Current reviews of allergy and clinical immunology. Primary prevention of asthma and allergy

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1 Current reviews of allergy an clinical immunology Series eitor: Harol S. Nelson, MD Primary prevention of asthma an allergy Reviews an Sye Hasan Arsha, DM, FRCP Stafforshire, Unite Kingom This activity is available for CME creit. See page 31A for important information. The relentless increase in the prevalence of asthma an allergic iseases highlights the nee for evising effective preventive strategies. Although the genetics of these isorers are being investigate, manipulation of known environmental risk factors remains the best available approach to this problem. However, the large number of potential environmental risk factors an our inability to accurately preict the evelopment of asthma an allergy has le to conflicting ata from recent prevention stuies. Nonetheless, some useful recommenations can be mae. Exclusive breast-feeing an avoiance of exposure to environmental tobacco smoke exposure can be safely recommene for the whole population, not only for prevention of allergy but also for other known benefits. Aitionally, for chilren at high risk of allergy, maternal exclusion iet uring lactation an protein hyrolysate as a supplement or alternative for chilren who coul not be breast-fe seems to provie further protection. The preventive effect of avoiance of house ust mite allergen alone uring pregnancy or after birth is isappointing. However, prospective ranomize stuies evaluating a combine foo an house ust mite allergen avoiance regimen show some protection against atopic ermatitis in infancy an asthma in later chilhoo. Urgent research is neee to accurately ientify chilren at high risk an to test novel preventative measures with the potential for immunomoulation. Further ranomize controlle trials are also neee with long-term follow up to evaluate combine approaches that might provie maximum benefit. (J Allergy Clin Immunol 2005;116:3-14.) Key wors: Asthma, allergy, atopy, prevention, allergen avoiance, house ust mite There has been a ramatic increase in the prevalence of asthma an other allergic iseases over the last few ecaes. They are now major public health problems 1 an are an enormous buren on health care resources. 2 Importantly, severe asthma an systemic allergic reactions are potentially life-threatening conitions. Aitionally, these iseases aversely affect the quality of life of millions of chilren an aults. There is an urgent nee From the University of Keele, Stafforshire. Disclosure of potential conflict of interest: None isclose. Receive for publication March 24, 2005; revise March 30, 2005; accepte for publication March 31, Available online May 24, Reprint requests: Sye Hasan Arsha, DM, Department of Respiratory Meicine, University Hospital of North Stafforshire, Newcastle R, Stoke-on-Trent, ST4 6QG, Unite Kingom. sha@soton.ac.uk /$30.00 Ó 2005 American Acaemy of Allergy, Asthma an Immunology oi: /j.jaci Abbreviations use ETS: Environmental tobacco smoke HDM: House ust mite PUFA: Polyunsaturate fatty aci RCT: Ranomize controlle trial to formulate strategies leaing to a reuction in morbiity an mortality from asthma an allergy. This can be achieve through either primary or seconary prevention, an improve efforts in both these areas are essential (Table I). Common clinical manifestations of allergy inclue asthma, allergic rhinitis, atopic ermatitis, an foo allergy. Subjects with allergic iseases are often atopic, manifeste by to common allergens. However, atopy is only one of many factors involve in the pathogenesis of these isorers. The contribution of atopy an atopy-relate genes might vary with the isease in question. For example, atopy plays a ominant role in IgE-meiate foo allergy, such as peanut allergy, but alternate immunologic pathways, riven irectly by T lymphocytes, assume significance in conitions such as nonatopic asthma. Allergic iseases are polygenic, with several genes on ifferent chromosomes involve in the genesis of these isorers. However, the phenotypic expressions, manifesting in clinical isorers, require an interaction of genes with environmental factors. Genetic manipulation to prevent these isorers is not yet in sight, an recent increases in prevalence argue strongly for a significant role of environmental factors. These factors might increase or ecrease the risk of allergy evelopment, an some might be amenable to manipulation. We thus have to rely on ientification an removal of environmental risk factors in an attempt to stem an reverse the rising trens in allergy. A number of risk factors have been ientifie, incluing early feeing, iet, infections, allergens, pollutants, an tobacco smoke. RISK FACTORS During early infancy, the chil is expose to small quantities of a variety of foo proteins through breast milk an larger quantities of cow s milk protein if formula fe. The normal response to the initial introuction of these 3

2 4 Arsha J ALLERGY CLIN IMMUNOL JULY 2005 Reviews an TABLE I. Definitions Allergy: Clinical manifestations of immunologically meiate reactions to foreign substances, usually proteins. Atopy: The genetic propensity to prouce IgE antiboies after exposure to allergen. This can be confirme by means of skin prick test or measurement of specific IgE antiboies in the serum (allergic ). At-risk population: Those who have a genetic preisposition an are at higher risk of evelopment of allergic iseases. At present, this is usually assesse through family history of allergy, presence of other allergic iseases, or allergic. Primary prevention: Preventing the evelopment of allergic manifestations, such as asthma, allergic rhinitis, or atopic ermatitis. Seconary prevention: Prevention of symptoms, exacerbation, or lung function eteriorations in those who alreay have an allergic isease. proteins is immune tolerance. However, in chilren with atopic preisposition, this immune tolerance breaks own. Thus to foos such as cow s milk an egg is common in infancy, an in a subset of these chilren, clinical allergic reactions occur that manifest in the form of skin rash urticaria, gastrointestinal manifestations, atopic ermatitis, an occasionally systemic allergic reactions. It has been propose that early introuction of allergenic foos might promote the evelopment of allergy, whereas later introuction might inuce tolerance. 3 Thus prevention of foo allergy coul be achieve by altering the ietary pattern of the at-risk infant. Exposure to aeroallergens might be relevant to the evelopment of respiratory allergy. 4,5 The specific type of aeroallergens varies accoring to the geoeconomic situation. For example, house ust mite (HDM) is the most important allergen in humi climates, pet allergens might be more relevant in col countries, Alternaria species assume significance in ry climates, an cockroach might be the ominant allergen in inner-city areas. Previous efforts at primary prevention have largely focuse on reuction of exposure to HDM allergen. The hygiene hypothesis proposes that exposure to certain infections an vaccines might influence the irection of immune responses an protect against the evelopment of atopy. 6-8 However, not all infections are protective. Recurrent lower respiratory tract infections in early chilhoo are a recognize risk factor for asthma in later chilhoo. 9 The most common respiratory pathogen in infancy is respiratory syncytial virus, an this has been linke to later evelopment of wheeze, asthma, an airways obstruction Maternal smoking uring an after pregnancy promotes an the evelopment of asthma. 13 However, Tariq et al 14 suggeste that maternal smoking is preominantly a risk factor for early chilhoo wheeze an nonatopic asthma. A number of stuies have supporte the link between exposure to environmental tobacco smoke (ETS) an evelopment of wheeze an asthma uring chilhoo Similarly, ietary factors, such as antioxiants (vitamin C an E an selenium), magnesium, soium, an omega-3 fatty acis, might affect the evelopment of allergic iseases WHAT ARE WE TRYING TO PREVENT? Allergic manifestations are protean, an there is a lack of uniformity in efinitions of outcome measures use in various stuies. The efinition an iagnosis of asthma an rhinitis in early chilhoo is most challenging in view of the lack of uniform criteria an availability of objective tests to support the iagnosis. Another complication is that early chilhoo allergic manifestations are often transient, an yet many stuies report short-term (<5 years) follow-up perios. Most stuies suggests that an intervention such as exclusive breast-feeing prevents wheeze in early chilhoo, 19 but recently, it has been reporte that it might increase the risk of asthma in early ault life. 20 Thus if short-term follow-up stuies efine early chilhoo wheeze as asthma, the same intervention can have positive or negative outcomes. Further confusion arises when there is a iscrepancy between the effects of preventive measures on subjective (symptoms an iagnosis) an objective (allergic, airway obstruction on lung function, an bronchial hyperresponsiveness) manifestations of asthma an allergy. Some stuies have attempte to prevent allergic as the principal outcome, but this might not necessarily have the esire effect of reucing clinical allergic isorers. There might also be a ifferential effect of the chosen intervention on the type of allergic manifestation. For example, ietary moifications, such as avoiance of cow s milk, might prevent cow s milk allergy an perhaps atopic ermatitis but might not influence allergic rhinitis or asthma, an the reverse might be true for aeroallergen avoiance. It is therefore important that each ranomize controlle trial (RCT) in primary prevention shoul have preefine specific outcomes, use stanarize efinitions as far as possible, an plan to follow-up chilren for an appropriate perio epening on the outcome being teste. PREVENTIVE STRATEGIES: ALLERGEN AVOIDANCE, DIETARY MANIPULATION, INFECTIONS-ENDOTOXIN, IMMUNOTHERAPY, AND DRUGS Although there is goo evience that allergen exposure leas to 21,22 an that is an important risk factor for the evelopment of allergic isease, 23,24 the irect relationship of allergen exposure in the causation of allergic isease is still questione. 25 The effect of exposure to allergen might epen on the nature of allergenic protein. Exposure to HDM is reporte to cause asthma, 26,27 whereas og or cat allergen exposure might be protective, although there remains some controversy regaring this issue. 31 It is also not

3 J ALLERGY CLIN IMMUNOL VOLUME 116, NUMBER 1 Arsha 5 clear whether any protective effect of pet exposure is ue to inuction of tolerance mechanisms (eg, moifie T H 2 response) or a concomitant increase exposure to infections or enotoxin. 32 In view of these conflicting reports, shoul we even be attempting to use allergen reuction as a strategy for primary prevention? That reuction in allergen exposure can lea to primary prevention of a specific allergy is exemplifie by latex allergy. During the last ecae, the incience of latex allergy has ecrease sharply with the increase in the use of latex-free gloves. 33 WHOLE POPULATION OR AT-RISK INDIVIDUALS Because primary prevention measures require motivation, effort, an expense, most stuies have targete infants at high risk of allergy to maximize the benefit Until chilren can be screene for specific genes with more accurate preiction for future evelopment of asthma an allergy, family history of allergy is often relie on to ientify chilren at high risk. Although family history of allergy is a well-known risk factor, it remains true that the majority of asthmatic chilren are from families with no asthma, an the same is true for atopic ermatitis an allergic rhinitis. 38,39 During the 1980s, it was propose that the level of IgE at birth (cor bloo IgE) coul more precisely inicate the risk of future allergic isease. However, cor bloo IgE has low sensitivity for preiction of allergy in general, 40 an it might preict allergic but not clinical allergic isease. 38,41 Despite these observations, in an attempt to inclue chilren at very high risk of allergy, some stuies have combine high cor IgE levels an family history of allergy in selecting chilren suitable for preventive measures. 42 Egg in early chilhoo has been shown to preict respiratory allergy. However, its sensitivity as a preictive marker is poor, an it cannot be usefully use to ientify chilren at high risk. 43 Other biomarkers, such as serum eosinophil cationic protein, urinary eosinophil protein X, an various cytokines, have not prove to be reliable preictive markers. 44 The Stuy on Prevention of Allergy in Chilren in Europe selecte school-age (6-8 years ol) chilren for primary prevention of HDM an asthma on the basis of a positive family history of atopy plus to other allergens but not HDM. Chilren can also be selecte on the basis of having one allergic isease an are thus at a higher risk of having another. For example, chilren with atopic ermatitis in early chilhoo an allergic rhinitis in later chilhoo are at increase risk of asthma. 45 For any prevention program, the population to be targete woul eventually epen on the safety an cost of the measure being recommene an whether there are any avantages for the low-risk population. For example, breast-feeing an avoiance of ETS are safe an inexpensive an have other avantages apart from possible prevention of allergic iseases. Therefore these measures can an shoul be recommene for the whole population, even in the absence of convincing evience for allergy prevention from RCTs. Other measures, such as maternal avoiance of allergenic foos, might not be completely safe, require convincing evience, an might be suitable for only the high-risk population. WHEN: PREGNANCY, INFANCY, LATER CHILDHOOD, OR ADULT The onset of allergic manifestations is usually uring early chilhoo. Hence primary prevention efforts have to commence soon after birth or preferably uring pregnancy. Animal moels support the hypothesis that contact with an allergen early in life inuces a state of general immune hyperresponsivenss, with increase prouction of specific IgE antiboies. 46 Pregnancy is a T H 2 environment with preominance of T H 2-type cytokines. After birth, the immune system matures to achieve a balance between T H 1 an T H 2 cytokine responses. 47 However, in chilren with atopic hereity, this balance might never be achieve, an at H 2 preominance persists, leaing to an allergic iseases. Thus a winow of opportunity exists in early life (infancy an early chilhoo), when manipulation of the environment in chilren with atopic hereity might restore the balance. The T H 1/T H 2 hypothesis has recently been challenge, an immune tolerance-suppression might involve regulatory T cells. 48 Whatever the precise mechanism, it is generally agree that primary prevention strategies have to focus on early chilhoo, before the immune system matures an exposure to allergens leas to. Observational stuies have suggeste that an intense exposure to a particular allergen, such as birch pollen, uring pregnancy coul increase the risk of offspring being sensitize to that allergen an having allergic asthma. 49 It is now known that allergens can pass through the placenta an sensitize the fetus. 50,51 A number of stuies have shown that cor bloo mononuclear cells recognize foo an inhalant allergenic epitopes an respon to stimulation by proliferation. 52 It has been suggeste that exposure to b-lactoglobulin an ovalbumin uring fetal life might influence the irection of immune responses such that there will be reuce T H 1-type cytokine releases, such as IFN-g, in turn increasing the risk of allergic iseases. 53 It is therefore argue that fetal exposure to allergens shoul be minimize to protect the eveloping immune system. This begs the question of whether preventive measures shoul be institute before birth. However, in the Chilhoo Asthma Prevention Stuy investigators were unable to emonstrate a correlation between maternal exposure to HDM allergen an cor bloo mononuclear cell cytokine responses, arguing against a beneficial effect of maternal HDM allergen avoiance. 54 Inee, in a rat moel Melkil et al 55 argue that exposure to allergen early in pregnancy might favor the evelopment of tolerance, with increase prouction of IgG2a antiboies an suppression of specific Reviews an

4 6 Arsha J ALLERGY CLIN IMMUNOL JULY 2005 Reviews an IgE antiboies. However, there is goo evience that smoking uring pregnancy increases the risk of chilhoo asthma an aversely affects lung function. 56,57 Use of rugs, such as paracetamol an ietary constituents, uring pregnancy might also influence the evelopment of asthma in the offspring. 58,59 Thus in principal primary prevention shoul start as early as possible uring pregnancy. The specific recommenations, however, shoul not be mae until the evience an risk/benefit ratio have been carefully consiere. PREVENTATIVE STRATEGIES The ientification of risk factors, such as allergen exposure, has le to evaluation of various strategies for primary prevention. The conclusive proof of effectiveness requires well-esigne ouble-blin RCTs. However, this is not always possible. For example, the effect of breastfeeing or maternal smoking cannot be teste by means of RCTs for ethical reasons. Blining might not be possible for practical reasons (eg, when testing the effect of exposure to pet allergens). Foo allergen avoiance Avoiance of cow s milk protein with exclusive breastfeeing (with or without maternal avoiance of allergenic foos) or hyrolyze formula has been suggeste for infants at risk of allergy. It has also been propose that introuction of other highly allergenic foos, such as eggs an nuts, to the infant is elaye. Exclusive breast-feeing. The extent of the preventive effect of breast-feeing on allergic iseases remains controversial. Exclusive breast-feeing oes seem to prevent wheeze an atopic ermatitis uring early chilhoo. 19,60 However, long-term prospective stuies have prouce conflicting ata. A relatively small stuy of at-risk chilren with 15 years prospective follow-up i show a reuction in allergic manifestations in the breast-fe chilren compare with those fe cow s milk or soya milk. 61 However, several large observational stuies faile to show a longterm protective effect of exclusive breast-feeing on asthma or other allergic manifestations. 9,20,62 Two systemic reviews on this subject reache the conclusion that exclusive breast-feeing oes seem to have some protective effect on the evelopment of allergy. 63,64 This effect might be ue to avoiance of cow s milk protein allergen, other ietary constituents of breast milk, an immunomoulatory effect, or a combination of these. It was recently suggeste that the effect of exclusive breast-feeing might be epenent on atopic hereity. Those with a genetic preisposition ha a lower incience of an allergic rhinitis, whereas chilren without such a preisposition ha an increase risk. 65 In this issue of the Journal, another article iscusses this subject in more etail. 66 Hyrolyze milk formulae. In an attempt to avoi exposure to cow s milk protein early in life, hyrolyze (casein or whey) formulae are suggeste as a replacement for or supplement to breast-feeing. A number of RCTs have been one over the last 2 ecaes to assess the preventive effect of replacing cow s milk formula with hyrolysate or soy milk formulae. Chanra et al 67,68 compare the evelopment of allergic iseases (asthma, atopic ermatitis, an foo allergy) in groups of chilren fe breast milk, hyrolyze formula, cow s milk formula, an soy formula. A significant preventive effect of breast milk an partially hyrolyze formula was shown consistently up to the age of 5 years. Another stuy, this one comparing cow s milk formula an whey hyrolysate, shows a reuction in cow s milk allergy an atopic ermatitis in the first year. 69 In a stuy by Marini et al, 70 exclusive breast-feeing combine with hyrolysate supplementation le to a significant reuction in various allergic manifestations up to the age of 3 years. Another RCT showe prevention of atopic ermatitis, but not asthma, with the use of hyrolysate formula. 71 Proteins can be extensively or partially hyrolyze in the infant formulae. For seconary prevention, in chilren with cow s milk allergy, it is generally agree that only extensive hyrolysate shoul be use to avoi any reaction in highly sensitize infants. There is some controversy regaring the extent of hyrolysis neee for primary prevention. In an RCT use of partially hyrolyze formula uring the first few months of life in genetically atrisk infants reuce the prevalence of atopic ermatitis, but not wheeze, in the first 2 to 3 years of life. 72 The German Infant Nutritional Intervention Stuy compare the preventive effect of 3 hyrolyze formulas (partially hyrolyze whey formula, extensively hyrolyze whey formula, an extensively hyrolyze casein formula), with cow s milk formula fe chilren as control subjects. The incience of allergic manifestations, such as atopic ermatitis, foo allergy, or allergic urticaria, was significantly reuce by using an extensively hyrolyze casein formula compare with a cow s milk formula. There was also some protective effect of partial (but not extensive) whey hyrolysate on reuction of atopic ermatitis. 73 However, other RCTs inicate a greater preventive effect of extensively hyrolyze milk compare with partially hyrolyze formula on allergic manifestations, particularly cow s milk allergy. 74,75 Overall, it seems that protein hyrolysate reuces allergic manifestations uring the first 2 to 3 years of life in chilren at high risk of atopy, as a supplement or alternative to breast-feeing. 76 These hyrolysates have been shown to be nutritionally aequate of the nees of the infant. 77 However, these have not been shown to be superior to exclusive breast-feeing. There remains some uncertainty as to the superiority of extensive versus partial hyrolysate in primary prevention. 78 Most stuies foun that soy formula o not protect against allergy in high-risk infants. 79 Maternal avoiance iet uring pregnancy. Several stuies have investigate the preventive effect of maternal avoiance of highly allergenic foos, such as cow s milk, egg, an nuts, uring pregnancy to protect the fetus from the effect of foo allergens ingeste by the mother. An RCT showe that maternal iet (excluing cow s milk an egg) uring late pregnancy oes not protect against the

5 J ALLERGY CLIN IMMUNOL VOLUME 116, NUMBER 1 Arsha 7 evelopment of allergic manifestation in genetically preispose chilren. 80,81 Aitionally, there was some concern regaring maternal an fetal weight gain. Zeiger et al 82 evaluate the effect of maternal avoiance of allergenic foo (cow s milk, egg, nuts, fish, an soy) uring late pregnancy an lactation, supplementation with extensive hyrolysate, an avoiance of solis up to 6 months. There was a reuction in foo on skin prick tests, foo allergic manifestations, an atopic ermatitis at the age of 2 years. However, no long-term benefit beyon early chilhoo was observe. 83 Weight gain uring the thir trimester was again a concern in mothers who practice an avoiance iet. Maternal avoiance iet uring lactation. In an RCT maternal avoiance of highly allergenic foo (airy prouce, egg, fish, peanut, an soy) uring lactation le to a reuction in the prevalence of atopic ermatitis at 18 months in high-risk infants. 84 In a Japanese stuy infants in the intervention group were exclusively breast-fe or given whey hyrolysate, whereas the lactating mothers were given the same whey hyrolysate as the only source of protein. These infants were compare for the evelopment of allergy with 2 other groups of chilren. One group was breast-fe with the mother consuming cow s milk, whereas in the thir group infants were given cow s milk formula. The active group infants showe lower incience of atopic ermatitis an cow s milk allergy. 85 In another RCT maternal avoiance iet (cow s milk, egg, an fish) uring the first 3 months of lactation reuce atopic ermatitis in early chilhoo, but there was no long-term benefit. 86,87 Herrmann et al, 88 however, faile to show a protective effect of maternal avoiance iet (cow s milk an egg) uring late pregnancy an lactation. Although a maternal avoiance iet uring lactation is ifficult to ahere to, none of the stuies reporte any averse nutritional effects for mother or chil. A Cochrane atabase review conclue that restricting maternal iet uring pregnancy oes not prevent allergy an might have averse consequences for maternal nutrition, fetal nutrition, or both. However, maternal foo allergen avoiance uring lactation might be of some benefit. 89 Late introuction of soli foos. Some observational stuies have supporte the concept that introuction of soli foos before the age of 4 months might increase the risk of atopic ermatitis in genetically preispose chilren. 90 However, other stuies coul not fin a beneficial effect of late introuction of soli foos. 60,91 Most intervention stuies have combine late introuction of solis with other intervention measures, an thus it is ifficult to know whether this strategy alone has any protective effect. 42,82 HDM avoiance In view of the link between exposure to HDM an evelopment of asthma suggeste by several cross-sectional an prospective stuies, there has been an attempt to reuce at-risk chilren s exposure to HDM allergen. 5,26,27 Three large prospective stuies have institute HDM avoiance measures uring pregnancy, at birth, an later in chilhoo an assesse chilren for asthma an allergic manifestations (Table II). Stuy of Prevention of Allergy in Chilren in Europe. The Stuy of Prevention of Allergy in Chilren in Europe was esigne to assess the effect of simple HDM avoiance measures, such as mattress covers, an a set of environmental eucational avice on the evelopment of to HDM an allergy manifestations. The researchers recruite 3 cohorts of chilren (newborns, tolers [2-4 years], an school-age chilren [5-7 years]) at high risk of to HDM. In the newborn cohort,, particularly to HDM, was reuce in the intervention group chilren at 1 year, but this effect was lost by the age of 2 years. Moreover, no ifference was observe in clinical allergic manifestation between the 2 groups. 37,92 In the toler 93 an school-age chilren cohorts, 94 a reuction in the incience of to HDM was observe at 1 year but not in the occurrence of allergic manifestations. This stuy provies evience that allergen avoiance coul protect at-risk chilren against to that allergen, even in later chilhoo. However, this might not protect chilren from clinical allergic manifestations. Further follow-up of the toler an school-age chilren will etermine whether reuction in allergen is sustaine an whether this translates into reuce occurrence of clinical allergy. Manchester Asthma an Allergy Stuy. The Manchester Asthma an Allergy Stuy use extensive environmental control measures uring pregnancy an infancy. These inclue impermeable mattress covers on parental bes from the secon trimester of pregnancy, mattress covers for chilren s bes, harwoo flooring in berooms, use of high-efficiency particulate air filter vacuum cleaners, an application of antimite foam, benzyl benzoate (Allergopharma, Reinbek, Germany), on soft furnishings to reuce ust mite numbers an allergen. A highly significant reuction in exposure to ust mite, cat, an og allergens was achieve. 36,95 At age 1 year, there was no ifference in mite, mil wheeze, or cough or atopic ermatitis. There was, however, a significant reuction in the occurrence of severe wheeze in the intervention group infants. 96 Further follow-up of this cohort will provie useful information. Prevention an Incience of Asthma an Mite Allergy. The Prevention an Incience of Asthma an Mite Allergy stuy evaluate the effectiveness of HDM avoiance measures, incluing allergen-impermeable (intervention group) an placebo (control group) mattress encasings, in the chilren s an parent s bes before birth an uring the first year of life. Although HDM allergen levels were reuce in the intervention group, 97 there was no ifference in the evelopment of atopy or asthma. At age 2 years, the only ifference seen was a slight but significant reuction in nighttime cough in chilren in the active group. 98,99 Multiple interventions The Isle of Wight prevention stuy. This RCT evaluate the effect of a combine foo an HDM allergen avoiance regimen implemente from birth up to the age Reviews an

6 8 Arsha J ALLERGY CLIN IMMUNOL JULY 2005 Reviews an TABLE II. Cohort intervention stuies (RCTs) with HDM allergen avoiance alone or in combination with ietary measures Stuy Stuy of Prevention of Allergy in Chilren of Europe, 3 cohorts: newborn, toler, school chilren 37,92-94 Number Intervention starte at: Intervention Newborn: 696 Birth HDM avoiance measures: mattress covers (infant an parent s bes) an general avice Toler: y Mattress covers an general avice School chilren: y Mattress covers an general avice Manchester Asthma an Allergy Stuy 36,95, Prenatal Extensive HDM avoiance measures inclue mattresses covers, HEPA filter, harwoo flooring, an use of Acarosan Prevention an Incience of Asthma an Mite Allergy Prenatal HDM avoiance measures: mattress covers an general avice Isle of Wight prevention 120 Birth Foo an HDM mite stuy 34,42,100,101 allergen avoiance Main outcome measures Allergic Allergic Allergic Allergic Wheeze Airway resistance (sraw) Reporte follow-up an outcome showing significant reuction in: 1 y: allergic 2 y: no effect 1 y: allergic 1 y: allergic HDM allergen levels 1 y: only severe wheeze Total IgE HDM allergen levels Specific IgE 2 y: nocturnal cough Cough, wheeze Atopic ermatitis Allergic HDM allergen levels 1 y: asthma, atopic Asthma ermatitis, an Allergic allergic rhinitis 2 y: atopic ermatitis Atopic an allergic ermatitis Foo allergy 4 y: atopic ermatitis an allergic 8 y: asthma an allergic Canaian Asthma Primary 545 Prenatal Dietary an environmental Allergic HDM allergen levels Prevention Stuy 35,103 avoiance 1 y: asthma an Asthma allergic rhinitis Allergic 2 y: asthma rhinitis Prevention of Atopic 531 Birth Dietary an environmental Asthma 4 y: any allergy Allergy 102 avoiance Atopic (incluing asthma, ermatitis atopic ermatitis, Rhinitis rhinitis, an urticaria) Urticaria Chilhoo Asthma 616 Prenatal HDM avoiance group Cough, 1.5 y: Diet group: Prevention Stuy 104,105 Diet (omega-3 fatty aci wheeze wheeze; HDM group: supplementation) group Asthma no effect Combine intervention Allergic 3 y: Diet group: cough; HDM group: Total IgE to HDM HEPA, High-efficiency particulate air. of 1 year in at-risk chilren (on the basis of family history an high cor IgE levels). Chilren were exclusively breast-fe, with maternal avoiance of highly allergenic foos, extensive hyrolysate use as a supplement or alternative to breast milk, an elaye introuction of soli foos. Environmental control measures inclue polyvinyl mattress covers an antiust mite spray, resulting in significant reuction of ust mite allergen in the intervention group. There was a sustaine reuction in to most allergens, incluing HDM, up to the

7 J ALLERGY CLIN IMMUNOL VOLUME 116, NUMBER 1 Arsha 9 Reviews an FIG 1. Schematic iagram of steps for primary an seconary prevention. reporte last follow-up at the age of 8 years. The intervention group chilren also showe a significant reuction in the prevalence of asthma an atopic ermatitis at 1 year, 42 atopic ermatitis at 2 an 4 years, 100,101 an asthma at 8 years. 34 This stuy supports the hypothesis that strict foo an aeroallergen avoiance in infancy in high-risk chilren might reuce the evelopment of allergic, leaing to less atopic ermatitis in infancy an asthma in later chilhoo. Prevention of atopic allergy. Bruno et al 102 reporte 48-month follow-up of a multicenter stuy of allergy prevention in 513 at-risk chilren (on the basis of family history). The intervention group chilren, after a program of reuction in foo allergen (exclusive breast-feeing or soya formula) an environmental exposure (house ust an ETS), were foun to have significantly less cumulative prevalence of allergic manifestations (asthma, rhinitis, atopic ermatitis, an urticaria). The Canaian Asthma Primary Prevention Stuy. This stuy use a multifacete program of intervention, incluing breast-feeing, elaye introuction of solis, reuction of HDM an pet allergen exposure, an ETS in at-risk infants (on the basis of family history). This RCT showe a reuction in asthma an wheeze, but not atopy, up to the age of 2 years. 35,103 However, the follow-up at present is too short to say whether it is early transient wheeze or asthma that is being prevente. Chilhoo Asthma Prevention Stuy. The Chilhoo Asthma Prevention Stuy was esigne to assess the benefit of omega-3 polyunsaturate fatty aci (PUFA) supplementation, HDM allergen avoiance, or a combination of these strategies. Outcome ata at the age of 18 months inicate a possible protective effect of ietary supplementation on wheeze, but not atopy. No benefit of HDM allergen avoiance was emonstrate at this age, an there was no synergistic effect with ietary supplementation. 104 At 3 years of age, a moest reuction was seen for cough, but not wheeze, in the iet group an HDM in the allergen avoiance group. 105 Although the stuy was reporte as showing benefit, the outcome is isappointing. For example, 14 chilren neee to avoi HDM allergen to prevent in 1 chil, an 10 chilren shoul be given ietary supplement of omega-3 fatty aci to prevent cough in 1 chil. Other strategies for primary prevention Diet. Some observational stuies link intake of antioxiants, such as vitamins C an E an selenium, an vitamin A with the occurrence of atopy an asthma. 59 However, RCTs fail to show a benefit of supplementation with these vitamins in asthmatic patients. 18 The primary preventive effect of antioxiant supplementation with RCT has not been stuie. Observational stuies consistently show a protective effect of omega-3 polyunsaturate fatty acis (omega-3 PUFAs) an an increase risk with high intake of omega-6 PUFAs. 59 Thus ietary moifications of supplementation with fish oil, rich in omega-3 PUFAs, might be of some benefit. A prospective observational stuy inicate that introuction of fish into the infant s iet reuces occurrence of rhinitis but not asthma. 106 An RCT of fish supplementation uring pregnancy inicate possible reuction in cytokine responses an allergic manifestations (skin test positivity an severity of atopic ermatitis). 107 Supplementation with gamma-lenolenic acis uring the first 6 months of life might reuce the severity of atopic ermatitis, but no effect on incience of atopic ermatitis or serum IgE was observe. 108 This subject is ealt with in more etail elsewhere in this issue of the Journal. 109 Exposure to enotoxin. Atopy is meiate by T H 2-type immune responses. The hygiene hypothesis proposes that stimulation of T H 1 cells by infections, vaccinations, or enotoxin exposure early in life reresses the T H 1/T H 2 balance an thus protects against atopy an allergic manifestations. Several epiemiologic stuies provie evience to support this notion, 110,111 but others coul not fin a protective effect of recurrent infections 112 or

8 10 Arsha J ALLERGY CLIN IMMUNOL JULY 2005 Reviews an enotoxin exposure. 113 Moreover, ranomize clinical trials to prove the effectiveness of this approach are lacking. Probiotics. In an RCT Lactobaccilus GG given uring pregnancy to mothers with a family history of atopy an for 6 months to their infants resulte in significant reuction in the occurrence of atopic ermatitis up to the age of 2 years. 114,115 Further etails of this important strategy are provie in a separate article in this issue of the Journal. 116 Vaccination. Vaccination against bacterial an viral iseases is often given in early chilhoo. There is some evience to suggest that it might influence the evelopment of allergy. For example, BCG vaccination, by stimulating T H 1 immune responses an altering the T H 1/T H 2 balance, might reuce the evelopment of allergic in eveloping countries. 117 However, this might not be true for western populations. 118 No clinical trials have been one to assess the immunomoulatory effect of vaccination in primary prevention of allergy. Allergen Immunotherapy. Specific allergen immunotherapy in chilren with respiratory symptoms an mono (sensitize to only one allergen) reuces the evelopment of new compare with those who are treate with meications only. 119,120 Whether this woul protect chilren from having other allergic manifestations is not known. Subjects with allergic rhinitis are at a higher risk of asthma evelopment. There is some evience to suggest that subsequent evelopment of asthma in those with allergic rhinitis can be prevente by using allergen immunotherapy at an early stage Drugs. In an RCT ketotifen was reporte to significantly reuce the evelopment of asthma in chilren with atopic ermatitis. 124 More recently, cetirizine was reporte to reuce the evelopment of asthma in chilren with atopic ermatitis who were sensitize to HDM or grass pollen. 125 Occupational asthma. We shoul keep in min that the best approach to manage occupational asthma is primary prevention (ie, reuction in exposure to occupational allergens in all susceptible iniviuals). 126 Problems in this area inclue measurement of airborne allergens in the workplace an efining the safe level of exposure. However, reuction in exposure can be achieve through the use of alternative an less-sensitizing agents, automation or moification of a process known to cause, an use of personal protective evices. Seconary prevention of asthma an allergy Seconary prevention of asthma an allergy with HDM avoiance measures remains a contentious issue. Stuies showing a beneficial effect an those unable to fin a benefit continue to appear in the literature. 127,128 A number of RCTs have shown that HDM avoiance is effective in the seconary prevention of atopic ermatitis. 129 Allergen avoiance shoul remain an essential part of the management of allergic iseases, even if the benefit of mattress covers is in oubt. 128 A separate article in this issue of the Journal eals with this subject. 130 SUMMARY (FIG 1) What we o know Exposure to ETS, especially uring pregnancy an early chilhoo, increases the risk of chilhoo wheeze an asthma, an avoiance of exposure to ETS must be inclue in all preventive avice. Maternal avoiance of allergenic foos uring pregnancy oes not work an coul be harmful. Breast-feeing for 4 to 6 months protects against the evelopment of early chilhoo wheeze an atopic ermatitis, but there is no evience of a long-term benefit. Maternal avoiance of allergenic foos uring lactation might have some aitional protective effect on reuction of cow s milk allergy an atopic ermatitis. However, this shoul only be unertaken by highly motivate mothers with a high risk of allergy in the offspring an uner strict ietary supervision. Convincing proof for the preventive effects of the elaye introuction of soli foos is lacking. Use of hyrolyze milk formula shows a preventive effect on cow s milk allergy an atopic ermatitis. The evience to support a preventive effect of HDM allergen avoiance for the evelopment of to HDM or respiratory allergy is not compelling. It might be that current methos of allergen reuction are not effective, that reuction in HDM allergen exposure alone is not sufficient, or that allergen-inuce inflammation is only one of many ifferent pathways for allergy evelopment. Results from further followup of the current large RCT are awaite. A strategy of combining foo an aeroallergen avoiance seems effective in reucing early chilhoo wheeze an atopic ermatitis an later chilhoo asthma. Further follow-up of current RCTs might provie more efinitive information. There is some evience that probiotics might be useful in preventing atopic ermatitis. What we nee to know We o not know how best to ientify the at-risk population, which woul inclue most chilren estine to become allergic. Further research in the genetics of asthma an allergy hol promise. More evience for the optimal time-age to implement preventive measures is require. Thus far, a clear benefit of prenatal intervention is not forthcoming (except smoking). Most prevention stuies have focuse on early chilhoo. However, new onset of asthma an allergic rhinitis is common in later chilhoo an early ault life. Prevention might still be possible in this age group, with the ae avantage of more accurate ientification of at-risk iniviuals

9 J ALLERGY CLIN IMMUNOL VOLUME 116, NUMBER 1 Arsha 11 (eg, those with transient early chilhoo wheeze, atopic ermatitis, or allergic ). Further research to evaluate the influence of exposure to pet allergens on the evelopment of the immune system in early chilhoo is neee. Until then, no avice can be given regaring exposure to animal allergen for primary prevention. No RCTs have yet been one on the primary preventive effect of specific reuction in cockroach or mol allergen. Although there is evience from epiemiologic an cross-sectional stuies of a link between various ietary constituents an asthma, RCTs to assess the preventive effect are either not available or fail to show a convincing benefit. More research is neee to evelop an test novel immunomoulatory agents, such as probiotics, vaccination, an pharmacologic agents. Combine strategies, such as allergen avoiance with ietary manipulation or pharmacologic intervention, nee further evaluation. 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