Current reviews of allergy and clinical immunology Series editor: Harold S. Nelson, MD Primary prevention of asthma and allergy Syed Hasan Arshad, DM, FRCP Staffordshire, United Kingdom This activity is available for CME credit. See page 31A for important information. The relentless increase in the prevalence of asthma and allergic diseases highlights the need for devising effective preventive strategies. Although the genetics of these disorders are being investigated, manipulation of known environmental risk factors remains the best available approach to this problem. However, the large number of potential environmental risk factors and our inability to accurately predict the development of asthma and allergy has led to conflicting data from recent prevention studies. Nonetheless, some useful recommendations can be made. Exclusive breast-feeding and avoidance of exposure to environmental tobacco smoke exposure can be safely recommended for the whole population, not only for prevention of allergy but also for other known benefits. Additionally, for children at high risk of allergy, maternal exclusion diet during lactation and protein hydrolysate as a supplement or alternative for children who could not be breast-fed seems to provide further protection. The preventive effect of avoidance of house dust mite allergen alone during pregnancy or after birth is disappointing. However, prospective randomized studies evaluating a combined food and house dust mite allergen avoidance regimen show some protection against atopic dermatitis in infancy and asthma in later childhood. Urgent research is needed to accurately identify children at high risk and to test novel preventative measures with the potential for immunomodulation. Further randomized controlled trials are also needed with long-term follow up to evaluate combined approaches that might provide maximum benefit. (J Allergy Clin Immunol 2005;116:3-14.) Key words: Asthma, allergy, atopy, prevention, allergen avoidance, house dust mite There has been a dramatic increase in the prevalence of asthma and other allergic diseases over the last few decades. They are now major public health problems 1 and are an enormous burden on health care resources. 2 Importantly, severe asthma and systemic allergic reactions are potentially life-threatening conditions. Additionally, these diseases adversely affect the quality of life of millions of children and adults. There is an urgent need to formulate strategies leading to a reduction in morbidity and mortality from asthma and allergy. This can be achieved through either primary or secondary prevention, and improved efforts in both these areas are essential (Table I). Common clinical manifestations of allergy include asthma, allergic rhinitis, atopic dermatitis, and food allergy. Subjects with allergic diseases are often atopic, manifested by sensitization to common allergens. However, atopy is only one of many factors involved in the pathogenesis of these disorders. The contribution of atopy and atopy-related genes might vary with the disease in question. For example, atopy plays a dominant role in IgE-mediated food allergy, such as peanut allergy, but alternate immunologic pathways, driven directly by T lymphocytes, assume significance in conditions such as nonatopic asthma. Allergic diseases are polygenic, with several genes on different chromosomes involved in the genesis of these disorders. However, the phenotypic expressions, manifesting in clinical disorders, require an interaction of genes with environmental factors. Genetic manipulation to prevent these disorders is not yet in sight, and recent increases in prevalence argue strongly for a significant role of environmental factors. These factors might increase or decrease the risk of allergy development, and some might be amenable to manipulation. We thus have to rely on identification and removal of environmen- tal risk factors in an attempt to stem and reverse the rising trends in allergy. A number of risk factors have been identified, including early feeding, diet, infections, aller- gens, pollutants, and tobacco smoke. RISK FACTORS During early infancy, the child is exposed to small quantities of a variety of food proteins through breast milk and larger quantities of cow’s milk protein if formula fed. The normal response to the initial introduction of these Abbreviations used ETS: Environmental tobacco smoke HDM: House dust mite PUFA: Polyunsaturated fatty acid RCT: Randomized controlled trial From the University of Keele, Staffordshire. Disclosure of potential conflict of interest: None disclosed. Received for publication March 24, 2005; revised March 30, 2005; accepted for publication March 31, 2005. Available online May 24, 2005. Reprint requests: Syed Hasan Arshad, DM, Department of Respiratory Medicine, University Hospital of North Staffordshire, Newcastle Rd, Stoke-on-Trent, ST4 6QG, United Kingdom. E-mail: [email protected]. 0091-6749/$30.00 Ó 2005 American Academy of Allergy, Asthma and Immunology doi:10.1016/j.jaci.2005.03.043 3 Reviews and feature articles
Transcript
Review
sand
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Current reviews of allergy and clinical immunology
Series editor: Harold S. Nelson, MD
Primary prevention of asthma and allergy
Syed Hasan Arshad, DM, FRCP Staffordshire, United Kingdom
This activity is available for CME credit. See page 31A for important information.
The relentless increase in the prevalence of asthma and allergic
diseases highlights the need for devising effective preventive
strategies. Although the genetics of these disorders are being
investigated, manipulation of known environmental risk factors
remains the best available approach to this problem. However,
the large number of potential environmental risk factors and
our inability to accurately predict the development of asthma
and allergy has led to conflicting data from recent prevention
studies. Nonetheless, some useful recommendations can be
made. Exclusive breast-feeding and avoidance of exposure to
environmental tobacco smoke exposure can be safely
recommended for the whole population, not only for prevention
of allergy but also for other known benefits. Additionally, for
children at high risk of allergy, maternal exclusion diet during
lactation and protein hydrolysate as a supplement or
alternative for children who could not be breast-fed seems to
provide further protection. The preventive effect of avoidance
of house dust mite allergen alone during pregnancy or after
birth is disappointing. However, prospective randomized
studies evaluating a combined food and house dust mite
allergen avoidance regimen show some protection against
atopic dermatitis in infancy and asthma in later childhood.
Urgent research is needed to accurately identify children at
high risk and to test novel preventative measures with the
potential for immunomodulation. Further randomized
controlled trials are also needed with long-term follow up to
evaluate combined approaches that might provide maximum
There has been a dramatic increase in the prevalence ofasthma and other allergic diseases over the last fewdecades. They are now major public health problems1
and are an enormous burden on health care resources.2
Importantly, severe asthma and systemic allergic reactionsare potentially life-threatening conditions. Additionally,these diseases adversely affect the quality of life ofmillions of children and adults. There is an urgent need
From the University of Keele, Staffordshire.
Disclosure of potential conflict of interest: None disclosed.
Received for publication March 24, 2005; revised March 30, 2005; accepted
for publication March 31, 2005.
Available online May 24, 2005.
Reprint requests: Syed Hasan Arshad, DM, Department of Respiratory
Medicine, University Hospital of North Staffordshire, Newcastle Rd,
� 2005 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2005.03.043
to formulate strategies leading to a reduction in morbidityand mortality from asthma and allergy. This can beachieved through either primary or secondary prevention,and improved efforts in both these areas are essential(Table I).
Common clinical manifestations of allergy includeasthma, allergic rhinitis, atopic dermatitis, and foodallergy. Subjects with allergic diseases are often atopic,manifested by sensitization to common allergens.However, atopy is only one of many factors involved inthe pathogenesis of these disorders. The contribution ofatopy and atopy-related genes might vary with the diseasein question. For example, atopy plays a dominant rolein IgE-mediated food allergy, such as peanut allergy,but alternate immunologic pathways, driven directly byT lymphocytes, assume significance in conditions such asnonatopic asthma. Allergic diseases are polygenic, withseveral genes on different chromosomes involved in thegenesis of these disorders. However, the phenotypicexpressions, manifesting in clinical disorders, require aninteraction of genes with environmental factors. Geneticmanipulation to prevent these disorders is not yet in sight,and recent increases in prevalence argue strongly for asignificant role of environmental factors. These factorsmight increase or decrease the risk of allergy development,and some might be amenable to manipulation. We thushave to rely on identification and removal of environmen-tal risk factors in an attempt to stem and reverse the risingtrends in allergy. A number of risk factors have beenidentified, including early feeding, diet, infections, aller-gens, pollutants, and tobacco smoke.
RISK FACTORS
During early infancy, the child is exposed to smallquantities of a variety of food proteins through breast milkand larger quantities of cow’s milk protein if formula fed.The normal response to the initial introduction of these
proteins is immune tolerance. However, in children withatopic predisposition, this immune tolerance breaks down.Thus sensitization to foods such as cow’s milk and egg iscommon in infancy, and in a subset of these children,clinical allergic reactions occur that manifest in the form ofskin rash–urticaria, gastrointestinal manifestations, atopicdermatitis, and occasionally systemic allergic reactions. Ithas been proposed that early introduction of allergenicfoods might promote the development of allergy,whereas later introduction might induce tolerance.3 Thusprevention of food allergy could be achieved by alteringthe dietary pattern of the at-risk infant.
Exposure to aeroallergens might be relevant to thedevelopment of respiratory allergy.4,5 The specific type ofaeroallergens varies according to the geoeconomic situa-tion. For example, house dust mite (HDM) is the mostimportant allergen in humid climates, pet allergens mightbe more relevant in cold countries, Alternaria speciesassume significance in dry climates, and cockroach mightbe the dominant allergen in inner-city areas. Previousefforts at primary prevention have largely focused onreduction of exposure to HDM allergen.
The hygiene hypothesis proposes that exposure tocertain infections and vaccines might influence the direc-tion of immune responses and protect against the de-velopment of atopy.6-8 However, not all infections areprotective. Recurrent lower respiratory tract infections inearly childhood are a recognized risk factor for asthma inlater childhood.9 The most common respiratory pathogenin infancy is respiratory syncytial virus, and this has beenlinked to later development of wheeze, asthma, andairways obstruction.10-12
Maternal smoking during and after pregnancy promotessensitization and the development of asthma.13 However,Tariq et al14 suggested that maternal smoking is pre-dominantly a risk factor for early childhood wheeze andnonatopic asthma. A number of studies have supported thelink between exposure to environmental tobacco smoke(ETS) and development of wheeze and asthma duringchildhood.13-15 Similarly, dietary factors, such as antiox-idants (vitamin C and E and selenium), magnesium,
TABLE I. Definitions
d Allergy: Clinical manifestations of immunologically mediated
reactions to foreign substances, usually proteins.
d Atopy: The genetic propensity to produce IgE antibodies after
exposure to allergen. This can be confirmed by means of skin
prick test or measurement of specific IgE antibodies in the serum
(allergic sensitization).
d At-risk population: Those who have a genetic predisposition
and are at higher risk of development of allergic diseases. At
present, this is usually assessed through family history of allergy,
presence of other allergic diseases, or allergic sensitization.
d Primary prevention: Preventing the development of allergic
manifestations, such as asthma, allergic rhinitis, or atopic
dermatitis.
d Secondary prevention: Prevention of symptoms, exacerbation,
or lung function deteriorations in those who already have an
allergic disease.
sodium, and omega-3 fatty acids, might affect the devel-opment of allergic diseases.16-18
WHAT ARE WE TRYING TO PREVENT?
Allergic manifestations are protean, and there is alack of uniformity in definitions of outcome measuresused in various studies. The definition and diagnosis ofasthma and rhinitis in early childhood is most challeng-ing in view of the lack of uniform criteria and avail-ability of objective tests to support the diagnosis.Another complication is that early childhood allergicmanifestations are often transient, and yet many studiesreport short-term (<5 years) follow-up periods. Moststudies suggests that an intervention such as exclusivebreast-feeding prevents wheeze in early childhood,19 butrecently, it has been reported that it might increase therisk of asthma in early adult life.20 Thus if short-termfollow-up studies defined early childhood wheeze asasthma, the same intervention can have positive ornegative outcomes. Further confusion arises when thereis a discrepancy between the effects of preventivemeasures on subjective (symptoms and diagnosis) andobjective (allergic sensitization, airway obstruction onlung function, and bronchial hyperresponsiveness) man-ifestations of asthma and allergy. Some studies haveattempted to prevent allergic sensitization as the princi-pal outcome, but this might not necessarily have thedesired effect of reducing clinical allergic disorders.There might also be a differential effect of the chosenintervention on the type of allergic manifestation. Forexample, dietary modifications, such as avoidance ofcow’s milk, might prevent cow’s milk allergy andperhaps atopic dermatitis but might not influence aller-gic rhinitis or asthma, and the reverse might be true foraeroallergen avoidance. It is therefore important thateach randomized controlled trial (RCT) in primaryprevention should have predefined specific outcomes,use standardized definitions as far as possible, and planto follow-up children for an appropriate period de-pending on the outcome being tested.
PREVENTIVE STRATEGIES: ALLERGENAVOIDANCE, DIETARY MANIPULATION,INFECTIONS-ENDOTOXIN,IMMUNOTHERAPY, AND DRUGS
Although there is good evidence that allergen exposureleads to sensitization21,22 and that sensitization is animportant risk factor for the development of allergicdisease,23,24 the direct relationship of allergen exposurein the causation of allergic disease is still questioned.25
The effect of exposure to allergen might depend on thenature of allergenic protein. Exposure to HDM isreported to cause asthma,26,27 whereas dog or cat allergenexposure might be protective,28-30 although there remainssome controversy regarding this issue.31 It is also not
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clear whether any protective effect of pet exposure is dueto induction of tolerance mechanisms (eg, modified TH2response) or a concomitant increased exposure to in-fections or endotoxin.32 In view of these conflictingreports, should we even be attempting to use allergenreduction as a strategy for primary prevention? Thatreduction in allergen exposure can lead to primaryprevention of a specific allergy is exemplified by latexallergy. During the last decade, the incidence of latexallergy has decreased sharply with the increase in the useof latex-free gloves.33
WHOLE POPULATION OR AT-RISKINDIVIDUALS
Because primary prevention measures require motiva-tion, effort, and expense, most studies have targetedinfants at high risk of allergy to maximize the benefit.34-37
Until children can be screened for specific genes withmore accurate prediction for future development ofasthma and allergy, family history of allergy is oftenrelied on to identify children at high risk. Althoughfamily history of allergy is a well-known risk factor, itremains true that the majority of asthmatic children arefrom families with no asthma, and the same is true foratopic dermatitis and allergic rhinitis.38,39 During the1980s, it was proposed that the level of IgE at birth (cordblood IgE) could more precisely indicate the risk of futureallergic disease. However, cord blood IgE has lowsensitivity for prediction of allergy in general,40 and itmight predict allergic sensitization but not clinical aller-gic disease.38,41 Despite these observations, in an attemptto include children at very high risk of allergy, somestudies have combined high cord IgE levels and familyhistory of allergy in selecting children suitable for pre-ventive measures.42 Egg sensitization in early childhoodhas been shown to predict respiratory allergy. However,its sensitivity as a predictive marker is poor, and it cannotbe usefully used to identify children at high risk.43 Otherbiomarkers, such as serum eosinophil cationic protein,urinary eosinophil protein X, and various cytokines, havenot proved to be reliable predictive markers.44
The Study on Prevention of Allergy in Children inEurope selected school-aged (6-8 years old) children forprimary prevention of HDM sensitization and asthma onthe basis of a positive family history of atopy plussensitization to other allergens but not HDM. Childrencan also be selected on the basis of having one allergicdisease and are thus at a higher risk of having another. Forexample, children with atopic dermatitis in early child-hood and allergic rhinitis in later childhood are atincreased risk of asthma.45
For any prevention program, the population to betargeted would eventually depend on the safety and costof the measure being recommended and whether there areany advantages for the low-risk population. For example,breast-feeding and avoidance of ETS are safe and inex-pensive and have other advantages apart from possible
prevention of allergic diseases. Therefore these measurescan and should be recommended for the whole population,even in the absence of convincing evidence for allergyprevention from RCTs. Other measures, such as maternalavoidance of allergenic foods, might not be completelysafe, require convincing evidence, and might be suitablefor only the high-risk population.
WHEN: PREGNANCY, INFANCY, LATERCHILDHOOD, OR ADULT
The onset of allergic manifestations is usually duringearly childhood. Hence primary prevention efforts have tocommence soon after birth or preferably during preg-nancy. Animal models support the hypothesis that contactwith an allergen early in life induces a state of generalimmune hyperresponsivenss, with increased production ofspecific IgE antibodies.46 Pregnancy is a TH2 environmentwith predominance of TH2-type cytokines. After birth, theimmune systemmatures to achieve a balance between TH1and TH2 cytokine responses.
47 However, in children withatopic heredity, this balance might never be achieved, anda TH2 predominance persists, leading to sensitization andallergic diseases. Thus a window of opportunity exists inearly life (infancy and early childhood), when manipula-tion of the environment in children with atopic hereditymight restore the balance. The TH1/TH2 hypothesis hasrecently been challenged, and immune tolerance-suppres-sion might involve regulatory T cells.48 Whatever theprecise mechanism, it is generally agreed that primaryprevention strategies have to focus on early childhood,before the immune system matures and exposure toallergens leads to sensitization.
Observational studies have suggested that an intenseexposure to a particular allergen, such as birch pollen,during pregnancy could increase the risk of offspring beingsensitized to that allergen and having allergic asthma.49 Itis now known that allergens can pass through the placentaand sensitize the fetus.50,51 A number of studies haveshown that cord blood mononuclear cells recognized foodand inhalant allergenic epitopes and respond to stimulationby proliferation.52 It has been suggested that exposure tob-lactoglobulin and ovalbumin during fetal life mightinfluence the direction of immune responses such thatthere will be reduced TH1-type cytokine releases, such asIFN-g, in turn increasing the risk of allergic diseases.53 It istherefore argued that fetal exposure to allergens should beminimized to protect the developing immune system. Thisbegs the question of whether preventive measures shouldbe instituted before birth. However, in the ChildhoodAsthma Prevention Study investigators were unable todemonstrate a correlation between maternal exposure toHDM allergen and cord blood mononuclear cell cytokineresponses, arguing against a beneficial effect of maternalHDM allergen avoidance.54 Indeed, in a rat modelMelkildet al55 argue that exposure to allergen early in pregnancymight favor the development of tolerance, with increasedproduction of IgG2a antibodies and suppression of specific
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IgE antibodies. However, there is good evidence thatsmoking during pregnancy increases the risk of childhoodasthma and adversely affects lung function.56,57 Use ofdrugs, such as paracetamol and dietary constituents, duringpregnancymight also influence the development of asthmain the offspring.58,59 Thus in principal primary preventionshould start as early as possible during pregnancy. Thespecific recommendations, however, should not be madeuntil the evidence and risk/benefit ratio have been carefullyconsidered.
PREVENTATIVE STRATEGIES
The identification of risk factors, such as allergenexposure, has led to evaluation of various strategies forprimary prevention. The conclusive proof of effectivenessrequires well-designed double-blind RCTs. However, thisis not always possible. For example, the effect of breast-feeding or maternal smoking cannot be tested by means ofRCTs for ethical reasons. Blinding might not be possiblefor practical reasons (eg, when testing the effect ofexposure to pet allergens).
Food allergen avoidance
Avoidance of cow’s milk protein with exclusive breast-feeding (with or without maternal avoidance of allergenicfoods) or hydrolyzed formula has been suggested forinfants at risk of allergy. It has also been proposed thatintroduction of other highly allergenic foods, such as eggsand nuts, to the infant is delayed.Exclusive breast-feeding. The extent of the preventive
effect of breast-feeding on allergic diseases remains con-troversial. Exclusive breast-feeding does seem to preventwheeze and atopic dermatitis during early childhood.19,60
However, long-term prospective studies have producedconflicting data. A relatively small study of at-risk childrenwith 15 years’ prospective follow-up did show a reductionin allergic manifestations in the breast-fed children com-pared with those fed cow’s milk or soya milk.61 However,several large observational studies failed to show a long-term protective effect of exclusive breast-feeding onasthma or other allergic manifestations.9,20,62 Two sys-temic reviews on this subject reached the conclusion thatexclusive breast-feeding does seem to have some protec-tive effect on the development of allergy.63,64 This effectmight be due to avoidance of cow’s milk protein allergen,other dietary constituents of breast milk, an immunomod-ulatory effect, or a combination of these. It was recentlysuggested that the effect of exclusive breast-feeding mightbe dependent on atopic heredity. Those with a geneticpredisposition had a lower incidence of sensitization andallergic rhinitis, whereas children without such a predis-position had an increased risk.65 In this issue of the Journal,another article discusses this subject in more detail.66
Hydrolyzed milk formulae. In an attempt to avoidexposure to cow’s milk protein early in life, hydrolyzed(casein or whey) formulae are suggested as a replacementfor or supplement to breast-feeding. A number of RCTs
have been done over the last 2 decades to assess thepreventive effect of replacing cow’s milk formula withhydrolysate or soy milk formulae. Chandra et al67,68
compared the development of allergic diseases (asthma,atopic dermatitis, and food allergy) in groups of childrenfed breast milk, hydrolyzed formula, cow’s milk formula,and soy formula. A significant preventive effect of breastmilk and partially hydrolyzed formula was shown consis-tently up to the age of 5 years. Another study, this onecomparing cow’s milk formula and whey hydrolysate,shows a reduction in cow’s milk allergy and atopicdermatitis in the first year.69 In a study by Marini et al,70
exclusive breast-feeding combined with hydrolysatesupplementation led to a significant reduction in variousallergic manifestations up to the age of 3 years. AnotherRCT showed prevention of atopic dermatitis, but notasthma, with the use of hydrolysate formula.71
Proteins can be extensively or partially hydrolyzed inthe infant formulae. For secondary prevention, in childrenwith cow’s milk allergy, it is generally agreed that onlyextensive hydrolysate should be used to avoid anyreaction in highly sensitized infants. There is some con-troversy regarding the extent of hydrolysis needed forprimary prevention. In an RCT use of partially hydrolyzedformula during the first fewmonths of life in genetically at-risk infants reduced the prevalence of atopic dermatitis,but not wheeze, in the first 2 to 3 years of life.72 TheGerman Infant Nutritional Intervention Study comparedthe preventive effect of 3 hydrolyzed formulas (partiallyhydrolyzed whey formula, extensively hydrolyzed wheyformula, and extensively hydrolyzed casein formula), withcow’s milk formula–fed children as control subjects. Theincidence of allergic manifestations, such as atopic der-matitis, food allergy, or allergic urticaria, was significantlyreduced by using an extensively hydrolyzed casein for-mula compared with a cow’s milk formula. There was alsosome protective effect of partial (but not extensive) wheyhydrolysate on reduction of atopic dermatitis.73 However,other RCTs indicate a greater preventive effect of exten-sively hydrolyzed milk compared with partially hydro-lyzed formula on allergic manifestations, particularlycow’s milk allergy.74,75 Overall, it seems that proteinhydrolysate reduces allergic manifestations during the first2 to 3 years of life in children at high risk of atopy, as asupplement or alternative to breast-feeding.76 Thesehydrolysates have been shown to be nutritionally adequateof the needs of the infant.77 However, these have not beenshown to be superior to exclusive breast-feeding. Thereremains some uncertainty as to the superiority of extensiveversus partial hydrolysate in primary prevention.78 Moststudies found that soy formula do not protect againstallergy in high-risk infants.79
Maternal avoidance diet during pregnancy. Severalstudies have investigated the preventive effect of maternalavoidance of highly allergenic foods, such as cow’s milk,egg, and nuts, during pregnancy to protect the fetus fromthe effect of food allergens ingested by the mother. AnRCT showed that maternal diet (excluding cow’s milk andegg) during late pregnancy does not protect against the
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development of allergic manifestation in geneticallypredisposed children.80,81 Additionally, there was someconcern regarding maternal and fetal weight gain. Zeigeret al82 evaluated the effect of maternal avoidance of aller-genic food (cow’s milk, egg, nuts, fish, and soy) duringlate pregnancy and lactation, supplementation with exten-sive hydrolysate, and avoidance of solids up to 6 months.There was a reduction in food sensitization on skin pricktests, food allergic manifestations, and atopic dermatitis atthe age of 2 years. However, no long-term benefit beyondearly childhood was observed.83 Weight gain during thethird trimester was again a concern in mothers whopracticed an avoidance diet.Maternal avoidance diet during lactation. In an RCT
maternal avoidance of highly allergenic food (dairy pro-duce, egg, fish, peanut, and soy) during lactation led to areduction in the prevalence of atopic dermatitis at 18months in high-risk infants.84 In a Japanese study infantsin the intervention group were exclusively breast-fed orgiven whey hydrolysate, whereas the lactating motherswere given the same whey hydrolysate as the only sourceof protein. These infants were compared for the develop-ment of allergy with 2 other groups of children. One groupwas breast-fed with the mother consuming cow’s milk,whereas in the third group infants were given cow’s milkformula. The active group infants showed lower incidenceof atopic dermatitis and cow’s milk allergy.85 In anotherRCT maternal avoidance diet (cow’s milk, egg, and fish)during the first 3 months of lactation reduced atopicdermatitis in early childhood, but there was no long-termbenefit.86,87 Herrmann et al,88 however, failed to show aprotective effect of maternal avoidance diet (cow’s milkand egg) during late pregnancy and lactation. Although amaternal avoidance diet during lactation is difficult toadhere to, none of the studies reported any adversenutritional effects for mother or child. A Cochrane data-base review concluded that restrictingmaternal diet duringpregnancy does not prevent allergy and might haveadverse consequences for maternal nutrition, fetal nutrit-ion, or both. However, maternal food allergen avoidanceduring lactation might be of some benefit.89
Late introduction of solid foods. Some observationalstudies have supported the concept that introduction ofsolid foods before the age of 4 months might increase therisk of atopic dermatitis in genetically predisposed chil-dren.90 However, other studies could not find a beneficialeffect of late introduction of solid foods.60,91 Most inter-vention studies have combined late introduction of solidswith other intervention measures, and thus it is difficult toknow whether this strategy alone has any protectiveeffect.42,82
HDM avoidance
In view of the link between exposure to HDM anddevelopment of asthma suggested by several cross-sec-tional and prospective studies, there has been an attempt toreduce at-risk children’s exposure to HDM allergen.5,26,27
Three large prospective studies have instituted HDMavoidance measures during pregnancy, at birth, and later
in childhood and assessed children for asthma and allergicmanifestations (Table II).Study of Prevention of Allergy in Children in Europe.
The Study of Prevention of Allergy in Children inEurope was designed to assess the effect of simple HDMavoidance measures, such as mattress covers, and a set ofenvironmental educational advice on the development ofsensitization to HDM and allergy manifestations. Theresearchers recruited 3 cohorts of children (newborns,toddlers [2-4 years], and school-aged children [5-7 years])at high risk of sensitization to HDM. In the newborncohort, sensitization, particularly to HDM, was reduced inthe intervention group children at 1 year, but this effectwas lost by the age of 2 years. Moreover, no differencewas observed in clinical allergicmanifestation between the2 groups.37,92 In the toddler93 and school-aged childrencohorts,94 a reduction in the incidence of sensitization toHDM was observed at 1 year but not in the occurrence ofallergic manifestations. This study provides evidence thatallergen avoidance could protect at-risk children againstsensitization to that allergen, even in later childhood.However, this might not protect children from clinicalallergic manifestations. Further follow-up of the toddlerand school-aged children will determine whether reduc-tion in allergen sensitization is sustained and whether thistranslates into reduced occurrence of clinical allergy.Manchester Asthma and Allergy Study. The
Manchester Asthma and Allergy Study used extensiveenvironmental control measures during pregnancy andinfancy. These included impermeable mattress covers onparental beds from the second trimester of pregnancy,mattress covers for children’s beds, hardwood flooring inbedrooms, use of high-efficiency particulate air filtervacuum cleaners, and application of antimite foam, benzylbenzoate (Allergopharma, Reinbek, Germany), on softfurnishings to reduce dust mite numbers and allergen. Ahighly significant reduction in exposure to dust mite, cat,and dog allergens was achieved.36,95 At age 1 year, therewas no difference in mite sensitization, mild wheeze, orcough or atopic dermatitis. There was, however, a signif-icant reduction in the occurrence of severe wheeze in theintervention group infants.96 Further follow-up of thiscohort will provide useful information.Prevention and Incidence of Asthma and Mite Allergy.
The Prevention and Incidence of Asthma andMite Allergystudy evaluated the effectiveness of HDM avoidancemeasures, including allergen-impermeable (interventiongroup) and placebo (control group) mattress encasings, inthe children’s and parent’s beds before birth and duringthe first year of life. Although HDM allergen levels werereduced in the intervention group,97 there was no differ-ence in the development of atopy or asthma.At age 2 years,the only difference seen was a slight but significant reduc-tion in nighttime cough in children in the active group.98,99
Multiple interventions
The Isle of Wight prevention study. This RCT evalu-ated the effect of a combined food and HDM allergenavoidance regimen implemented from birth up to the age
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TABLE II. Cohort intervention studies (RCTs) with HDM allergen avoidance alone or in combination with dietary measures
Study Number
Intervention
started at: Intervention
Main outcome
measures
Reported follow-up and
outcome showing
significant reduction in:
Study of Prevention
of Allergy in Children
of Europe, 3 cohorts:
newborn, toddler,
school children37,92-94
Newborn: 696 Birth HDM avoidance measures:
mattress covers (infant
and parent’s beds) and
general advice
d Allergic
sensitization
d 1 y: allergic
sensitization
d 2 y: no effect
Toddler: 636 2-4 y Mattress covers and general
advice
d Allergic
sensitization
d 1 y: allergic
sensitization
School
children: 242
5-7 y Mattress covers and general
advice
d Allergic
sensitization
d 1 y: allergic
sensitization
Manchester Asthma
and Allergy Study36,95,96620 Prenatal Extensive HDM avoidance
measures included
mattresses covers,
HEPA filter, hardwood
flooring, and use of
Acarosan
d Allergic
sensitization
d HDM allergen levels
d 1 y: only severe wheeze
d Wheeze
d Airway
resistance
(sRaw)
Prevention and Incidence
of Asthma and
Mite Allergy97-99
810 Prenatal HDM avoidance measures:
mattress covers and
general advice
d Total IgE d HDM allergen levels
d Specific IgE d 2 y: nocturnal cough
d Cough,
wheeze
d Atopic
dermatitis
Isle of Wight prevention
study34,42,100,101120 Birth Food and HDM mite
allergen avoidance
d Allergic
sensitization
d Asthma
d Allergic
rhinitis
d Atopic
dermatitis
d HDM allergen levels
d 1 y: asthma, atopic
dermatitis, and
allergic sensitization
d 2 y: atopic dermatitis
and allergic
sensitization
d Food allergy d 4 y: atopic
dermatitis and allergic
sensitization
d 8 y: asthma and
allergic sensitization
Canadian Asthma Primary
Prevention Study35,103545 Prenatal Dietary and environmental
avoidance
d Allergic
sensitization
d Asthma
d HDM allergen levels
d 1 y: asthma and
allergic rhinitis
d Allergic
rhinitis
d 2 y: asthma
Prevention of Atopic
Allergy102531 Birth Dietary and environmental
avoidance
d Asthma d 4 y: any allergy
(including asthma,
atopic dermatitis,
rhinitis, and urticaria)
d Atopic
dermatitis
d Rhinitis
d Urticaria
Childhood Asthma
Prevention Study104,105616 Prenatal d HDM avoidance group d Cough,
wheeze
d Asthma
d 1.5 y: Diet group:
wheeze; HDM group:
no effect
d 3 y: Diet group:
cough; HDM group:
sensitization to HDM
d Diet (omega-3 fatty acid
supplementation) group
d Combined intervention d Allergic
sensitization
d Total IgE
HEPA, High-efficiency particulate air.
of 1 year in at-risk children (on the basis of family historyand high cord IgE levels). Children were exclusivelybreast-fed, with maternal avoidance of highly allergenicfoods, extensive hydrolysate used as a supplement oralternative to breast milk, and delayed introduction of
solid foods. Environmental control measures includedpolyvinyl mattress covers and antidust mite spray, result-ing in significant reduction of dust mite allergen in theintervention group. There was a sustained reduction insensitization to most allergens, including HDM, up to the
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FIG 1. Schematic diagram of steps for primary and secondary prevention.
reported last follow-up at the age of 8 years. Theintervention group children also showed a significantreduction in the prevalence of asthma and atopic derma-titis at 1 year,42 atopic dermatitis at 2 and 4 years,100,101
and asthma at 8 years.34 This study supports the hypoth-esis that strict food and aeroallergen avoidance in infancyin high-risk children might reduce the development ofallergic sensitization, leading to less atopic dermatitis ininfancy and asthma in later childhood.Prevention of atopic allergy. Bruno et al102 reported
48-month follow-up of a multicenter study of allergyprevention in 513 at-risk children (on the basis of familyhistory). The intervention group children, after a programof reduction in food allergen (exclusive breast-feeding orsoya formula) and environmental exposure (house dustand ETS), were found to have significantly less cumula-tive prevalence of allergicmanifestations (asthma, rhinitis,atopic dermatitis, and urticaria).The Canadian Asthma Primary Prevention Study. This
study used a multifaceted program of intervention, in-cluding breast-feeding, delayed introduction of solids,reduction of HDM and pet allergen exposure, and ETS inat-risk infants (on the basis of family history). This RCTshowed a reduction in asthma and wheeze, but not atopy,up to the age of 2 years.35,103 However, the follow-up atpresent is too short to say whether it is early transientwheeze or asthma that is being prevented.Childhood Asthma Prevention Study. The Childhood
Asthma Prevention Study was designed to assess thebenefit of omega-3 polyunsaturated fatty acid (PUFA)supplementation, HDM allergen avoidance, or a combi-nation of these strategies. Outcome data at the age of18 months indicate a possible protective effect of dietarysupplementation on wheeze, but not atopy. No benefit ofHDM allergen avoidance was demonstrated at this age,and there was no synergistic effect with dietary supple-mentation.104 At 3 years of age, a modest reduction wasseen for cough, but not wheeze, in the diet group andHDM sensitization in the allergen avoidance group.105
Although the study was reported as showing benefit,the outcome is disappointing. For example, 14 childrenneeded to avoid HDM allergen to prevent sensitizationin 1 child, and 10 children should be given dietary supple-ment of omega-3 fatty acid to prevent cough in 1 child.
Other strategies for primary prevention
Diet. Some observational studies link intake of anti-oxidants, such as vitamins C and E and selenium, andvitamin A with the occurrence of atopy and asthma.59
However, RCTs fail to show a benefit of supplementationwith these vitamins in asthmatic patients.18 The primarypreventive effect of antioxidant supplementation withRCT has not been studied. Observational studies consis-tently show a protective effect of omega-3 polyunsatu-rated fatty acids (omega-3 PUFAs) and an increased riskwith high intake of omega-6 PUFAs.59 Thus dietarymodifications of supplementation with fish oil, rich inomega-3 PUFAs, might be of some benefit. A prospectiveobservational study indicated that introduction of fish intothe infant’s diet reduces occurrence of rhinitis but notasthma.106 An RCT of fish supplementation during preg-nancy indicated possible reduction in cytokine responsesand allergic manifestations (skin test positivity andseverity of atopic dermatitis).107 Supplementation withgamma-lenolenic acids during the first 6 months of lifemight reduce the severity of atopic dermatitis, but no effecton incidence of atopic dermatitis or serum IgE wasobserved.108 This subject is dealt with in more detailelsewhere in this issue of the Journal.109
Exposure to endotoxin. Atopy is mediated by TH2-typeimmune responses. The hygiene hypothesis proposes thatstimulation of TH1 cells by infections, vaccinations, orendotoxin exposure early in life redresses the TH1/TH2balance and thus protects against atopy and allergicmanifestations. Several epidemiologic studies provideevidence to support this notion,110,111 but others couldnot find a protective effect of recurrent infections112 or
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endotoxin exposure.113 Moreover, randomized clinicaltrials to prove the effectiveness of this approach arelacking.Probiotics. In an RCT Lactobaccilus GG given during
pregnancy to mothers with a family history of atopy andfor 6 months to their infants resulted in significantreduction in the occurrence of atopic dermatitis up to theage of 2 years.114,115 Further details of this importantstrategy are provided in a separate article in this issue ofthe Journal.116
Vaccination. Vaccination against bacterial and viraldiseases is often given in early childhood. There is someevidence to suggest that it might influence the develop-ment of allergy. For example, BCG vaccination, by sti-mulating TH1 immune responses and altering the TH1/TH2balance, might reduce the development of allergic sensi-tization in developing countries.117 However, this mightnot be true for western populations.118 No clinical trialshave been done to assess the immunomodulatory effect ofvaccination in primary prevention of allergy.Allergen Immunotherapy. Specific allergen immuno-
therapy in children with respiratory symptoms and mono-sensitization (sensitized to only one allergen) reduces thedevelopment of new sensitization compared with thosewho are treated with medications only.119,120 Whetherthis would protect children from having other allergicmanifestations is not known. Subjects with allergicrhinitis are at a higher risk of asthma development.There is some evidence to suggest that subsequent de-velopment of asthma in those with allergic rhinitis can beprevented by using allergen immunotherapy at an earlystage.121-123
Drugs. In an RCT ketotifen was reported to signifi-cantly reduce the development of asthma in children withatopic dermatitis.124 More recently, cetirizine was re-ported to reduce the development of asthma in childrenwith atopic dermatitis who were sensitized to HDM orgrass pollen.125
Occupational asthma. We should keep in mind that thebest approach to manage occupational asthma is primaryprevention (ie, reduction in exposure to occupationalallergens in all susceptible individuals).126 Problems inthis area include measurement of airborne allergens in theworkplace and defining the safe level of exposure.However, reduction in exposure can be achieved throughthe use of alternative and less-sensitizing agents, automa-tion or modification of a process known to cause sensi-tization, and use of personal protective devices.
Secondary prevention of asthma and allergy
Secondary prevention of asthma and allergy withHDM avoidance measures remains a contentious issue.Studies showing a beneficial effect and those unable tofind a benefit continue to appear in the literature.127,128 Anumber of RCTs have shown that HDM avoidanceis effective in the secondary prevention of atopic derma-titis.129 Allergen avoidance should remain an essentialpart of the management of allergic diseases, even if the
benefit of mattress covers is in doubt.128 A separate articlein this issue of the Journal deals with this subject.130
SUMMARY (FIG 1)
What we do know
d Exposure to ETS, especially during pregnancy andearly childhood, increases the risk of childhoodwheeze and asthma, and avoidance of exposure toETS must be included in all preventive advice.
d Maternal avoidance of allergenic foods during preg-nancy does not work and could be harmful.
d Breast-feeding for 4 to 6 months protects against thedevelopment of early childhood wheeze and atopicdermatitis, but there is no evidence of a long-termbenefit.
d Maternal avoidance of allergenic foods during lacta-tion might have some additional protective effect onreduction of cow’s milk allergy and atopic dermatitis.However, this should only be undertaken by highlymotivated mothers with a high risk of allergy in theoffspring and under strict dietary supervision.
d Convincing proof for the preventive effects of thedelayed introduction of solid foods is lacking.
d Use of hydrolyzed milk formula shows a preventiveeffect on cow’s milk allergy and atopic dermatitis.
d The evidence to support a preventive effect of HDMallergen avoidance for the development of sensitiza-tion to HDM or respiratory allergy is not compelling.It might be that current methods of allergen reductionare not effective, that reduction in HDM allergen ex-posure alone is not sufficient, or that allergen-inducedinflammation is only one of many different pathwaysfor allergy development. Results from further follow-up of the current large RCT are awaited.
d A strategy of combining food and aeroallergen avoid-ance seems effective in reducing early childhoodwheeze and atopic dermatitis and later childhoodasthma. Further follow-up of current RCTs mightprovide more definitive information.
d There is some evidence that probiotics might be usefulin preventing atopic dermatitis.
What we need to know
d We do not know how best to identify the at-riskpopulation, which would include most children des-tined to become allergic. Further research in thegenetics of asthma and allergy hold promise.
d More evidence for the optimal time-age to implementpreventive measures is required. Thus far, a clearbenefit of prenatal intervention is not forthcoming(except smoking). Most prevention studies havefocused on early childhood. However, new onset ofasthma and allergic rhinitis is common in later child-hood and early adult life. Prevention might still bepossible in this age group, with the added advantageof more accurate identification of at-risk individuals
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(eg, those with transient early childhood wheeze,atopic dermatitis, or allergic sensitization).
d Further research to evaluate the influence of exposureto pet allergens on the development of the immunesystem in early childhood is needed. Until then, noadvice can be given regarding exposure to animalallergen for primary prevention.
d No RCTs have yet been done on the primary preven-tive effect of specific reduction in cockroach or moldallergen.
d Although there is evidence from epidemiologic andcross-sectional studies of a link between variousdietary constituents and asthma, RCTs to assess thepreventive effect are either not available or fail toshow a convincing benefit.
d More research is needed to develop and test novelimmunomodulatory agents, such as probiotics, vacci-nation, and pharmacologic agents.
d Combined strategies, such as allergen avoidance withdietary manipulation or pharmacologic intervention,need further evaluation.
d It might be that individuals with different risk profilesrequire different preventive strategies. Thus in thefuture, a child could be screened for identification ofhis or her risk profile (genetic and likely environmentalfactors), and an appropriate preventive strategy couldbe recommended.
REFERENCES
1. Weiss KB, Sullivan SD. The health economics of asthma and rhinitis. I.
Assessing the economic impact. J Allergy Clin Immunol 2001;107:3-8.
2. National Heart, Lung, and Blood Institute. Asthma statistics. Bethesda
(MD): National Institutes of Health, Public Health Service; 1999.
3. Oddy WH, Peat JK, de Klerk NH. Maternal asthma, infant feeding and
the risk of childhood asthma. J Allergy Clinical Immunol 2002;110:
65-7.
4. Litonjua AA, Burge HA, Weiss ST, Gold DR. Exposure to cockroach
allergen in the home is associated with incident doctor-diagnosed
asthma and recurrent wheezing. J Allergy Clin Immunol 2001;107:
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