Prevention

Prevention strategies for asthma — secondary prevention

S econdary prevention of asthma is defined as interven-tions) for infants and children who are at high riskfor die development of asthma but who have not yet

developed asthma symptoms or signs. These patients havea family history of allergic disease and 1 or more of the fol-lowing: atopic dermatitis or eczema, allergic rhinitis, foodallergy, bronchial hyperreacdvity, blood eosinophilia, ele-vated total IgE levels, elevated allergen-specific IgE, orskin-test reactivity to specific allergens.'"^

Literature review

The evidence base for effective measiires in the area ofsecondary prevention of asthma is small. All of the studiesidentified in a A^LEDLINE search are included in this re-view. Criteria for diagnosis of asthma are those describedby the individual investigators.

Current evidence

Evidence-based therapeutic interventions for the sec-ondary prevention of asthma fall into 3 categories:• pharmacologic treatment^"• control of environmental allergens and environmental

tobacco smoke"""• allergen-specific immunotherapy^^"

Pharmacologic treatment

H,-antihistamine medications are of limited therapeuticbenefit when administered in the usual doses to those withestablished asthma.'' Nevertheless, in 3 prospective, double-blind, placebo-controlled studies,̂ "^ the first-generation H rantihistamine ketotifen and the second-generation H,-anti-histamine cetirizine, both of which have anti-allergic andanti-inflammatory properties/'^ were used with some suc-cess in the secondary prevention of asthma.

In a double-blind, parallel-group, placebo-controlledstudy,̂ 121 infants and children with atopic dermatitis, whowere 1-36 months old at study entry, received ketodfentwice daily for 1 year; the dose for those <14 kg was 0.8 mgand for those 14-23 kg the dose was 1.2 mg. At the end of

I this time, only 13.1% of the ketotifen-treated children hadc asthma in contrast with 41.6% of the placebo-treated chil-1 dren (p < 0,001); however, the beneficial effect of ketotifenS was observed only in children who had a raised total serum2 IgE level at study entry. Adverse effects, including sedation,g were noted in the ketotifen-treated children. Children withQ atopic dermatitis frequently have elevated total IgE; how-

ever, IgE does not correlate with asthma in the absence ofatopic dermatitis. Adverse effects, including sedation, werenoted in 6 of the 61 ketotifen-treated children comparedwith 0 of the 60 children in the placebo group. Subsequenttrials to support this approach have not been published andketotifen is seldom used.

In a subsequent double-blind, placebo-controlled, paral-lel-group study,^ 100 pre-asthmatic infants with a familyhistory of allergy and elevated total serum IgE levels weretreated with ketotifen at a dose of 0.5 mg every 12 h forthose <3 years of age and 1 mg every 12 h for those >3years of age. Treatment was continued for 3 years. At theconclusion of treatment, 9% of the 45 infants who weregiven ketotifen had developed asthma and 35% of the 40children given placebo had developed asthma (p = 0.003).Adverse effects were not discussed in the report of thestudy.

In a larger, rigorously designed, randomized, double-blind, placebo-controlled investigation^ (the Early Treat-ment of the Atopic Child [ETAC] study) of 817 childrenaged 12-24 months at entry, cetirizine in a dose of 0.25mg/kg or matching placebo was given twice daily for 18months. There was a 6-month double-bhnd follow-up andan additional 36-month open follow-up. At entry, no childhad a history of wheezing, nocturnal cough or pulmonarydisease of any kind. Asthma was defined as 3 episodes ofnocturnal cough with sleep disturbance or wheezing sepa-rated by at least 7 days in a clinical setting where asthmawas likely and other conditions had been excluded.

In contrast to placebo, cetirizine treatment delayedasthma onset in children sensitized to house dust mites(HDMs) (35 of 68 v. 16 of 56,/J = 0.005) and in diose sensi-tized to grass pollen (20 of 34 v. 10 of 36, p = 0.002), al-though not in the entire group enrolled in the study (inten-tion-to-treat population; 150 of 398 v. 151 of 397).̂ In thegrass pollen-sensitized children, the effect was sustained for36 months after treatment was discontinued (p = 0.008). Inthe children sensitized to HDMs, there was a gradual nar-rowing of the difference between cetirizine and placebotreatments in terms of cumulative prevalence of asthma atthe end of 36 months, but no evidence of a rebound afterthe treatment was stopped (p = 0.04). The effect on preven-tion of asthma symptoms, which was maintained after ceti-rizine treatment was discontinued, was attributed to down-regulation of ICAM-1 expression and eosinophilicinflammation.**'̂ In the placebo-treated children, there was asignificantly higher risk of the development of asthma inthose sensitized to grass pollen, HDM, cat or egg allergenat study entry.^

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Becker et al

In the ETAC study, cetirizine also had a topical gluco-corticoid-sparing effect in atopic demiatitis'° and decreasedthe frequency of acute urticaria episodes, which occurred in5.8% of the cetirizine-treated children in contrast with16.2% of the placeho-treated children." Unlike the preven-tadve effect against asthma, the preventadve effect againsturticaria disappeared when treatment was stopped. Despitethe relatively high cedrizine dose administered (0.25 mg/kgtwice daily), the long-term safety profile was excellent andthere were no adverse effects on growth, behaviour, psy-chosocial or cognidve development, as rigorously assessedduring acdve treatment and follow-up using validated in-struments, including the McCarthy Scales of Childrens'AbiUty.'̂ -'-̂

There are 2 additional relevant studies. A 24-monthstudy in which loratadine prevented viral upper respiratorytract infecdons and associated wheezing and coughing inchildren aged 24-30 months has been completed but notyet published.'^ A long-term, prospective, randomized,double-blind, placebo-controlled study of levocedrizine(the pharmacologically acdve enandomer of the racematecedrizine), 0.125 mg/kg twice daily, in children aged 12-24months is also underway.

Prospective, randomized, double-blind, placebo-controlled phannacologic intervendons are needed to testother classes of medicadons, including inhaled glucocord-coids"^ and oral leukotriene modifiers,'^ which are effecdvein infants and young children with an established diagnosisof asthma, but have not been studied for their secondaryprevendon effects in high-risk children who have not yetdeveloped asthma. Also, the topically apphed calcineuroninhibitors, such as pimecrolimus and tacrolimus, intro-duced recendy for relief of skin inflammadon in infants andchildren with atopic dermadds or eczema are of interestwith regard to their potendal role in the secondary preven-tion of asthma.'^ The possibility that allergen exposuremight decrease responsiveness to pharmacologic treatmentneeds to be explored further." In addition, new im-munomodulators, which appear to be safe and effecdve inclinical trials in humans, should eventually be studied forthe secondary prevendon of asthma in at-risk individuals.Examples of these intervendons include and-IgE with^° orwithout^' specific allergen immunotherapy, cytoldne antag-onists^' and DNA vaccines, including immunosdmulatorysequences with^' or widiout specific allergen.

Overall, studies of secondary prevendon have been dis-appointing, but in children already sensidzed to HDM orgrass pollen allergens who do have atopic dermadds, treat-ment with cetrizine may have some benefit.

Infection, environmental allergens andenvironmental tobacco smoke

The long-term ramificadons of the amount, dming andextent of exposure to infecdons, environmental and food

allergens and environmental tobacco smoke and other res-piratory irritants and the complex interacdons of these fac-tors with genedc factors are currendy incompletely under-stood.' Although sensidzadon of children can be preventedby avoidance of environmental allergens, such as HDMs,"there is no evidence that this is associated with secondaryprevendon of asthma. However, most research efforts inthis area to date have focused on primary and terdary pre-vendon, rather than secondary prevendon.''^''^^

The associadon between passive smoking and asthma inchildren, including asthma development and asthma sever-ity, is well-documented.^^ However, it should be noted thatalthough avoidance of tobacco smoke exposure in at-dskinfants and children is logical and universally recom-mended by physicians, there are no studies proving thatavoidance of passive smoking is useful in the secondary pre-vention of asthma. Moreover, long-term changes inparental smoking habits are difficult to

Allergen-specific immunotherapy

Allergic rhinids often precedes the onset of asthma. A2-year rigorously designed, prospecdve, randomized, double-blind, placebo-controlled study^^ followed 44 patients,mean age 19 years (range 10-38 years), with a documentedhistory of perennial atopic rhinids, but no history of asthmaand normal pxilmonary funcdon tests, who were monosen-sidzed to HDM {Dermatophagoides pteronyssintis) and had noother allergies. In this group, D. pteronyssinus immunother-apy reduced the progression of rhinids to asthma and pre-vented an associated increase in bronchial hyperreacdvity.After 1 year of treatment, padents receiving immunother-apy had increased PD20 EEV, for methacholine (2.88-foldincrease, 95% CI 2.09-3.98) and showed further improve-ment after 2 years (OR 4.1, 95% CI 2.09-5.7). At die endof the study, the PDjo EEVi was within the normal rangefor 50% of the treated padents (p < 0.0001) and signifi-candy higher in this group than in those receiving placebo(p < 0.0001); PD,o FEV, > 8 mmol versus 2.9 mmoi. Noneof the patients treated with immunotherapy developedasthma, yet 9% of those given placebo did. The invesdga-tors concluded that immunotherapy administered to care-fully selected, monosensidzed padents with perennial aller-gic rhinids but no asthma reduces airway responsivenessand thus holds some promise for secondary prevendon ofasthma.

In another study,^^ 205 children, mean age 10.7 years(range 6-14 years) with grass or birch pollen allergy (orboth) but widiout any other chnically important allergy orasthma needing daily medicadons were randomly chosen toreceive allergen-specific immunotherapy for 3 years or as-signed to an open control group. After 3 years, amongthose without asthma, the treated children had significantlyfewer asthma symptoms, as evaluated by clinical diagnosis(OR 2.52, 95% CI 1.3-5.1). The results of mediacholinebronchial provocadon tests improved significandy in the

S26 JAMC • 13 SEPT. 2005; 173 (6)

Prevention

treatment group during the winter (PC20 OR 2.75, 95% CI1.2-6.3), but not during the allergy season (PC20 OR 1.43,95% CI 0.8-2.7). The investigators concluded that im-munotherapy can reduce the development of asthma inchildren with seasonal rhinoconjunctivids. However, theconclusions that can be drawn from tbis randomized, clini-cal trial are limited by tbe fact that it was not double-blindor placebo-controlled and that, before the start of im-munotherapy, 20% of the children likely had mild asthma,although they did not need daily treatment.

In other studies that were prospective, but not random-ized, double-blind or placebo-controlled,''^''^ and in a retro-spective^ study," the investigators concluded that allergen-specific immunotherapy may prevent the onset of newsensitization in children with respiratory symptoms andmonosensitization to HDMs.

Implications for research

1. Future research should consist of appropriately timedand adequately powered, randomized, double-blind,placebo-controlled studies of tbe following: additionalHi-andhistamines with and-allergic, and-inflammatoryeffects; addidonal classes of pharmacologic treatment,such as inhaled glucocordcoids, leukotriene modifiersand topical calcineuron inhibitors; new immunomodu-lators, such as and-IgE; and allergen-specific immuno-/therapy.

2. Also needed are randomized, controlled studies of therole of avoidance of environmental allergens and to-bacco smoke in the secondary prevendon of asthma.

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