antihistamines in asthma.pdf

Advanced Studies in Medicine S517

Although it is generally considered thatmany antihistamines have little or noefficacy in managing asthma, they areworth another look, because histamineis a major mediator that can cause air-

way smooth muscle constriction and because it is amajor product of mast cells and basophils, the prima-ry cells responsible for allergic reactions. In addition,bronchial hyperresponsiveness to histamine is a keyfeature in the diagnosis of asthma. The role of hista-mine, through its H1 receptors, in activating variousimmune system cells, such as macrophages, dendriticcells, or even lymphocytes, and contributing to airwayinflammation should not be underestimated.

The failure of antihistamines to produce meaningfulclinical effects in asthma can be attributed to drug poten-cy, dose-limiting anticholinergic effects and central ner-vous system side effects, particularly with first-generationagents, and redundancy in the immune system whereother mediators, such as leukotrienes and prostanoids,are also potent causes of lower airway obstruction.

ANTIHISTAMINES HAVE ANTI-INFLAMMATORY EFFECTS

Studies have shown that antihistamines have a dose-response effect on the release of various mediators inhuman and animal allergic reaction models. Other anti-inflammatory properties have also been recognized.1 Forexample, one study using ovalbumin (OVA) stimulatedT-cells from mice treated with desloratadine and chal-lenged with OVA found that desloratadine reduced

proinflammatory Th2 cytokines but had no significanteffect on anti-inflammatory Th1 cytokines.2

Several studies evaluating the role of antihistaminesin blood-cell trafficking in asthma and seasonal allergicrhinitis suggest that antihistamines reduce the move-ment of inflammatory cells from the circulation into thetissues.3-5 In one study, antihistamines produced a signif-icant dose-related reduction in soluble intracellular adhe-sion molecule-1 from nasal epithelial cells cultured in thepresence of eosinophils treated with latex beads, and thiswas associated with a dose-related attenuation ofeosinophil adherence to endothelial cells.3

Similarly, a study of 20 children with seasonal aller-gic rhinitis in which nasal lavage was performed beforeand after seasonal treatment with cetirizine found thatthe antihistamine reduced the number of eosinophils inthe nasal lavage, suggesting decreased trafficking into thenasal mucosa.4 A similar finding was noted in a study of12 asthmatic patients who were treated with cetirizine 15mg twice daily or placebo for 4 weeks in the beginningof the pollen season and then challenged with allergen.Bronchial alveolar lavage 24 hours after allergen chal-lenge revealed significantly fewer eosinophils in the ceti-rizine group compared with the placebo group.5

SEASONAL ALLERGIC RHINITIS WITH ASTHMA

Several studies evaluating the effects of antihista-mines on asthma in the context of seasonal allergicrhinitis have found that these agents exert beneficialeffects on asthma symptoms. In a 6-week parallel-group study comparing cetirizine with placebo in 90patients with asthma and seasonal allergic rhinitis dur-ing pollen season, cetirizine significantly reduced asth-ma symptoms, such as chest tightness, wheezing,breathlessness, and cough.6 Patients taking cetirizinealso reported improvement in quality of life measures and

SELECTED PRESENTATION

ARE ANTIHISTAMINES USEFUL IN MANAGING ASTHMA?*

Based on a presentation by Andrew Wilson, MD

*Based on a presentation given by Andrew Wilson,MD, at a luncheon seminar held in conjunction with the2003 World Allergy Congress.

Department of Clinical Pharmacology, NinewellsHospital, Dundee, Scotland.

S518 Vol. 4 (7A) July 2004


were more likely to continue with the study comparedwith those taking placebo. These results are a far cryfrom a recommendation made in 1983 that antihista-mines be contraindicated in asthma. A more recent 4-week study of desloratadine 5 mg once daily versusmontelukast 10 mg once daily versus placebo, whichincluded patients with severe asthma, found that bothactive treatments improved symptom severity scoresand reduced bronchodilator requirements.7 It is notknown whether these beneficial effects result from thereduction in the magnitude of the nasal airway diseaseor whether they reflect direct effects of antihistamineson the lower airways.

BRONCHIAL HYPERRESPONSIVENESS

Antihistamines have been shown in several studies toexert beneficial effects on bronchial hyperresponsiveness.In one study, 16 patients who were shown to have a dualresponse to allergen challenge were treated with twice-daily cetirizine 15 mg or placebo.8 Although there was nochange in early allergic response, there was a significantreduction in the late allergic response in the cetirizine-treated group versus placebo, as measured by maximumfall in forced expiratory volume in 1 second (FEV1) andarea under the curve at 3 and 8 hours.

Exercise-challenge testing in 11 children takingloratadine or placebo demonstrated improved airwayfunction during exercise with loratadine versus place-bo.9 Mannitol-challenge testing in 20 subjects withmild asthma who had received either fexofenadine 180mg or montelukast 10 mg 2 days prior to challengerevealed that fexofenadine significantly increased theprovocation dose (PD 15) compared with placebo anddelayed recovery from baseline, whereas theleukotriene antagonist montelukast showed no changein PD 15 compared with placebo but significantlyimproved return to baseline.10

ATOPIC MARCH

Asthma often coexists with allergic conditions,such as eczema, dermatitis, and rhinitis. In a study ofchildren at high risk for developing asthma because ofallergy, high immunoglobulin E levels, and a strongpositive family history of allergy, only 3 of 45 childrentaking ketotifen for 3 years developed asthma, com-pared with 14 of 40 children taking placebo, a statisti-cally significant difference.11

Another important study, the Early Treatment ofthe Atopic Child (ETAC) study evaluated the devel-opment of asthma in children aged 1 to 2 years withatopic dermatitis and a positive family history of atopybut no history of wheezing after 6 months of age after18 months of treatment with cetirizine 0.25 mg/kgtwice daily or placebo.12 Although there was no signif-icant effect with cetirizine therapy, when the entiresubject population was considered, cetirizine showedsignificant protective effects against developing asthmain children with high IgE levels to grass pollen andhouse dust mites. These effects were maintained afterdiscontinuation of treatment.

ADDITIVE THERAPY

Histamine and the leukotrienes are released in con-cert during the early phase of allergic reactions.Similarly, increased levels of histamine andleukotrienes are found in the airways during the latephase. A study by Roquet and colleagues showed thatthe combination of loratadine (antihistamine) andzafirlukast (leukotriene receptor antagonist) hadimpressive, additive inhibitory effects on both theearly and the late bronchoconstrictive reactioninduced by allergen inhalation challenge in subjectswith asthma.13 In a placebo-controlled study evaluat-ing combined therapy with montelukast (also aleukotriene receptor antagonist) and loratadine in 117patients with moderate persistent asthma and highrates of allergic rhinitis (95%), the investigators foundthat the addition of the antihistamine to theleukotriene antagonist had a statistically significantbeneficial effect on FEV1, morning and evening peakexpiratory flow, and beta-agonist use.14

In a single-blind, double-dummy, randomizedcrossover study comparing cetirizine plus montelukastwith inhaled and intranasal corticosteroids in 14patients with moderately severe asthma and seasonalallergic rhinitis during grass pollen season, Wilson andhis colleagues found that the combination of cetirizineand montelukast had a significantly greater effect onadenosine monophosphate challenge compared withinhaled and intranasal budesonide, but the cortico-steroids were significantly better in terms of exhalednitric oxide measurements. There was no significantdifference between the cetirizine/montelukast combi-nation and the corticosteroids in terms of symptomscores and bronchodilator use.15


CONCLUSION

Antihistamines protect the lower airways from thebronchoconstrictive effects of allergic reactions, haveanti-inflammatory effects, and seem to influencebronchial hyperresponsiveness and the atopic march.There is evidence that antihistamines are beneficial inasthma, especially when it coexists with seasonalallergic rhinitis or when antihistamines are combinedwith leukotriene antagonists. More studies arerequired to examine whetherand most important-ly, in what instancesantihistamines should be usedalone or in combination with other agents for thetreatment of asthma.

REFERENCES

1. Togias A. H1-receptors: localization and role in airwayphysiology and in immune functions. J Allergy Clin Immunol.2003;112(4 suppl):S60-S68.

2. Bryce PJ, Geha R, Oettgen HC. Desloratadine inhibits aller-gen-induced airway inflammation and bronchial hyperre-sponsiveness and alters T-cell responses in murine models ofasthma. J Allergy Clin Immunol. 2003;112(1):149-158.

3. Abdelaziz MM, Devalia JL, Khair OA, Bayram H, Prior AJ,Davies RJ. Effect of fexofenadine on eosinophil-inducedchanges in epithelial permeability and cytokine release fromnasal epithelial cells of patients with seasonal allergic rhini-tis. J Allergy Clin Immunol. 1998;101(3):410-420.

4. Ciprandi G, Tosca M, Ricca V, et al. Cetirizine treatment ofrhinitis in children with pollen allergy: evidence of antialler-gic activity. Clin Exp Allergy. 1997;27(10):1160-1166.

5. Redier H, Chanez P, De Vos C, et al. Inhibitory effect ofcetirizine on the bronchial eosinophil recruitment induced byallergen inhalation challenge in allergic patients with asth-ma. J Allergy Clin Immunol. 1992;90(2):215-224.

6. Grant JA, Nicodemus CF, Findlay SR, et al. Cetirizine inpatients with seasonal rhinitis and concomitant asthma:prospective, randomized, placebo-controlled trial. J AllergyClin Immunol. 1995;95(5, pt 1):923-932.

7. Baena-Cagnani CE, Berger WE, DuBuske LM, et al.Comparative effects of desloratadine versus montelukast onasthma symptoms and use of beta 2-agonists in patientswith seasonal allergic rhinitis and asthma. Int Arch AllergyImmunol. 2003;130(4):307-313.

8. Wasserfallen JB, Leuenberger P, Pecoud A. Effect of certi-rizine, a new H1 antihistamine, on the early and late aller-gic reactions in a bronchial provocation test with allergen. J Allergy Clin Immunol. 1993;91(6):1189-1197.

9. Baki A, Orhan F. The effect of loratadine in exercise-induced asthma. Arch Dis Child. 2002;86(1):38-39.

10. Brannan JD, Anderson SD, Gomes K, King GG, Chan HK,Seale JP. Fexofenadine decreases sensitivity to and mon-telukast improves recovery from inhaled mannitol. Am JRespir Crit Care Med. 2001;163(6):1420-1425.

11. Bustos GJ, Bustos D, Bustos GJ, Romero O. Prevention ofasthma with ketotifen in preasthmatic children: a three-yearfollow-up study. Clin Exp Allergy. 1995;25(6):568-573.

12. Allergic factors associated with the development of asthmaand the influence of certirizine in a double-blind, ran-domised, placebo-controlled trial: first results of ETAC. EarlyTreatment of the Atopic Child. Pediatr Allergy Immunol.1998;9(3):116-124.

13. Roquet A, Dahlen B, Kumlin M, et al. Combined antago-nism of leukotrienes and histamine produces predominantinhibition of allergen-induced early and late phase airwayobstruction in asthmatics. Am J Respir Crit Care Med.1997;155(6):1856-1863.

14. Reicin A, White R, Weinstein SF, et al. Montelukast, aleukotriene receptor antagonist, in combination with lorata-dine, a histamine receptor antagonist, in the treatment ofchronic asthma. Arch Intern Med. 2000;160(16):2481-2488.

15. Wilson AM, Orr LC, Sims EJ, Dempsey OJ, Lipworth BJ.Antihistaminic effects of mediator blockade versus topicalcorticosteroids in allergic rhinitis and asthma. Am J RespirCrit Care Med. 2000;162(4, pt 1):1297-1301.


S520 Vol. 4 (7A) July 2004

Inhaled corticosteroids are first-line therapy forasthma in the United States and many othercountries; however, particularly at high doses,they can produce unwanted local and systemicside effects. Physicians should therefore consid-

er the potential side effects of these agents in everypatient receiving them and at every visit.

Corticosteroids exert their beneficial effects onasthma symptoms and lung function by interactingwith a corticosteroid receptor. Because the cortico-steroid receptor in the lung is the same as the cortico-steroid receptors elsewhere in the body, the amount ofinhaled drug that actually gets into the systemic circu-lation is the major determinant of systemic risk. Thelower the percentage of drug that gets into the lung,the higher the percentage of drug that is lost to depo-sition in the oropharynx, where it is swallowed andultimately becomes available to circulate throughoutthe body. Absorption of corticosteroids by the lungand subsequent distribution into the systemic circula-tion is another source of systemic exposure. The questfor the ideal inhaled corticosteroid thus begins withthe requirement that the agent be highly potent in thelung and inactive elsewhere. The pharmacologic prop-erties needed for an agent to produce such effects clin-ically are summarized in the Sidebar.

Is there such an agent? Recent and accumulatingdata show that ciclesonide, a novel inhaled cortico-steroid that is currently under investigation, possessessome of these properties, is the safest inhaled cortico-

steroid studied to date, and may be the ideal corti-costeroid for the treatment of asthma. The efficacy andsafety of ciclesonide were evaluated in a double-blind,randomized, placebo-controlled clinical trial including360 asthma patients with a forced expiratory volumein 1 second of 60% to 90% and evidence of reversibil-ity.1 Patients were pretreated with beclomethasonedipropionate and, after 2 weeks, were randomized toinhaled ciclesonide (80 g and 320 g) or placeboonce daily in the morning for 12 weeks. The efficacyof the study regimens was estimated as follows: 62%for ciclesonide 80 g, 77% for ciclesonide 320 g, and45% for placebo. Compared with baseline, morningpeak expiratory flow increased by 129 mL and 192 mLin patients taking the 80 g and 320-g doses ofciclesonide, respectively, and decreased by 28 mL inpatients taking placebo. No significant differencesbetween treatments were found in the incidence ofadverse events.


THE IDEAL INHALED CORTICOSTEROID*

Based on a presentation by Michael A. Kaliner, MD

*Based on a presentation given by Michael A. Kaliner,MD, at a dinner symposium held in conjunction with the2003 World Allergy Congress.

Medical Director, Institute for Asthma and Allergy, andClinical Professor of Medicine, George WashingtonUniversity School of Medicine, Washington, DC.

The Ideal Inhaled Corticosteroid

NEGLIGIBLE LOCAL SIDE EFFECTSInactive parent compoundLow oropharyngeal depositionLimited exposure of oropharynx to active molecule

HIGH POTENCYHigh affinity for glucocorticoid receptorProlonged residence time in lungLipid conjugation in airways

NEGLIGIBLE SYSTEMIC SIDE EFFECTSLow oral bioavailability/first-pass metabolismRapid systemic clearanceComplete plasma protein binding

Adapted from Derendorf H. Pharmacokinetic and pharmacodynamicproperties of inhaled corticosteroids in relation to efficacy and safety.Respir Med. 1997;91(suppl A):22-28.



Similar efficacy was observed in a group of 283patients with persistent asthma who had receivedciclesonide (160 g and 640 g once daily) or placebofor 12 weeks.2 These patients were included in anopen-label extension study to determine the long-termsafety of ciclesonide. Patients first received a dose of640 g of ciclesonide once daily or twice daily for 4weeks, followed by an individualized dose rangingfrom 160 g to 1280 g daily for another 36 weeks.The incidence of oropharyngeal adverse events duringthe extension study was low and consisted mainly ofpharyngitis (4%), voice alteration (2%) and oral can-didiasis (1%). No relevant systemic or oral adverseevents were reported, and most respiratory adverseevents were considered unlikely or unrelated tociclesonide. Long-term administration of ciclesonidewas associated with a 28% increase in 24-hour urinecortisol excretion.

Fluticasone propionate, the most frequently pre-scribed inhaled corticosteroid for asthma in the UnitedStates, possesses several of the properties listed in theSidebar. Both fluticasone and ciclesonide are potent;have high receptor-binding affinities; have prolongedresidence time in the lung, albeit by different mecha-

nisms; and are rapidly cleared from the systemiccirculation by the liver. However, considerablymore oropharyngeal deposition and considerablyless pulmonary deposition occur with fluticasonethan with ciclesonide (Table). The high percentageof oropharyngeal deposition with fluticasone isassociated with several local side effects, includingdysphonia, pharyngitis, and oral candidiasis. Bycomparison, ciclesonide is inhaled as an inactiveparent compound that converts to desciclesonide,or activated ciclesonide, in the lung, leaving verylittle activated compound to be deposited in theoropharynx.3

With fluticasone and several other inhaled corti-costeroids, the dose response in terms of improve-ment in lung function is rather flat. A higher dosewill not necessarily produce additional clinicalimprovement but will increase suppression of corti-sol and will produce other unwanted effects.Increased cortisol suppression with fluticasone ismost commonly seen in patients taking a daily doseof 880 g or more.4 The daily dose should thereforebe lowered to 660 g or less. In contrast, studieshave shown that ciclesonide has no effect on theadrenals and very little cortisol suppression.

REFERENCES

1. Langdon CG, Adler M, Mehra S, Drollmann A.Ciclesonide is effective in the treatment of asthma: a 12-week, placebo-controlled study. Presented at: the 4th WorldAsthma Meeting; February 16-19, 2004; Bangkok,Thailand. Abstract P-234.

2. Chapman KR, Boulet LP, DUrzo AD, Oedekoven C,Engelstaetter R. Long-term administration of ciclesonide issafe and well tolerated in patients with persistent asthma.Presented at: the 4th World Asthma Meeting; February 16-19, 2004; Bangkok, Thailand. Abstract P-232.

3. Richter K, Nave R, Biberger C, Bethke TD, Magnussen H.Low oropharyngeal deposition of inhaled ciclesonide inhealthy subjects and asthma patients. Presented at: the 4thWorld Asthma Meeting; February 16-19, 2004; Bangkok,Thailand. Abstract P-235.

4. Brus R. Effects of high-dose inhaled corticosteroids on plas-ma cortisol concentrations in healthy adults. Arch InternMed. 1999;159(16):2549-2550.

Table. Pharmacologic Properties of Ciclesonide andFluticasone Propionate

Ciclesonide/ FluticasoneDesciclesonide Propionate

Formulation Solution Suspension

Inhaled form Inactive parent Active compoundcompound

Particle size 1.1 m to 2.1 m 65% >5 m

Oropharyngeal 38% (total) 72% to 78% depositionOral bioavailability

S522 Vol. 4 (7A) July 2004

THE CASE FOR

Immunotherapy is a viable treatment option for asth-ma, particularly allergic and established asthma. Currenttherapies for asthma, such as inhaled corticosteroids,improve lung function but do not cure the disease; how-ever, they may also mask symptoms of allergy, an impor-tant cause of asthma that warrants treatment itself.Immunotherapy is an important alternative because ittreats allergy rather than masking it.

As demonstrated in a meta-analysis of clinical stud-ies evaluating the efficacy of immunotherapy against awide range of allergens, immunotherapy was associat-ed with reductions in symptom scores, exacerbations,and both specific and nonspecific airway responses,the most important endpoints in clinical trials.1

The scale of improvement can be substantial. Forexample, a 1-year, randomized, placebo-controlled, dou-ble-blind trial in 31 adults with asthma and allergy tohouse dust mites found that specific immunotherapy sig-nificantly reduced inhaled steroid use by 38%, beta-ago-nist use by 46%, and symptom score by 57% andsignificantly increased forced expiratory volume in 1 sec-ond (FEV1) from 85% to 89% of predicted values.2

Another important observation comes from a 3-year prospective nonrandomized study in 22 childrenyounger than 6 years of age with asthma and allergy tohouse dust mites and with or without rhinitis. Thestudy included 22 age-matched controls and demon-strated that specific immunotherapy prevents theonset of new sensitizations.3

With regard to disease prevention, a randomized,but not double-blind, study of pollen immunotherapyin 205 children between 6 and 14 years of age withmoderate-to-severe hay fever symptoms and with andwithout mild asthma symptoms demonstrated thatimmunotherapy reduced the risk of developing asth-ma.4 Although no children in the study had asthmarequiring daily treatment at study entry, 20% werefound to have mild asthma, as evaluated clinically andby peak flow, during the pollen season. In the studypopulation as a whole, 26% developed asthma after 3years of pollen immunotherapy, compared with 44%in the control group.

Immunotherapy also has beneficial effects on dis-ease progression. In a 4-year study of hyposensitizationtherapy for mild and moderate bronchial asthma inchildren, 70% of the subjects who received therapyoutgrew their asthma by 16 years of age, comparedwith only 21% of those in the untreated controlgroup. Any symptoms in the treated group were clas-sified mostly as mild, whereas asthma in 70% of theuntreated group (at age 16 years) was graded as mod-erate or severe.5

Although immunotherapy takes time to exert itsbeneficial effects, which may prompt physicians toavoid using it or discontinue it too soon, these effectsare more sustained than those of inhaled steroids. Thiswas demonstrated in a head-to-head comparison ofimmunotherapy and inhaled budesonide in 51 youngpatients with bronchial asthma who were given onetreatment or the other for 1 year and assessed for glob-al symptom scores and FEV1 values.6 When both treat-ments were discontinued abruptly at 1 year and theeffects of cessation were analyzed, it was clear thatbudesonide produced faster and more strikingimprovement during the first few months of treatmentthan immunotherapy, but its benefits declined rapidly

DEBATE

IMMUNOTHERAPY FOR ASTHMA: YES OR NO?

Based on presentations by Anthony Frew, MD* (the case for), and N. Franklin Adkinson, Jr, MD (the case against).

*Head, Department of Medical Specialties, University ofSouthampton, Southampton, United Kingdom; Professor ofMedicine, Johns Hopkins University School of Medicine,Baltimore, Maryland.


DEBATE

once therapy was discontinued. Immunotherapy, bycomparison, produced slow but steady improvementduring the treatment period and a more gradualdecline in beneficial effect after therapy was stopped.The effects of combining immunotherapy withinhaled steroids have not been formally studied.

Another reason to consider immunotherapy in asth-ma management is cost. Asthma is an expensive disease,with drugs accounting for most of the costs associatedwith mild asthma and a considerable portion of costsassociated with moderate and more severe disease.

A 2-year study comparing immunotherapy withplacebo in adults with asthma exacerbated by seasonalragweed exposure found that the reduced medicationcosts in patients receiving immunotherapy were coun-terbalanced by the costs of immunotherapy.7 Theimportant point, however, is that specificimmunotherapy may be cost effective if it reduces theneed for medication in future years or stops progres-sion of disease.

Several surveys assessing the safety of immunother-apy have found that a high proportion of deaths attrib-uted to this treatment occurred in patients withasthma. Most of these deaths, however, were from pre-cipitation of asthma rather than anaphylaxis, suggest-ing that safety can be considerably improved withcareful patient selection and appropriate managementof treatment-induced asthma. Other strategies toimprove safety include adequate staff training and theuse of antihistamine premedication.

THE CASE AGAINST

The use of immunotherapy for asthma does nothinge on whether it is effective but on whether it is clin-ically indicated. Although immunotherapy may be effec-tive in treating asthma, it is not clinically indicated ifbetter therapies can accomplish the same clinical end-pointstherapies that are more efficacious, produce lessmorbidity and mortality, and are more cost effective. Inaddition, immunotherapy is not clinically indicated if itsunique benefits (ie, an additive effect, the ability to pro-mote earlier or more frequent remissions, or the abilityto alter long-term outcome) are not significant.

The proposal to consider, then, is that allergenimmunotherapy is not clinically indicated for mostcases of allergic asthma, especially those involvingmoderate or severe persistent asthma, becauseimmunotherapy is no better than currently available

therapies and because there is little or no evidence thatits unique benefits are significant. For example, in a 2-year study comparing immunotherapy with placebo inadults with asthma exacerbated by ragweed allergy, thepositive clinical effects of immunotherapy on objectivemeasures of asthma and allergy were limited, andmany were not sustained over the course of the study.7

A meta-analysis of 24 studies of prophylacticinhaled corticosteroid use in children with asthmafound that the average relative improvement in morn-ing peak flow with inhaled steroids was 11%, twicethat of immunotherapy.8

In the only study comparing inhaled cortico-steroids with immunotherapy in patients with asthma,there was no significant difference between the earlyresponse to budesonide in moderate doses and thedelayed response to immunotherapy.6 Although avaliant study, it excluded patients with rhinitis and didnot evaluate higher doses of immunotherapy. A ran-domized, controlled, parallel-group study is needed.

In contrast, a randomized, double-blind, con-trolled study done at Johns Hopkins Universityassessed the effects of immunotherapy in 121 childrenwith asthma and 4 to 7 major allergic sensitivities whowere already practicing allergy avoidance.9 The studyfound no discernible effect of immunotherapy onmedication requirements, days of oral steroid use, useof medical care for asthma, reported asthma symp-toms, methacholine sensitivity, or the rate of partial orcomplete remission from asthma.

Historical data indicate that there are 3 to 5 deathsper year in the United States due to immunotherapy,with 75% of the deaths occurring in patients with asth-ma. A French team has defined risk for systemic reac-tions to immunotherapy as a function of the depressionin FEV1 measurements taken at the time of injection,indicating very clearly that uncontrolled asthma is amajor risk factor for all types of systemic reactions.10

As a result, practice standards now include guide-lines that underscore the need to observe patients andmonitor pulmonary function. These guidelines, how-ever, do not appear to have altered fatal outcomes ofimmunotherapy in the United States. This reflectsthe fact that immunotherapy is often administered bygeneral practitioners and specialists in areas otherthan allergy and that treatment errors and patientfactors are not completely understood. In contrast,inhaled steroids are not yet known to produce iatro-genic mortality.

S524 Vol. 4 (7A) July 2004

Several potential unique benefits of immunothera-py have been touted. One is immunologic specificity,which differs from anti-inflammatory agents and anti-immunoglobulin E therapy. Specificity, however, is adouble-edged sword and may not be an advantage.Another potential unique benefit is compliance, whichmay be an advantage in patients with mild asthma andin populations with limited access to medical care butnot in patients with moderate or severe asthma.

Cost is purported to be an advantage, but becausethe costs of immunotherapy and inhaled cortico-steroids vary so widely, it is difficult to determine costeffectiveness. In the United States, however, estimatessuggest that the cost of 1 year of immunotherapy is thesame as or slightly higher than the cost of 1 year ofinhaled corticosteroids.

With regard to nonspecific bronchial hyperreactiv-ity as assessed by methacholine challenge, most studiesshow no consistent change, and all multiallergenimmunotherapy studies have been negative. Responsesseen with immunotherapy are comparable to thoseseen with moderate doses of inhaled corticosteroids.The effects of both therapies on bronchial hyperreac-tivity are very small relative to the gap between asth-matic and normal subjects. Furthermore, no evidencehas demonstrated that immunotherapy produces per-manent changes in airway hyperreactivity. The poten-tial unique benefit of immunotherapy regardingremission rates requires further study.

Groups that appear to derive the most benefit fromimmunotherapy include children, patients with mildasthma, and individuals with restricted sensitivities (ie,monosensitized). The most positive immunotherapystudies reported over the past decade were conductedin monosensitized subjects. Most immunotherapy inthe United States, however, is administered to patientswho are polysensitized.

Although immunotherapy is not appropriate forpatients with moderate or severe persistent asthma

who are already taking inhaled corticosteroids, itappears to hold promise in preventing disease progres-sion in patients with early and mild asthma. Efforts toreduce the risk of systemic reactions, including death,are still needed.

REFERENCES

1. Abramson M, Puy R, Weiner J. Immunotherapy in asthma: anupdated systematic review. Allergy. 1999;54(10):1022-1041.

2. Olsen OT, Larsen KR, Jacobsan L, Svendsen UG. A 1-year,placebo-controlled, double-blind house-dust-mite immunothera-py study in asthmatic adults. Allergy. 1997;52(8):853-859.

3. Des Roches A, Paradis L, Menardo JL, Bouges S, Daures JP,Bousquet J. Immunotherapy with a standardizedDermatophagoides pteronyssinus extract. VI. Specificimmunotherapy prevents the onset of new sensitizations inchildren. J Allergy Clin Immunol. 1997;99(4):450-453.

4. Moller C, Dreborg S, Ferdousi HA, et al. Pollenimmunotherapy reduces the development of asthma in chil-dren with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109(2):251-256.

5. Johnstone DB, Dutton A. The value of hyposensitization ther-apy for bronchial asthma in children: a 14-year study.Pediatrics. 1968;42(5):793-802.

6. Shaikh WA. Immunotherapy vs inhaled budesonide inbronchial asthma: an open, parallel, comparative trial. Clin Exp Allergy. 1997;27(11):1279-1284.

7. Creticos PS, Reed CE, Norman PS, et al. Ragweedimmunotherapy in adult asthma. N Engl J Med.1996;334(8):501-506.

8. Calpin C, Macarthur C, Stephens D, Feldman W, ParkinPC. Effectiveness of prophylactic inhaled steroids in child-hood asthma: a systemic review of the literature. J AllergyClin Immunol. 1997;100(4):452-457.

9. Adkinson NF Jr, Eggleston PA, Eney D, et al. A controlledtrial of immunotherapy for asthma in allergic children. N Engl J Med. 1997;336(5):324-331.

10. Bousquet J, Hejjaoui A, Dhivert H, Clauzel AM, Michel FB.Immunotherapy with a standardized Dermatophagoidespteronyssinus extract. Systemic reactions during the rush pro-tocol in patients suffering from asthma. J Allergy ClinImmunol. 1989;83(4):797-802.

DEBATE


The role of cats and other fur-bearing petson allergies and asthma is now a contro-versial topic. As such, it has engenderednumerous discussions, articles, and debates,as well as a host of questions that go beyond

a recommendation to kill the cat or buy one.For example, do pets exacerbate allergies and/or

increase the risk for asthma? Is the prevalence of pet own-ership in a community related to the prevalence of aller-gy and asthma in that community? Does having a pet inchildhood promote or protect against the developmentof asthma in adulthood? Is there a dose-response rela-tionship between cat allergen exposure and sensitizationrates? Are avoidance measures effective?

KILL THE CAT

There is considerable evidence in support of elimi-nating cat exposure, in particular as a part of the man-agement of cat-allergic patients. Studies have shownthat sensitization to cat allergen is an important riskfactor for asthma, and that commonly used avoidancemeasures, such as high-efficiency particulate arrest aircleaners, high-filtration vacuum cleaners, and washingthe cat, are ineffective in reducing the amount ofinhaled cat allergen (vacuum cleaners may actuallyincrease it). Thus, for cat-allergic cat owners who expe-rience symptoms upon exposure, the only solution isto remove the cat from the home.

The relationship between cat ownership and thedevelopment of allergy and asthma is much morecomplex. However, a number of studies have shownthat owning a cat is a significant risk for sensitizationto cat, and that there is a significant correlation

between community prevalence of cat ownership andcommunity prevalence of respiratory symptoms andasthma. It has also been shown that the chances ofbeing sensitized in adulthood increase with the dura-tion of exposure to cats in the home during childhood.

Other studies have shown that cat ownership inchildhood is associated with more asthma in sensitizedadults who grew up in communities with a low fre-quency of cat ownership, but not in communities witha high proportion of cat ownership. The relationshipbetween cat ownership and the development of aller-gic disease differs between different areas and agegroups, and is additionally influenced by the familyhistory of allergy.

BUY A CAT

There is now evidence that increasing exposure tocat allergens, ie, a cat in the home, does not increaseeither the prevalence of sensitization or the risk ofasthma.1 The reason(s) for these observations are notunderstood. Do cats in the environment promoteexposure to bacteria or to bacterial products that alterthe immune system towards a low allergy phenotype(hygiene hypothesis), or do cat antigens promote aspecific form of immune tolerance? In most recentstudies, the presence of cats is not associated withincreased airborne endotoxin in a house; therefore, thesecond possibility appears more plausible.

It is quite possible that some allergens are createdmore equal than others and this may have extensivebiological and clinical implications. The early forms ofthe hygiene hypothesis predicted that nonallergic indi-viduals would have a Th1 immune response to aller-gens. However, both serological and T-cell resultssuggest that the tolerant response to cat allergens hasthe features of a modified Th2 response.2,3 This may

DEBATE

KILL THE CAT, OR BUY ONE?

Based on presentations by Adnan Custovic, MD,* and Thomas Platts-Mills, MD

*University of Manchester, Manchester, United Kingdom;University of Virginia Medical Center, Charlottesville, Virginia

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not be the case with other allergens. The problem withthese data is that they do not provide any informationon what will happen to a particular individual. Even ifbuying 2 cats would be good advice for the averageallergic person, it could still be very bad advice for asizeable minority.

RECOMMENDATIONS

Before making a recommendation to kill the cator buy one, physicians should carefully assess all caus-es of all allergic/asthmatic symptoms, the level of aller-gen exposure, the presence of other allergic conditionssuch as allergic dermatitis and the propensity for aller-gy (family history). At this point, allergen avoidance

(including cat) may still need to be recommended inhighly atopic individuals. More data will be hopefullyavailable in the near future to clarify this matter.

REFERENCES

1. Ownby D, Johnson C, Peterson E. Exposure to dogs andcats in the first year of life and risk of allergic sensitizationat 6 to 7 years of age. JAMA. 2002;288(8):963-972.

2. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R.Sensitization, asthma, and a modified Th2 response in chil-dren exposed to cat allergen: a population-based cross-sec-tional study. Lancet. 2001;357(9258):752-756

3. Reefer AJ, Carneiro RM, Custis NJ, et al. A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events indevelopment of the modified Th2 response to cat allergen. J Immunol. 2004;172(5):2763-2772


BENEFIT OF MONTELUKAST FOR ASTHMA IN PATIENTSWITH BOTH ASTHMA AND ALLERGIC RHINITIS: A POST-HOC ANALYSIS FROM THE COMPACT TRIAL

Based on an oral presentation by Price DB,* Swern AS,

Tozzi CA, Phillip G, Polos P, Yu Q

*General Practice and Primary Care, University ofAberdeen, Aberdeen, Scotland; Merck & Co, Inc, Rahway,New Jersey

A post-hoc analysis of the multicenter ClinicalObservation of Montelukast as a Partner Agent forComplementary Therapy (COMPACT) trial has foundthat adding montelukast to budesonide is superior todoubling the budesonide dose in improving morningpeak flow in the subgroup of asthma patients withconcomitant allergic rhinitis. The initial COMPACTstudy demonstrated that adding montelukast to budes-onide was at least as effective as doubling the budes-onide dose in improving morning peak flow inpatients with asthma.1

The COMPACT trial included 889 patientsbetween 15 and 70 years of age with chronicasthma for 1 year or longer who were not optimal-ly controlled (as judged by an investigator) despitethe use of inhaled corticosteroids (ie, 600 g to1200 g daily of budesonide or equivalent) for atleast 12 weeks. All had a minimal level of daytimesymptoms and beta-agonist use prior to random-ization. After a 4-week, single-blind, run-in phaseduring which all patients received budesonide 400g twice daily, patients were randomized in dou-ble-blind fashion to receive montelukast 10 mgonce daily plus budesonide 400 g twice daily (n = 448) or budesonide 800 g twice daily (n = 441) for 12 weeks.

In this post-hoc analysis, the effect of montelukastplus budesonide versus double-dose budesonide wascompared in the subgroup of patients with concomi-tant allergic rhinitis, defined by both a positive patienthistory and a confirmed physician diagnosis.Reasons for pursuing this line of investigation includethe following: rhinitis occurs in more than 75% ofpatients with allergic asthma; the same triggers (ie,allergens) can cause rhinitis and asthma; rhinitis canbe a risk factor for asthma exacerbations; and upperand lower airways share a common and probablyinterconnected inflammatory process, as evidencedby common inflammatory cells and mediators and thefact that nasal challenge leads to bronchial inflam-mation and vice versa.2 Moreover, optimal manage-ment of rhinitis may be beneficial in managingcoexistent asthma, and montelukast, which isapproved for the treatment of asthma, has recentlybeen approved for the treatment of allergic rhinitis inseveral countries, including the United States.

Overall, 410 patients in the COMPACT trial withasthma had concomitant allergic rhinitis (defined byhaving both a positive patient history of rhinitis and aconfirmed physician diagnosis), whereas 479 hadasthma without both a patient history and physician-confirmed allergic rhinitis. Of the 448 patients ran-domized to montelukast plus budesonide, 216 hadasthma and concomitant allergic rhinitis; 33 wereusing rhinitis medications, such as intranasal steroids,antihistamines, or other rhinitis treatments, prior to ran-domization. Of the 441 patients randomized to dou-ble-dose budesonide, 184 had asthma withconcomitant allergic rhinitis; 23 were using rhinitismedications prior to randomization.

At the end of the 12-week, double-blind treatmentphase, there were increases in morning peak flow

POSTER PRESENTATIONS

SELECTED ORAL AND POSTER PRESENTATIONS

The following are based on oral and poster presentations from the 2003 World Allergy Congress, held September 7-12, 2003, in Vancouver, British Columbia.

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values in patients randomized to montelukast plusbudesonide of 8.6% in the total group and 9.2% inthose with asthma and allergic rhinitis; these valueswere noted versus increases in patients randomizedto double-dose budesonide of 7.7% in the total groupand 6.0% in those with asthma and allergic rhinitis.

The addition of montelukast to budesonide signifi-cantly improved morning peak flow in patients withconcomitant asthma and allergic rhinitis (P < .03 vsdouble-dose budesonide). Furthermore, this addition-al treatment effect of montelukast was greatest inpatients taking rhinitis medication prior to randomiza-tion (n = 33). The treatment effect of doubling thedose of budesonide among patients taking rhinitismedication prior to randomization (n = 23) was lessthan adding montelukast (increases in peak flow val-ues of 12.1% for patients taking montelukast plusbudesonide vs 1.9% for those taking double-dosebudesonide; P < .02).

Results of this post-hoc analysis suggest the poten-tial for additional treatment benefit with montelukast inthe large population of asthmatics who have con-comitant allergic rhinitis. Further study, includingprospectively designed clinical trials, should beundertaken to evaluate this hypothesis.

REFERENCES

1. Price DB, Hernandez D, Magyar P, et al. Randomised con-trolled trial of montelukast plus inhaled budesonide versusdouble dose inhaled budesonide in adult patients with asth-ma. Thorax. 2003;58(3):211-216.

2. Togias A. Rhinitis and asthma: evidence for respiratory systemintegration. J Allergy Clin Immunol. 2003;111(6):1171-1183.

DEPOSITION OF EXTRA-FINE HYDROFLUOROALKANE-BECLOMETHASONE DIPROPIONATE INHALED VIAPRESSURIZED METERED-DOSE INHALERSPACER INASTHMATIC CHILDREN

Based on an oral presentation by Roller CM,* OwenJL,* Troedson RG, LeSouef PN,* Devadason SG*

*University of Western Australia, Perth; PrincessMargaret Hospital for Children, Perth, Western Australia.

Using gamma scintigraphy, a team of Australianinvestigators has demonstrated that inhalation of anextra-fine aerosol reformulation of beclomethasonedipropionate (smaller particles result by mixingbeclomethasone with the hydrofluoroalkane propel-lant), delivered via metered-dose inhaler with anattached detergent-coated holding chamber, signifi-cantly decreases unnecessary oropharyngeal and gas-trointestinal drug deposition while maintaining highlevels of lung deposition in children with mild asthma.

Because airway targeting largely determines theefficacy of inhaled corticosteroids, maximizing theamount of drug that gets into the lung is a major fac-tor in optimizing inhalation therapy in asthmatic chil-dren. The smaller the particle size that is deliveredby an aerosol device, such as an inhaler, the betterthe deposition into the airways. This issue is evenmore important in children because of their smallerairway diameters. Holding chambers are widelyrecommended for children in order to minimizeunnecessary oropharyngeal and gastrointestinaldrug deposition, which can contribute to both localand systemic side effects.

To assess the total body deposition and distributionof extra-fine beclomethasone in children, the investiga-tors had 12 boys inhale 99 m technetium-radiolabeleddrug via metered-dose inhaler and spacer. Eight boys,5 to 10 years of age, took 5 tidal breaths through thespacer after each actuation, while 4 boys older than10 years of age used a slow maximal inhalation fol-lowed by a 10-second breath hold. Simultaneous ante-rior and posterior planar gamma scintigraphic scans ofthe lungs were recorded.

Mean lung deposition, expressed as an attenua-tion-corrected percentage of the exactuated dose,was 35.1% in 4 boys between 5 and 7 years ofage, 47.5% in 4 boys between 8 and 10 years ofage, and 58.4% in 4 boys between 11 and 15years of age. Gastrointestinal deposition was 25%,10.3%, and 20.8%, respectively, in these same agegroups. The percentage of the drug remaining in thespacer was 39.5%, 41.5%, and 20.3%, respective-ly. Lung deposition of extra-fine beclomethasoneincreased significantly with age (P < .04).

The extra-fine particle metered-dose inhalerspac-er combination gave more efficient delivery of steroidby minimizing unwanted oropharyngeal and gas-trointestinal drug deposition while maintaining highdrug deposition to the airways.


A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED,CROSSOVER TRIAL OF MONTELUKAST IN ADULTS WITHNASAL POLYPOSIS

Based on a poster presented by Keith P, Ferrie P, ConwayM, Wasserman S, Schmuck M, Denburg J

Department of Medicine, McMaster University,Hamilton, Ontario, Canada

In this study of 23 adults with bilateral nasalpolyps, once-daily therapy with montelukast 10 mgfor 4 weeks was significantly superior to placebo inimproving global assessment of symptoms and quali-ty of life. Active treatment also showed a trendtoward reduction of blood eosinophil counts. Thesefindings demonstrate that montelukast, a cysteinylleukotriene receptor antagonist with clinical benefitsfor both asthma and allergic rhinitis, has beneficialeffects for nasal polyposis, a chronic eosinophilicinflammatory condition.

Study subjects were randomized in this double-blind, placebo-controlled, crossover study to compare4 weeks of montelukast therapy with placebo. Therewas a 4-week washout period between treatment peri-ods. All subjects remained off intranasal steroids for atleast 4 weeks prior to treatment and throughout thestudy. Global assessment of nasal polyp symptoms,quality of life assessment specific to patients with nasalpolyps, and blood eosinophil counts were performedat the completion of each treatment period.

Nasal polyp symptoms were assessed on a +3 to3 scale, with +3 being equivalent to very much bet-ter, 0 to no better, and 3 to very much worse.There was a significant improvement in symptomscore for montelukast treatment compared with place-bo, with scores of 1.8 for active treatment versus 0.4for placebo after the first treatment period, and 1.3for active treatment versus 0.8 for placebo after thesecond treatment period (P = .001).

Similarly, quality of life, as assessed by a disease-specific questionnaire that employed a 7-point scale,was significantly better with montelukast comparedwith placebo, with an improvement of 0.6 for activetreatment versus 0.21 for placebo after the first treat-ment period, and 0.6 for active treatment versus 0.0for placebo after the second treatment period (P =.01). The investigators conclude that montelukasttreatment globally improves the symptoms of nasalpolyposis and health-related quality of life.

SINGLE-INHALER THERAPY WITHBUDESONIDE/FORMOTEROL

Three of the posters presented at the WorldAllergy Organization Congress in Vancouverdescribed studies evaluating fixed andadjustable dosing with budesonide/formoterol,an inhaled glucocorticosteroid and a long-act-ing fast-onset beta-adrenergic agonist, in a sin-gle inhaler device. Because all 3 studiesevaluated the same combination, and because 2of the studies used the same design and patientpopulation, they are presented here as a unit. Thefirst, by FitzGerald et al, assesses the effects onasthma exacerbations. The second, by Sears etal, examines the effects on symptom severity in thesame patient population. The third, by Aalbers etal, compares adjustable versus fixed dosing withbudesonide/formoterol and adjustable dosingwith budesonide/formoterol versus fixed dosingwith salmeterol/fluticasone.

BUDESONIDE/FORMOTEROL ADJUSTABLE MAINTENANCEDOSING REDUCES ASTHMA EXACERBATIONS COMPAREDWITH FIXED DOSING: A 5-MONTH STUDY IN CANADA

Based on a poster presented by FitzGerald JM,* BouletLP, McIvor A, Becker A, Sears MR,|| Ernst P, GeorgijevNS,# Lee J#

*University of British Columbia, Vancouver; LavalUniversity, Quebec City, Quebec; Dalhousie University,Halifax, Nova Scotia; University of Manitoba, Winnipeg;||McMaster University, Hamilton, Ontario; McGillUniversity, Montreal, Quebec; #AstraZeneca Canada Inc,Canada

In this 5-month, randomized, open-label, parallel-group study involving 995 patients with asthma at 95healthcare and hospital centers in Canada,adjustable maintenance dosing with budesonide/for-moterol in a single inhaler was significantly moreeffective than fixed dosing with the same agents inreducing asthma exacerbations.

Patients were 12 years of age or older (mean,40.6 years in the adjustable-dosing group and 42.8years in the fixed-dosing group), met AmericanThoracic Society criteria for asthma, had postbron-

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chodilator forced expiratory volume in 1 second (FEV1)values above 70% of predicted, and had been takingconstant-dose inhaled corticosteroids for 6 months, withthe dose constant (250 g to 1000 g daily) for at least30 days prior to study entry. Patients were consideredsymptomatic if they used a short-acting beta2-agonist onat least 2 occasions in the previous 7 days, had asth-ma symptoms on at least 2 days in the previous 7 days,or had at least 2 nighttime awakenings due to asthmain the previous 30 days.

After a 1-month run-in period during which allpatients received fixed-dose budesonide/formoterol(80/4.5 g or 160/4.5 g, 2 inhalations twicedaily) to gain control of their asthma, patients wererandomized to receive an additional 5 months oftreatment with either fixed dosing or adjustable dos-ing. In the adjustable-dosing protocol, patients couldstep down from 2 inhalations twice daily to 1 inhala-tion twice daily if patients felt their asthma was wellcontrolled in the previous 7 days, used reliever med-ication no more than 2 times during this period, andhad no nighttime awakenings due to asthma duringthis interval. Patients could step up from 1 inhalationtwice daily to 4 inhalations twice daily if they had 2consecutive nights with awakenings due to asthma or2 consecutive days with morning peak flow valuesthat were below 85% of their mean baseline value,or with the need to use reliever medications 3 or moretimes daily. Patients could again step down after 7 or14 days of step-up treatment, from 4 inhalationstwice daily to 1 inhalation twice daily, if they met allof the step-down criteria presented above.

Exacerbation was defined as the need for addi-tional inhaled and/or oral corticosteroids for asthma,emergency department treatment due to asthma wors-ening, an asthma-related serious adverse event,and/or withdrawal from the study due to the need foradditional asthma maintenance therapy. Severe exac-erbation was defined as the need for oral cortico-steroids due to asthma worsening, emergencydepartment treatment or hospitalization due to asthmaworsening, and/or an asthma-related seriousadverse event.

Patients in both study groups were well matchedregarding age, sex, mean postbronchodilator FEV1,peak expiratory flow during the run-in period, inhaledcorticosteroid and long-acting beta2-agonist use atstudy entry, and stratification by budesonide/for-moterol dose during the fixed-dose run-in phase. Of

those receiving the 80/4.5-g fixed dose during therun-in phase, 140 were randomized to adjustable dos-ing and 129 to fixed dosing. Of those receiving the160/4.5-g fixed dose during run-in, 359 were ran-domized to adjustable dosing and 367 to fixed dosing.

At the end of the 5-month randomization phase, sig-nificantly fewer patients in the adjustable-dosing groupexperienced exacerbations, with the mean number ofexacerbations reduced by 57% compared with thefixed-dosing group (P = .001). This was accomplishedat an overall lower dose of the budesonide/formoterolinhaler (mean, 2.5 vs 3.9 inhalations daily) and cost(mean savings, $141 Canadian) compared with fixeddosing. In addition, fewer patients in the adjustablegroup had 1 or more severe exacerbations, with themean number of such exacerbations reduced by 47%compared with the fixed-dosing group. Time to firstexacerbation was significantly prolonged in theadjustable-dosing group (P = .001) compared with thefixed-dosing group.

The study demonstrates that adjustable dosingimproves patient outcomes in asthma, a disease withfluctuating symptoms and periodic exacerbations,and reduces the potential for periods of undertreat-ment or overtreatment associated with fixed dosing.

BUDESONIDE/FORMOTEROL ADJUSTABLE MAINTENANCEDOSING EFFECTIVELY IMPROVES ASTHMA SYMPTOMSEVERITY: A MULTICENTER CANADIAN STUDY

Based on a poster presented by Sears MR,* McIvor A,

Becker A, FitzGerald JM, Boulet LP,|| Ernst P, GeorgijevNS,# Lee J#

*McMaster University, Hamilton, Ontario; DalhousieUniversity, Halifax, Nova Scotia; University of Manitoba,Winnipeg; University of British Columbia, Vancouver;||Laval University, Quebec City, Quebec; McGill University,Montreal, Quebec; #AstraZeneca Canada Inc, Canada

Using the same study design, dosing regimens,step-up and step-down criteria, and patient popula-tion as the study described by FitzGerald et al (seeabove), this report showed that adjustable mainte-nance dosing with budesonide/formoterol in a single

POSTERS


inhaler lessened or maintained control of asthmasymptoms in the vast majority of patients despite alower overall dose than fixed dosing (2.5 vs 3.9inhalations daily).

In addition to being well matched regarding thedemographics and baseline characteristics describedin the report above, study participants were wellmatched for symptom severity, with similar numbers inboth the adjustable-dosing and fixed-dosing groupshaving severe persistent asthma (n = 9 and n = 7,respectively), moderate persistent asthma (n = 210and n = 221, respectively), mild persistent asthma (n = 280 and n = 267, respectively), and mild inter-mittent asthma (n = 0 and n = 1, respectively).

Patients recorded nighttime awakenings due toasthma as well as study medication and reliever med-ication (short-acting beta2-agonist) use on a dailydiary card. Asthma symptom severity was assessed ineach patient at visits 1 (at the beginning of the 1-month run-in phase) and 5 (at the end of the 5-monthrandomization phase) by a modification of theNational Heart, Lung, and Blood Institute ExpertPanel Report asthma severity classification. Adverseevents, serious adverse events, and study discontinu-ation due to adverse events were also reported.

At the end of the randomization phase, asthmasymptom severity was reduced or constant in 64% ofpatients in the adjustable-dosing group and 34% ofpatients in the fixed-dosing group. There was no sig-nificant difference between the groups in nighttimeawakening or reliever medication use during thestudy. In addition, the percentage of patients withmoderate or mild persistent asthma decreased by20% to 30%, and more than 50% of patients in bothgroups had mild intermittent asthma, the lowest levelof severity, at studys end.

Regimens were well tolerated in both groups, with nodeaths and a low incidence of serious adverse events (n = 5 in the adjustable-dosing group and n = 7 in thefixed-dosing group), discontinuations due to adverseevents (n = 9 and n = 13, respectively), and discontinu-ations due to asthma exacerbation (n = 2 and n = 6,respectively). The study investigators note that guided self-management coupled with adjustable maintenance dos-ing, as shown in this study, enables patients to achieveand maintain asthma control with a lower dose.

ADJUSTABLE DOSING WITH BUDESONIDE/ FORMOTEROLREDUCES THE RATE OF ASTHMA EXACERBATIONSCOMPARED WITH FIXED-DOSING SALMETEROL/FLUTICASONE

Based on a poster presented by Aalbers R,* Backer V,

Kava TTK, Welte T, Omenaas ER,|| Bergqvist PBF,

Sandstrm T#

*Department of Pulmonology, Martini Hospital,Groningen, The Netherlands; Respiratory Unit,Department of Internal Medicine, Bispebjerg Hospital,Copenhagen, Denmark; Department of RespiratoryMedicine, Central Hospital of Northern Karelia, Joensuu,Finland; Department of Pneumology and Intensive CareMedicine, University of Magdeburg, Magdeburg, Germany;||Centre for Clinical Research, Haukeland UniversityHospital, Bergen, Norway; AstraZeneca R&D Lund,Lund, Sweden; #Department of Respiratory Medicine andAllergy, University Hospital, Umea, Sweden

This 7-month study is the first to compareadjustable maintenance dosing with budesonide/for-moterol in a single inhaler with fixed dosing with thesame agents, as well as with fixed dosing with sal-meterol/fluticasone. The investigators concluded thatadjustable maintenance dosing with budesonide/for-moterol is more effective in reducing exacerbationsthan fixed dosing with the same agents and moreeffective in controlling the variability of asthma thanfixed dosing with salmeterol/fluticasone.

The randomized, 2-phase, multicenter study,which involved a total of 658 patients and includeda 1-month double-blind phase and a 6-month open-extension phase, was preceded by a 2-week run-inphase during which patients continued their usualinhaled corticosteroids and were then randomized toadjustable-dose (n = 219) or fixed-dose budes-onide/formoterol (n = 215) or fixed-dose salme-terol/fluticasone (50/250 g, 1 inhalation twicedaily; n = 224). During the 1-month double-blindphase, in which patients who were randomized toeither scheme of budesonide/formoterol therapyreceived the fixed dose (160/4.5 g, 2 inhalationstwice daily), the fixed-dose combinations were com-pared with each other.

At the end of the double-blind phase, patients ini-tially randomized to adjustable dosing who met the cri-teria for dose adjustment stepped down to 1 inhalation

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twice daily; those who did not remained on 2 inhala-tions twice daily. Patients were eligible for a step-downadjustment if, during the last 7 days of the double-blindperiod, they had no nighttime awakenings due to asth-ma and if they used reliever medication no more thanonce per day for not longer than 2 days.

During the open-extension phase, patients ran-domized to adjustable dosing with budesonide/for-moterol could increase their dose temporarily, up to 4inhalations twice daily, if their symptoms worsened(ie, if they required reliever medication on 2 consec-utive days on 3 or more occasions, of if they hadnighttime awakenings due to asthma on 2 consecu-tive days). All patients were permitted to use short-act-ing beta2-agonists (terbutaline or salbutamol) asneeded for symptom relief throughout the study.

Study participants were at least 12 years of age(mean age, 47 years in the adjustable-dosing groupand 46 years in both fixed-dosing groups), with symp-tomatic asthma despite current medications, prebron-chodilatory forced expiratory volume in 1 second(FEV1) value 50% or more of predicted, and meanpeak expiratory flow between 50% or higher and 85%of postbronchodilatory peak expiratory flow. All weretaking inhaled corticosteroids for at least 3 monthsbefore study entry and at a constant daily dose of 500g to 1200 g during the month before the run-inphase. All had total daily symptom scores that

were above 0 on at least 4 of the last 7 days of therun-in period. Patients in each of the 3 treatmentgroups were well matched regarding age, sex, meanasthma symptom score, mean dose of inhaled corti-costeroids at study entry, beta2-agonist use at studyentry, and mean FEV1.

During the study, exacerbationsdefined as oralsteroid treatment for at least 3 days and/or emergencydepartment visits with or without hospitalizationswere recorded. Asthma symptoms and reliever med-ication use were recorded on patient diary cards.

At the end of the study, there was a 40% reductionin the rate of exacerbations in the group receivingadjustable-dose budesonide/formoterol compared withthe group receiving fixed-dose salmeterol/fluticas-one. The difference was even more impressive in thelast 100 days of treatment (4-fold decrease in thenumber of exacerbations). There were also fewerexacerbations, fewer hospitalizations and/or emer-gency department visits, and less use of extra inhaledsteroids in the group receiving adjustable-dose budes-onide/formoterol than in both groups receiving fixed-dose treatment.

Study drug use was somewhat higher in theadjustable-dose group (average daily budesonide,550 g) compared with the fixed-dose group (averagedaily fluticasone, 500 g).

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antihistamines in asthma.pdf

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