversible with corticosteroid the- factorsmay improve the control of difficult asthma to a rapy.Obtention of lung tissue would be usefulin grading considerableextent [64]. Two areas that deserve particular thisprocess and defining potential therapeutic avenues. investigationrelate to the role of allergen exposure and psychosocialfactors.

Glucocorticoidresponsiveness

Theproposed definition of difficult/ therapy-resistant Allergenavoidance asthmarests very much on the therapeutic response of asthmaticpatients to inhaledor oralcorticosteroid therapy. Reversalof bronchial hyperresponsiveness, with a re- Tosomeextent, difficult asthma may be viewedas a spec- ductionin oral steroid requirement during prolonged trumof disease that responds suboptimally to inhaled or hospitalizationin an environment with a lowlevel of house oralcorticosteroids, thus necessitating high doses of these dustmites, has been reported in mild-to-moderately-severe treatmentsat the risk of side-effects. Much work has asthmatics[65]. Sensitization and seasonal exposure to focusedon "steroid-resistant" asthma, defined for research Alternaria hasbeen proposed as a riskfactor for sudden purposesas asthma in whichairways obstruction improves deathcaused by asthma [66]. The degree of exposureof after ß-agonistbronchodilator inhalation but not following patientswith severe brittle asthma to relevant aeroaller- acourseof oral prednisolone, usually taken at a doseof 40 gensin their homes is not known, but may be relevant to mg.day-1 for 2weeks[57]. A failureof patientsto dem- therapid onset of episodes of deterioration in these onstratean improvement in morning PEFs orFEV 1 by patients.It is not clear whether or not residence at high >15%has been used. However, resistance to corticoster- altitudein an atmosphere devoid of allergens improves oidsis relative because beneficial responses can be ob- symptomsin patients with difficult asthma. Assessment tainedif the doses are increased to even higher levels ofallergenexposure would probably require a homevisit [58]. andmeasurement of the levels of the common home Thetypical inflammatory infiltrate of eosinophils ob- allergens,with specific measures being taken to reduce servedin the airways submucosa in the steroid-resistant exposure.The role of certain allergens in causing diffi- asthmaticis similarto that in the steroid-sensitive patient. cult/therapy-resistantasthma needs further evaluation, and However,corticosteroid treatment does not cause a reduc- thereare no studiesat present that indicate that effective tionin the number of eosinophils or suppression of ex- allergenavoidance reduces the likelihood of asthmaexa- pressionof IL-4 andIL-5 messengerribonucleic acid in cerbationsor alters the natural history of thedisease. 1204 K.F.CHUNG, P .GODARD

Psychosocialfactors therapeuticgains at higher doses of inhaled corticoster- oids.Recently, hydrofluoroalkane aerosols with a finer Retrospectiveanalysis of patients who have died of particlesize and a greaterdegree of distal penetration asthmaindicates that psychosocial factors may have con- havebeen introduced, with the potential for improved tributedto poor control of asthmaand, therefore, to death therapeuticeffects, as reported for beclomethasonedi- causedby asthma. These have included social isolation, propionate[73]. This needs close evaluation. The use of maritalproblems, alcoholism, anxiety and depression [14, topicalcorticosteroids delivered from anebulizerhas 67].An association between psychiatric disturbances and beenadvocated but more data demonstrating efficacy are asthmamorbidity has been reported in near-fatal asthma required. attacks.In particular, the importance of denialas a barrier Oral corticosteroidsmay be addedunder various clinic- tothe use of appropriateself-management plans has been alsituations. 1) Patientswith chronic uncontrolled symp- emphasized.It is often difficult to clarify how psycho- tomsand exacerbations may be started on a trialof socialfactors and pathophysiological determinants of the prednisolonefollowed by astep-downstrategy to find the diseaseinterrelate in determining the severity of asthma. minimumeffective dose. 2) Patientswith intermittent fre- However,patients commonly cite emotional factors or quentexacerbations of asthmadespite maintenance high- stressas an exacerbating factor. doseinhaled corticosteroid therapy when frequent short Poorcontrol of asthma can result from poorcompli- coursesof oral corticosteroid therapy for theseexacerba- anceto therapy [68]. Patients with the highest levels of tionsare needed. 3) Patientsalready on amaintenancedose compliancehad significantly fewer exacerbationsthan oforal corticosteroids needing higher doses to maintain thosewith a confirmedrecord of poor compliance [69]. controlor treatexacerbations of asthma[58, 74]. Reportedlevels of compliance to treatment with inhaled corticosteroidtherapy have ranged from aslowas 30%in Short-acting ß-adrenergicagonists. Short-acting(SA) in- adolescentsto 55% in adults [25]. In another study, haled ß2-adrenergicagonists are used for theimmediate althoughmean compliance with inhaled therapy was 60– reliefof asthma symptoms. Their use in asthma is one 70%,treatment was onlytaken as prescribed on 30–40% measureof the severity of the disease. Excessive reli- ofdays [26]. The degree of adherence to prescribed anceon these agents is not advisable because of the fol- therapyin difficult asthma is difficultto estimate but this lowingcontroversial issues. 1) Regular use of high-dose shouldalways be attempted. Finally, the reasons behind SA ß2-agonistsmay cause a partialloss of effectiveness, thetendency to poor adherence to therapy need to be whichin turn may lead to the use of evenhigher doses. established.These may be relatedto psychosocialfactors, 2)High doses of SA ß2-agonistsmay be detrimental to therelationship between carer andpatient, poor patient thecontrol of asthma, perhaps by interfering with cor- educationand comprehension, too complicated antiasth- ticosteroidaction [75]. What constitutes an optimal and maregimens and fear ofunwantedeffects. "safe" levelof SA ß2-agonisthas not yet been deter- Patienteducation has been advocated as a pivotalpart of mined.Preventing excessive use of SA ß2-agonists (i.e. . -1 theintegrated therapeutic process [70]. Educational pro- >24puffs salbutamol day )neverthelessappears to be grammescan be useful for thepatient with difficult areasonablestep to take. Studies of ß2-adrenoreceptor asthma.Through education, these patients are helped to polymorphismsmay be helpful in determining which integratespecific knowledge, attitudes and practical skills patientswill be relatively unresponsive to SA ß2-ago- intoappropriate behaviour to optimally cope with asthma. nisttherapy or show severe tolerance to the effects of thesedrugs. One study showed an arginine 16 to gly- Detaileddescriptions of the potentials and limits of edu- 16 cationalmethods are required. cine mutationto be associated with a greaterdegree ofbronchodilator desensitization compared to the wild- type ß2-receptor[76] but this needs confirmation. The use of SA ß2-agonistsdelivered at high doses from a Specifictherapy nebulizershould be reserved for thetreatment of exac- erbations.On occasion, continuous subcutaneous admin- Corticosteroids. Bydefinition,the difficult asthmatic will istrationof terbutaline may be helpful in controlling bereceivinghigh doses of inhaledcorticosteroid therapy, attacksof brittleasthma [77]. How abeneficialeffect is oftentogether with oral corticosteroids. One of the grey achievedfrom asubcutaneousinfusion of terbutaline is areasis whether further increases in dose will bring fur- unclear.Patients with type 2 brittleasthma should be therbenefit. Studies of dose– response relationships of givena syringepreloaded with adrenalin to be self- inhaledcorticosteroids indicate that, in terms of sympt- administeredin extreme situations. omsand PEFs, thereis a progressivelydiminishing resp- onseabove 800 µg.day-1 ofbudesonide or 400 µg.day-1 Long-acting ß-adrenergicagonists. Complementaryac- fluticasonepropionate [71– 72]. Individual patients, how- tionof long-acting ß2-agonistswith medium or high ever,may respond to higher doses. The precise side-effect dosesof inhaledcorticosteroid therapy has been reported profileof higher doses of inhaledsteroids is not known. lt inmoderately severe asthma in terms of both improve- wouldtherefore be advisableto perform a trialof higher mentin lung function and prevention of asthma exac- dosesof inhaled steroids in difficult asthmatics for a erbations[78, 79]. Such benefits have been shown to limitedperiod. The introduction of potent topical cor- persistfor upto 1 yr.Therefore,the addition of long- ticosteroidshas been beneficial in reducing the need for acting ß2-agoniststo corticosteroid therapy in difficult oralcorticosteroid therapy in some severe therapy-res- asthmais areasonablestep. This may also help to reduce istantasthmatics. The search for evenmore potent topic- anyexcessive use of SA ß2-agonists.There are no reports alcorticosteroids continues despite their potential for tosuggest that such an addition worsens asthma control increasedsystemic side-effects and the apparent limited oracceleratesdecline in lung function. DIFFICULT/THERAPY-RESISTANTASTHMA 1205

Theophylline. Theophylline,in addition to its bronchodila- Europeangroup (the European Network For Understand- torproperties, has immunomodulatory properties in asth- ingMechanisms of Severe Asthma), funded partly by a ma[80, 81]. Its potentialvalue in difficult asthma is EuropeanUnion collaborative grant gathering such data. unclear.Addition of slow-release theophylline to mod- Largepopulations that have been characterized clinically eratedoses of inhaledcorticosteroids in moderately sev- andin terms of their responses to corticosteroids and of ereasthma provided similar or better control of asthma airwayinflammatory response are needed to study the comparedto high-dose inhaled corticosteroid therapy epidemiologyand risk factors, economic impact and natu- [82].Beneficial effects of theophyllinehave been report- ralhistory of difficult asthma. A cohortof patients with edin five cases of severedifficult asthma already estab- nondifficultasthma, preferably well-controlled on inhaled lishedon high-doseinhaled and oral corticosteroids [83]. therapy,should serve as a comparativegroup. Leukotrieneinhibitors. Leukotrieneinhibitors, particular- lyleukotriene receptor antagonists, have been added in patientsalready taking inhaled corticosteroids, with or Factorsassociated with difficult/ therapy-resistantasthma withoutoral corticosteroid therapy, with consequent im- provementin lung function and reduction in SA -ago- ß2 Whichfactors are associated with the development of nistuse [84, 85]. An inhaled steroid-sparing effect of oneleukotriene receptor antagonist has been demon- difficult/therapy-resistantasthma? Are therewell-defined stratedin moderate-to-severe asthma [86], whereas other clinicalsubgroups of difficult asthma, and are they suf- preliminarystudies show equivocal effects. Leukotriene ficientlydifferent to invoke different pathophysiological inhibitorshave been shown to be of particular benefit in mechanisms?T oolsand measures for theassessment of patientswith aspirin-induced asthma [87]. Corticoster- severityshould be validated and developed; some effort oidsdo not reduce leukotriene biosynthesis as measured needsto be expended in examining clinical outcome byurinary leukotriene E 4 excretion,and, therefore, the measures,the use of lung function parameters, the quan- combinationof leukotriene inhibitors with corticosteroids tificationof severity of acute episodes ("exacerbations") mayprovide additional benefit for somepatients with andthe use of theamount and kind of therapiesneeded to difficultasthma already taking high-dose inhaled or oral controlasthma symptoms or attacks. Studies of genetic corticosteroidtherapy. This requires further study. Such polymorphismswould be possible with such large cohorts dataindicate that, in certain patients with difficult asthma, ofpatientswith difficult asthma. theseverity of the asthma may result from increasing sulphidopeptideleukotriene metabolism.

Immunosuppressantsand antimetabolites. Theuse of me- Specificareas for investigation thotrexate,gold salts and cyclosporin A hasbeen examined inoral corticosteroid-dependent asthmatics in double-blind Otherimportant areas for investigationin well-defined placebo-controlledstudies and significant oral corticoster- groupsinclude the following. 1) Assessment of the in- oid-sparingeffects have beenfound [88– 91]. On average, a flammatoryresponse using induced sputum and bronchial halvingof the dose of corticosteroids has been reported biopsies,and evaluation of the sampling of distal airway after4– 5 monthsof continuous therapy. These medi- cationsare potentially toxic and should be instituted in changesusing transbronchial biopsies and, possibly ,video- specializedcentres. Other treatments that have been assistedthoracoscopic surgery .Thevalue of biomarkersof reportedinclude intravenous immunoglobulins (particu- asthmaobtained by meansof noninvasivemethods needs larlyin children), lignocaine aerosols, dapsone, colchi- tobe determined,but they are more likely to be usefulin cineand hydroxychloroquine, but these trials have been followingthe course of diseaseactivity .2)Studyingcor- openand small [92, 93]. These agents cannot be generally ticosteroid-responsivenessas a basisfor thedefinition of recommendedat present. difficultasthma relies on thepoor response of symptomsto athresholddose of corticosteroid therapy. What are the factorsthat determine corticosteroid responsiveness in Areasfor research severeasthma and what can be done to reversethe lack of corticosteroidresponsiveness? In order to classify difficult Definitionof clinical phenotype asthmainto varying degrees of corticosteroidresponsive- ness,means of measuringthis response either by clinical Amajorproblem in attempting to understand difficult andphysiological methods or by assayingthe numbers of asthmalies in the difficulty in recruiting large cohorts of circulatingcells such as mononuclear cells are needed. appropriatepatients for specificstudies. A definitionfor Theseresponses need to becorrelated with those in airway difficult/therapy-resistantasthma based on practical and cells.3) Specific focus on theparticular group of "brittle" theoreticalconsiderations should lay the foundation for a asthma,in which severe life-threatening attacks are not largedatabase. Records of such patients undergoing a preventedby corticosteroidtherapy .Therapidity of onset standardizedprotocol of investigations and possibly of ofthese attacks is typical and may invoke specific managementshould be kept in regionalcentres throughout mechanismssuch as rapid activation of mastcells through Europe.It would be mostimportant for suchpatients to be eitherallergic or neural mechanisms leading to broncho- clinicallycategorized as fully as possible, particularly with constriction.In such patients, the experience or the con- theidentification of patientswho may not turn out to have tinuedapprehension of suchattacks may form thebasis of asthma,or whose "difficulty" may be due to lack of importantpsychosocial disturbances that have been des- complianceor "psychosocial" factors. There is already a cribedpreviously . 1206 K.F.CHUNG, P .GODARD

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