Pediatr Allergy Immunol 2004: 15 (Suppl.

16): 9–32 Copyright
2004 Blackwell Munksgaard

Printed in UK. All rights reserved
PEDIATRIC ALLERGY AND
IMMUNOLOGY

Prevention of allergic disease in childhood:

clinical and epidemiological aspects of
primary and secondary allergy prevention
Susanne Halken
Department of Pediatrics, Sønderborg Hospital, Sønderborg, Denmark

first year of life, whereas allergy to inhalant

Introduction and background
allergens mostly occurs later.
Atopic diseases represent a major and increasing Characteristically, sensitization evolves in the
health problem in industrialized countries. The order of exposure: food, indoor allergens, out-
prevalence of atopic diseases in childhood door allergens. Sensitization to milk and egg most
(asthma, atopic dermatitis, and allergic rhinocon- frequently occurs during the first 2–3 yr of life,
junctivitis) has increased considerably in devel- while sensitization to inhalant allergens occurs
oped countries (1) in the last 30 yr. Although later in childhood with increasing prevalence with
several studies have shown this increase, it has age (8–10). Sensitization to indoor airborne
been argued that increased awareness and allergens (house dust mites (HDM) and pets)
improved ability to diagnose atopic diseases often occurs at a lower age than sensitization to
might account, at least in part, for this increase. pollen (birch and grass) (9, 11, 12). The cumula-
However, population-based studies using identi- tive prevalence of different allergic diseases and of
cal methods of ascertainment at intervals of 10– proven IgE-mediated allergy related to the differ-
15 yr have also shown a significant increase in the ent allergic symptoms is shown in Table 1.
prevalence of atopic diseases in children (2–7). It has been shown that children with atopic
Therefore, possible effective allergy preventive dermatitis have an increased risk for develop-
measures are exceedingly warranted. Preventive ment of asthma (13), children with allergic
strategies may address the normal population or rhinoconjunctivitis often develop asthma and
a defined Ôhigh-riskÕ population, and different that children with asthma often have allergic
approaches may be needed for different forms of rhinoconjunctivitis (12, 14). The prognosis of
atopic diseases. Preventive strategies should food allergy (FA) is good and children with FA
include effective measures aiming at primary, often outgrow their FA; but they are prone to the
secondary and tertiary prevention. development of allergy against inhalant allergens
and both asthma and allergic rhinoconjunctivitis,
especially in case of IgE-mediated FA (15–17).
Natural course
Recent prospective studies have reported early
The expression of allergic diseases may vary with sensitization against cow’s milk, hen’s egg and
age, and symptoms may disappear and be HDM highly predictive for sensitization and also
replaced by other symptoms. In infancy the main for clinical allergic disease, persistent atopic
atopic symptoms are atopic dermatitis, gastroin- dermatitis and asthma later in childhood (18–
testinal symptoms, and recurrent wheezing, 20) especially in high-risk (HR) infants (10, 21–
whereas bronchial asthma and allergic rhinocon- 23) or infants with early atopic manifestations
junctivitis are the main problems later in child- such as atopic dermatitis or wheezing (24, 25).
hood. Adverse reactions to foods, mainly cow’s Thus, IgE-mediated allergic disease early in
milk protein (CMP), are most common in the childhood is associated with a high risk of severe
allergic disease later on. This natural course of
the allergic diseases – the so called Ôallergic
Correspondence: Susanne Halken, Department of Pediatrics, Sønderborg
Hospital, DK-6400 Sønderborg, Denmark marchÕ – is very important to take into consid-
Tel: +45 74182765 eration, when evaluating factors that may influ-
Fax: +45 74182952 ence the development of allergic diseases.
9
Table 1. Atopic diseases in childhood. Prevalence of disease and prevalence to be taken into account. The study design should
of allergy in children with atopic disease
be prospective and include accepted well-defined
Prevalence (%) Proven IgE mediated (%) diagnostic criteria/outcome measures, a sufficient
duration of follow-up, and a proper sample size
Food allergy 7–8 40–60 for adequate statistical evaluation. Furthermore,
Atopic dermatitis 15–20 20–70 interventional studies should include proper
Asthma/recurrent wheezing <5 yr 31–34 30–50
Asthma >5 yr 7–10 60–90
randomization, double blinding and a control
for confounders, as well as proper registration of
Frequencies of IgE-mediated reactions vary with age and selection. Different compliance and follow-up of dropouts.
phenotypes, e.g. infectious asthma vs. atopic asthma. Due to recall bias and selection bias, neither
retrospective nor cross-sectional studies are suit-
The objective for this review was to evaluate able for assessment of cause–effect relationships
possible preventive measures as regards preven- between exposure to allergens/adjuvant factors
tion of development of allergic disease in child- and development of allergic diseases. In general,
hood – primary prevention – and also some prospective non-interventional studies can be
aspects of the effect of specific allergy treatment used to generate hypotheses on the relationship
as regards secondary prevention in children with between cause and effect in development of
allergic asthma and allergic rhinoconjunctivitis. allergic diseases; however, proper confirmation
of a possible cause–effect relationship requires
demonstration of the causative mechanism and
Development of allergic diseases effect of elimination/prevention of the suspected
The development and phenotypic expression of causative factors (27, 28).
atopic disease depends on a complex interaction
between genetic and several environmental factors Atopic heredity
such as environmental exposure to food and
inhalant allergens, and non-specific adjuvant fac- It has been shown that around 30% of newborns
tors (e.g. tobacco smoke, air pollution, and have at least one parent/or older sibling with
infections) (Fig. 1). At present, it is estimated that previous or current atopic disease, around 5% of
genetic factors account for around 50% of asthma newborns have double parental atopic heredity
and allergy (26). It is unlikely that a change in and around 10% have one sibling and one parent
genetic factors can explain the increased preval- with atopic heredity. Around 60–65% are with-
ence of asthma and allergy seen during the last out atopic heredity (29–33). In children without
decades. It is evident that environmental factors atopic heredity around 10% develop allergic
play a major role in the development of sensitiza- disease, whereas 20–30% of children with single
tion and allergic disease, and that many different atopic heredity (parent or sibling) and around
environmental factors may contribute to the 40–50% of infants with double parental heredity
increase in the prevalence of the allergic diseases. have been shown to develop atopic disease (29,
When evaluating possible risk factors for the 33). However, it should be emphasized that the
development of allergic diseases and the possible extent of exposure to environmental factors, such
effect of preventive measures, several factors have as allergens and tobacco smoke as well as the
extent of possible preventive measures such as
breastfeeding, pharmacological measures, etc.
will always influence such estimates heavily.
Allergen exposure

Genetic predisposition
+ Dietary factors
Breastfeeding. More than 60 yr ago Sanford and
Early sensitization
Grulee reported that undiluted cow’s milk gave a
sevenfold increase in the risk of ÔeczemaÕ at
Immune modulation (b)
Allergen exposure (a)
+ +/– – infections 9 months of age in a huge cohort of children
– intestinal microflora
– other factors compared with babies that were breastfed and
fed mixed food (34). One cohort study has
Development of clinical allergy demonstrated an association between early cow’s
milk formula feeding and development of cow’s
(a) and (b): Not mutually exclusive
milk protein allergy (CMA) (35). In a Finnish
Fig. 1. Development of allergic disease. (a) and (b): not study of non-selected, non-high risk newborns
mutually exclusive. followed until 17 yr of age, 6 months exclusively
10
breastfeeding was associated with less ÔeczemaÕ ted retrospectively at the age of 3 yr and the
and FA at 1 and 3 yr as well as a lower Ôscore of information on ÔatopicÕ heredity is uncertain
respiratory allergyÕ (not well defined) up to 17 yr without clear definitions and without inclusion
of age compared with exclusively breastfeeding of atopic dermatitis and atopic siblings. No
for less than 3 months (36). Another prospective significant effect of exclusively breastfeeding for
study (37) found that non-atopic children (neg- at least 4 wk was found and no data or
ative skin prick test) at age 6 yr, who had not conclusion on exclusively breastfeeding for a
been breastfed had increased risk of wheezing longer duration are presented.
recurrently when compared with breastfed chil- Prospective birth cohort studies including data
dren (odds ratio 3.03, 95% CI 1.06–8.69), but the on preventive effects of breastfeeding on FA,
same association was not found for atopic atopic dermatitis, sensitization and respiratory
children. In a recent Australian study (38–42) symptoms are shown in Table 2 (35–39, 41, 42,
introduction of milk other than breastmilk 44, 46–54).
before 4 months of age was a significant risk Common factors apparent in studies reporting
factor for all asthma and ÔatopyÕ outcomes in benefit of breastfeeding were: (a) prolonged
children up to 6 yr (odds ratio 1.25, 95% CI breastfeeding (>4–6 months) and (b) late solid
1.02–1.52), and for current asthma (odds ratio food introduction (after 4–6 months).
1.31, 95% CI 1.05–1.64). Breastfeeding has also A possible protective effect of breastfeeding on
been shown to reduce the risk of wheezy the development of allergic diseases may be due
bronchitis during infancy (43, 44). Meanwhile, to either: (a) a protective effect of human milk
contradictory results exist, e.g. in a recent large (the constituents) or (b) avoidance of Ôhigh-doseÕ
prospective study from 3 to 21 yr of age, the of cow’s milk proteins.
authors concluded that breastfeeding for at least In a few studies (45, 53, 54) an association
4 wk does not protect children from atopy and between breastfeeding and asthma or atopic
asthma and may even increase the risk (45). dermatitis may be explained as Ôreverse cautionÕ,
However, the methods and data presented in that meaning that those with the highest degree of
study do not seem to confirm the conclusion. atopic heredity will tend to be breastfed for the
Thus, e.g. data on breastfeeding were documen- longest period.

Table 2. Dietary allergy prevention – breastfeeding. Non-interventional prospective studies in unselected infants

Follow-up Diet period

Study n (years) Diet (months) Health effect

Saarinen et al. (46) 236 3 Excl BF 6 fl FA and AD at 1 and 3 yr in –FH

43% +FH fl FA and AD at 1 and 3 yr in +FH
Gruskay (47) 328 +FH 15 BF vs. ‡4 fl AD and Asthma
580 –FH Soy/CMP
Pratt (48)* 122 +FH 5 Excl BF ‡3 fl Eczema in children +FH
76 –FH fi Eczema in children –FH
Moore et al. (49)* 475 +FH 1 Excl BF ‡1 fl Eczema at 3 and 6 months
Høst et al. (35) 1749 1 Excl BF ‡3 Incidence of CMA: 0.5%
vs. CMF 0–3 › CMA at 1 yr
Saarinen and Kajosaari (36)* 150 17 Excl BF 6 fl Respiratory allergy score* at 17 yr
Wright et al. (50) 1006 4 months BF 4 fl Wheezing
Wright et al. (37) 988 6 BF Any fl Wheezing at 6 yr in non-atopics
Elder et al. (51) 560 pre-term 1 BF Any fl Wheezing
Wilson et al. (44) 674 1 Excl. BF £ 15 wk › Respiratory illness
Tariq et al. (52) 1218 4 Excl. BF £3 › Asthma
Oddy et al.à (38) 2187 6 BF £4 › Asthma
Wright et al. (53) 1246 11 BF 4 fl Wheeze up to 6 yr
Oddy et al. (41, 42) 2602 6 Excl BF £4 › Asthma
Bergmann et al. (54)* 1314 7 Excl BF ‡1 › Atopic eczema§

AD, atopic dermatitis; CMA, cow's milk allergy; FA, food allergy; FH, family history of atopy; BF, breastfeeding compared with formula feeding.
Effect of infants diet indicated by arrows: ›, increase; fl, decrease; fi, no change in the incidence of disease/symptoms in infants having the diet as mentioned.
*Diagnostic criteria loose (diagnostic uncertainties).
Of 1749 subjects, 39 developed CMA, in which nine with CMA were exclusively BF, but had received supplement of CM formula during 0–3 days in newborn
nursery. None of 210 exclusively breastfed without supplement of CM formula developed CMA.
àLogistic regression analyses adjusted for important confounders: sex, GA, ETS, early childcare.
§Reverse causation cannot be excluded.

11
Solid foods. As for introduction of CMP before allergens (HDM and cat allergens) and asthma
4 months of age, the introduction of comple- up to the age of 7 yr was found. Although no
mentary foods (solid foods) before 4 months of direct association has been found between early
age has been associated with a higher risk of exposure to indoor allergens and development of
atopic dermatitis (44, 55) up the age of 10 yr (56) allergic/non-allergic asthma (69), an association
(Table 3). between exposure to indoor allergens and devel-
opment of allergic asthma cannot be ruled out
Other dietary factors. Based on the results of (61, 66, 71, 72, 74). An association with allergen
cross-sectional studies (57–59) there is some exposure should only be expected as regards
evidence that dietary factors such as low intake allergic asthma.
of fresh fish, omega-3 fatty acids, high sodium Data from recent cross-sectional and retro-
intake or inadequate intake of antioxidants may spective studies have suggested that early expo-
influence respiratory symptoms and asthma. sure to pets might provide an asthma-protective
However, prospective studies are needed to effect for children (67, 75). The association
elucidate and confirm these possible causal between exposure to pets and the risk of asthma
relationships. has been difficult to evaluate because of different
study design, and selection bias may explain this
controversy (66, 67), e.g. parents of atopic
Environmental factors
predisposed or asthmatic children are more likely
Exposure to inhalant allergens. Airway hyperre- to remove pets from the home and active to
sponsiveness in children is often associated with avoid pets outside home (70, 76–78). Active
allergic sensitization (60–62). Chronic asthma is avoidance of allergen, both as a consequence of
associated with sensitization to indoor allergens, disease and as a primary preventive effort,
which are more important than the outdoor complicates interpretation of sensitization during
allergens, probably because of time spent indoors childhood and may very well explain different
(63–65). In a longitudinal follow-up of 881 results in different studies. In addition, exposure
children to 18 yr in New Zealand children born outside home (e.g. schools, day-care centres,
in winter exhibited a greater prevalence of homes of friends and relatives) and contamin-
sensitization with cats and mites (62). ation of Ôpet-freeÕ homes and even clothing have
There seems to be a dose-dependent relation- shown to result in hidden exposure sufficient to
ship between exposure to aeroallergens and induce sensitization and symptoms (79–85).
sensitization (63, 66–70), as well as an association Thus, the community prevalence of keeping pets
between sensitization and development of asth- (community exposure), especially cats, might
ma (61, 66, 67, 69–73). A dose–response rela- influence the results of studies of pet exposure.
tionship between exposure to HDM and Recent prospective observational studies sug-
development and severity of asthma has been gest that early pet exposure is associated with a
demonstrated (70–72, 74). Other longitudinal reduced risk of developing asthma until 4 yr of
studies have shown that sensitization to HDM age (86), dog exposure in early life might prevent
and animal dander antedate, and are risk factors the development of asthma-like symptoms, but
for development of asthma in children (10, 21, not allergic sensitization until 4 yr of age (87)
24, 25, 60, 61). However, in a recent prospective and exposure to two or more cats in the first year
observational study (69) no direct significant of life may reduce subsequent risk of allergic
association between early exposure to indoor sensitization against a panel of allergens,
although not to cats, until 7 yr of age (88).
Meanwhile, in none of these studies selection bias
Table 3. Non-interventional studies – role of solid food introduction
can be excluded, most of the information is
Follow-up Diet period collected by means of questionnaires and the
Study n (years) Diet (months) Health effect analyses did not include sibling asthma/allergy,
which might heavily influence the familiesÕ choice
Kajosaari and 135 +FH 1 Solid foods £6 › FA and atopic
Saarinen (55) eczema at 1 yr
of having pets. In one study the follow-up rate
Fergusson 1210 10 Solid foods £4 › Childhood was very low (57%), a very high percentage of
et al. (56)* eczema parents had asthma (21%) and allergy (49%) and
Wilson 674 1 Solid foods £ 15 wk › Wheeze atopic heredity was not clearly defined (88).
et al. (44) Although two of these studies (86, 88) included
FA, food allergy; FH, family history. allergen measurements in the methods, these
› indicates the increase in the effect of infant diet. values were not included in the analyses. A
*Diagnostic criteria loose (diagnostic uncertainties). systematic review (66) concludes that exposure to
12
pets appears to increase the risk of asthma and between sensitization and development of asth-
wheezing in children. Epidemiological studies ma has been documented. It has been hypothes-
suggest that in areas with low levels of allergens ized that the airway inflammation in asthmatics
in homes, the prevalence of sensitization is low might precede the development of sensitization
(67). to environmental allergens. This does not seem to
Several studies indicate a positive correlation be the normal course in development of atopy
between exposure to pets, especially during the and asthma considering the above-mentioned
first year(s) of life, and sensitization and subse- course of the allergy march in high-risk infants
quent development of atopic disease [for review and the documented predictive capacity of early
see (89)]. In a recent published Swedish pros- sensitization to food and airborne allergens as
pective study (70) of infants referred with asthma regards development of allergic asthma (10, 13,
it was found that exposure to cats during the first 16, 18, 19, 21, 23–25, 52, 60, 91–93). Nor is there
2 yr of life was associated with increased sensi- any convincing evidence of such a hypothesis in
tization to cat allergens and more severe asthma the group of so-called non-atopic asthmatics with
at 4 yr of age. Moreover synergistic associations asthma symptoms caused by viral infections as
between early exposure to cat, parental smoking, elucidated in recent studies (94, 95).
signs of poor ventilation, and sensitization to cat
and dog was found as well as exposure to high Exposure to tobacco smoke. Several studies have
levels of cat allergen in the home in combination shown a significant association between parental
with parental smoking at the age of 2 yr was (particularly maternal) smoking and increased
found to be associated both with the develop- wheezing and asthma in children (96–98). This
ment of severe asthma and continued sensitiza- association is strongest up to 6 yr of age (96, 97).
tion to cat. One recently published prospective A Danish prospective non-interventional cohort
study (90) with follow-up from birth to 5 yr of study of 276 unselected infants (99) revealed that
age showed that exposure to cat/cat allergen at at least two episodes of wheezing before the age
age 2 months was significantly associated with an of 18 months were diagnosed in 25% of infants,
increased risk of wheezing at or after the age of who were daily exposed to tobacco smoke at
3 yr among children whose mothers had a home, and/or in day care, and in 30% of children
history of asthma, whereas the risk was reduced whose mothers smoked daily. The corresponding
in children whose mothers had no such history. figure for infants who were not exposed to
The allergens associated with asthma depend tobacco smoke was 15% (p < 0.05%). In the
on climatic, seasonal and social factors and same study 66% of unselected children were daily
housing conditions. In temperate and humid exposed to tobacco smoke at home and/or in day
regions allergy to HDM shows the strongest care, 58% were exposed at home by at least one
association with asthma followed by allergy to parent and 42% by the mother. In this and later
furred pets (especially cats). In the USA in arid studies (99–102) it was also shown that HR
climates allergy to the fungus Alternaria spp. is infants were significantly less exposed especially
important, and in urban communities allergy to from the mothers, as only 25% of these mothers
cockroach may be important, especially in inner were cigarette smokers. In infants and young
cities. These relationships have been reviewed by children with recurrent wheezing exposure to
Platts-Mills et al. (65). passive smoking is associated with a significantly
Allergic rhinitis is mostly associated with increased risk for persistent wheezing later on.
allergy against outdoor allergens, e.g. birch and The severity and frequency of symptoms is
grass, but in case of perennial symptoms also related to the extent of exposure in the home
indoor allergens is relevant (12). Recent studies (96, 98). Furthermore, passive smoking has been
demonstrated that being born in spring or early associated with sensitization to indoor allergens
summer was a risk factor for development of in some studies (70, 97, 98, 103, 104), but not in
seasonal allergic rhinitis until the age of 7 yr, a others (96). Importantly, maternal smoking dur-
positive dose response was indicated as at least ing pregnancy is significantly associated with
two pollen seasons were needed before manifest reduced respiratory function in early infancy and
symptoms (91). Another recent study showed recurrent wheezing during infancy and early
that exposure to high levels of birch pollen in childhood (105–114).
infancy increased the risk of sensitization to the
same allergen as well as the risk of pollen- and Domestic air quality. In countries with a so-
animal dander-induced allergic asthma (92). called Ôwestern life styleÕ, most people spend more
A clear association between exposure and than 95% of their time in well-insulated modern
sensitization as well as a clear association buildings with reduced ventilation. Consequently,
13
an increased load of HDM and mould has become (132–135). Two of these studies (132, 133) are
a normal phenomenon (115). Furthermore, an cross-sectional including a small number of
increased burden of particulate materials associ- children at the ages of 2 yr and 13 months with
ated with bio-fuel combustion and smoking is and without atopic symptoms. In one prospective
possible as well as an increased load of chemical study (134) of 76 atopic predisposed infants a
vapours and gasses including nitrogen dioxide, significant difference in the bacterial cellular fatty
formaldehyde, and volatile organic compounds. acid profile of stool samples was found at 3 wk,
There seems to be an increasing significance of but not at 3 months of age in atopic infants as
such indoor pollutants, although further pros- compared with non-atopic infants. Atopic infants
pective studies on the possible cause-effect rela- (n ¼ 18) were defined as having at least one
tionship as regards development of particularly positive skin prick test to any of 16 allergens at
atopic respiratory diseases are warranted (116, the age of 12 months. The authors conclude that
117). differences in the neonatal gut microflora precede
the development of atopy, suggesting a crucial
Outdoor pollution. There is convincing evidence role of the balance of indigenous intestinal
of a cause–effect relationship between exposure bacteria for the maturation of human immunity
to outdoor pollution and induction of allergic to a non-atopic mode. Meanwhile, the study does
respiratory symptoms (118). As regards the not provide firm evidence for such a conclusion.
possible relationship between outdoor air pol- Convincing evidence for this theory, as well as the
lution and development of asthma/allergic air- hypothesis (speculation) that an unclean lifestyle
way disease, the findings of many studies are with lots of infections during early childhood may
weak or contradictory (118–121). prevent development of atopic disease, needs
confirmation by prospective studies.
Immune modulation. Although viral respiratory
infections frequently trigger acute exacerbations Other factors. Many other factors have been
of asthma, the relationship between such infec- implicated in hypotheses and speculations on the
tions and asthma is not clear, in part because of possible cause- effect relationship or increased
the difficulty in defining asthma in young chil- susceptibility to development of asthma and
dren (122). other allergic diseases. Some of these factors
Recent studies indicate that early viral infec- seem to be important such as low birth weight,
tions are primarily associated with the so-called day care outside home, and low socio-economic
infectious type of asthma with a more favorable status (62, 136, 137); but confirming results from
prognosis as regards recovery before 10–11 yr of prospective studies are needed. Present data from
age (94, 95, 123). However, early viral infections cross-sectional studies are contradictory (137,
do not seem to increase the risk of later allergic 138).
asthma (123, 124). Based on results from a cross-sectional study a
Family size (number of siblings) has been so-called anthroposophic lifestyle (139) and Ôliv-
hypothesized to be inversely related to the risk of ing on a farmÕ (140) has been proposed to be
atopy (125), but prospective studies have not associated with a lower prevalence of atopy in
been able to confirm this finding (62, 93, 126). children. However, prospective studies on the
Recently, it has been suggested that tuberculosis possible influence of such possible protective
and even BCG (Bacille Calmette-Guerin) vaccin- lifestyle factors are needed.
ation might have a preventive effect on the
development of asthma and atopy due to a
Prevention of allergic diseases
change in the TH1/TH2 balance in favor of the
TH1 response (127). However, recent investiga- Prevention may consist of a variety of prophy-
tions have shown that BCG vaccination does not lactic measures and can be directed to the
prevent atopy in children (126, 128, 129). The avoidance of sensitization, the avoidance of
possible influence of other vaccinations, i.e. development of disease manifestations in an
pertussis vaccination on the development of asymptomatic individual and the avoidance of
atopic responses in children (126, 130, 131) has disease manifestations and progression of disease
been investigated; but at present there is no in a symptomatic individual. Thus, allergy pre-
evidence of a causal relationship. vention could aim at:

Intestinal microbial flora. It has been hypothes- • Reducing the incidence of allergic diseases.
ized that the intestinal microbial flora may • Reducing the risk for development of new
influence the development of sensitization atopic manifestations in diseased individuals.
14
• Reducing the severity of the disease and the of life come from families without an atopic
proportion of patients with severe disease. heredity. Thus, the majority of children with
• Increasing the possibility of remission. recurrent wheezing/asthma do not belong to
• Increasing the quality of life in the patients. HR groups for development of atopic disease
(29), whereas a higher proportion of children
Different levels of prevention of allergic diseases with allergic disease, including also other
in childhood have been proposed: manifestations than asthma, will have atopic
heredity (33).
• Primary prevention addresses healthy children Infants with a pronounced atopic predisposi-
with the aim to prevent development of allergic tion may have a primary immunoregulatory
disease. defect, which can be identified by various meth-
• Secondary prevention addresses already dis- ods, e.g. elevated cord blood (CB) IgE, low
eased children with the aim to prevent symp- numbers of T cells, disturbed ratio of T-helper/
toms and further progression. T-suppressor cells, and decreased function of
• Tertiary prevention addresses patients with T-suppressor cells (144). Unfortunately, none of
chronic disease in order to prevent progression the tests are suitable for general allergy risk
and deterioration. screening. However, elevated CB IgE has been
shown to be a better predictor of specific
Sensitization may precede development of allergy sensitization especially to inhalant allergens later
or may be a normal and often transitory harm- in childhood than parental history (30, 145).
less phenomenon especially in early childhood In a prospective study (30) of a 1-yr birth
(141), which may even be present already pren- cohort we were able to identify a HR group
atally (17, 142, 143). The detection of sensitiza- with rather high positive and negative predict-
tion depends on many factors, e.g. the sensitivity able values (PPV and NPV) as regards devel-
of the test. Therefore, the aim of primary opment of severe allergic disease (atopic
prevention must be to prevent development of symptoms combined with a high IgE response)
disease and not only sensitization. – especially allergic asthma until the age of 5 yr
It can also be argued, whether measures to (Tables 4 and 5). In this study the optimal HR
reduce the risk for development of new allergic group was defined by either double parental
symptoms in diseased children are primary or atopic predisposition or single atopic predispo-
secondary prevention, e.g. prevention of devel- sition [one parent and/or one or more older
opment of asthma in children with atopic sibling(s)], the latter combined with a CB IgE
dermatitis or allergic rhino conjunctivitis. ‡0.3 kU/l.
Preventive measures may include both expo- At present the combination of atopic heredity
sure to allergens and adjuvant risk/protective and elevated CB IgE seems to result in the best
factors and pharmacological treatment. These predictive discrimination as regards develop-
measures may address the general population, ment of allergic disease (29, 30, 144, 145). CB
children at risk for development of atopic disease IgE may therefore help to define HR groups
(HR infants), children with early symptoms of appropriate for allergy-preventive measures (30,
allergic disease or children with chronic disease. 31, 144, 145).
Some preventive measures may be beneficial for Defining an HR group as either double
the general population and supplementary meas- parental atopic predisposition or severe single
ures may be beneficial and recommendable only (perennial or ‡2 different symptoms in one
for HR individuals, and different preventive parent and/or one or more siblings) the latter
approaches may be helpful in different forms of combined with CB IgE ‡0.3 kU/l resulted in a
atopic diseases. HR group at 8–10 % of a birth cohort, compared
with 16–20% if CB IgE is not used and 30–40%
if all with at least single atopic predisposition is
Target groups for intervention
included (30).
Primary prevention. From prospective studies
many possible predictive factors of develop- Secondary prevention. Obvious target groups
ment of allergic diseases have been identified. for secondary allergy preventive measures could
Although it is well documented that atopic be children with early/mild atopic symptoms
heredity is associated with an increased risk for before severe chronic disease has developed,
development of allergic diseases (29–31), it has especially in case of co-existing early sensitiza-
also been demonstrated that most children who tion to foods (milk, egg) or inhalant allergens
develop atopic symptoms during the first years (HDM, cat).
15
Table 4. Prediction of allergy (i.e. allergic disease + high IgE) at 5 yr of age 7, 11 and 14 yr. In one study (147, 150) the
(30)
diagnostic criteria were unspecific and outcome
PPV NPV Sensitivity Specificity measures were mainly based on questionnaires.
A recent randomized study including a large
FH 9.7 91.7 51.7 52.5 number (n ¼ 6209) of full term, unselected
CB-IgE ‡ 0.3 kU/l 18.6 95.6 66.7 71.3 newborns (151) indicated that feeding of CMF
CB-IgE ‡ 0.5 kU/l 15.8 92.2 25.0 86.9
FH + CB-IgE ‡ 0.5 kU/l 13.0 91.3 10.0 93.4
at maternity hospital increases the risk of CMA
FH + CB-IgE ‡ 0.3 kU/l 24.5 94.0 43.3 86.9 when compared with feeding an extensively
High-risk group 1 11.9 91.2 8.3 93.1 hydrolyzed whey formula, but exclusively breast-
High-risk group 2 26.0 93.3 33.3 90.7 feeding for 8 wk did not eliminate the risk of
FH, family history; CB-IgE, cord blood IgE; PPV, positive predictable value; NPV,
CMA. Meanwhile, the dietary intervention only
negative predictable values. included the first 4 days of life and no data on the
PPV ¼ true positives/(true positives + false positives); NPV ¼ true negatives/ diet after that period are given.
(true negatives + false negatives); sensitivity ¼ true positives/(true Another large prospective study investigated
positives + false negatives); specificity ¼ true negatives/(true negatives the overall health benefits of an allergen-reduced
+ false positives).
High-risk groups 1 and 2: biparental atopic predisposition or severe single
dietary regimen in a large unselected study
predisposition + CB-IgE ‡ 0.5/0.3 kU/l. population (n ¼ 1130 healthy newborns) (152,
153) allocated (not randomized) to an interven-
tion and a non-intervention cohort according to
place of birth. The authors concluded that an
Table 5. Prediction of asthma and allergic asthma (i.e. asthma + high IgE) at allergen-reduced dietary recommendation that
5 yr of age (30) includes a partially hydrolysed whey hydrolysate
infant formula led to improved general health
PPV NPV Sensitivity Specificity
status, mainly due to improvements in skin
Bronchial asthma findings when compared with a control cohort
High-risk group 1 26.2 95.9 26.2 95.9 (152). However, the two study cohorts were
High-risk group 2 27.3 97.1 50.0 92.2 significantly different as regards duration of
Allergic bronchial asthma
High-risk group 1 6.4 98.1 20.0 93.3
breastfeeding, introduction of solid foods, edu-
High-risk group 2 20.3 99.7 86.7 90.2 cation of parents, household pets, number of
older siblings, exposure to tobacco smoke, and
CB-IgE, cord blood IgE; PPV, positive predictive value; NPV, negative predictive urban residence. This study did not include
value. specific allergic symptoms as an outcome meas-
PPV ¼ true positives/(true positives + false positives); NPV ¼ true negatives/
(true negatives + false negatives); sensitivity ¼ true positives/(true positives
ure and does not allow any conclusions as
+ false negatives); specificity ¼ true negatives/(true negatives + false posi- regards allergy prevention.
tives).
High-risk groups 1 and 2: biparental atopic predisposition or severe single
predisposition + CB-IgE ‡ 0.5/0.3 kU/l.
Table 6. Dietary allergy prevention: interventional studies in unselected
infants

Dietary intervention Follow-up

Study n (years) Diet Health effect
Unselected/non-high-risk infants. Only a few pros-
pective intervention studies (Table 6) have been Lucas et al. 777 1 1/2 Human bank fi Atopic disease
performed in infants without a hereditary atopic (146)* milk vs. CMF fi CMA
Lindfors et al. 183 4–6 BM € CMFà fi Atopic symptoms
predisposition. In premature unselected infants (149)
Lucas (146) found no difference in the develop- Schmitz et al. 189 1 pHF vs. CMFà fi Total and
ment of atopic symptoms or CMA whether the (148) asp-CM-IgE
infants were fed human bank milk or cow’s milk- de Jong et al. 1533 2 CMFà vs. no CMF fi Atopic symptoms
based formula (CMF). In other studies (147–149) (147, 150) fi RAST
Saarinen 5385 18–34 CMFà vs. eHF/BM › CMA
it was concluded that CMF given during the first et al. (151) months
few days of life did not increase the risk of atopic
disease when determined at the age of 2 (147), 5 CMA, cow's milk allergy; CMF, cow's milk formula; BM, breastmilk; pHF, par-
(150) and 4–6 yr (149). These studies implemen- tially hydrolyzed formula; eHF, extensively hydrolyzed formula.
ted an intervention diet only during the first few Effect of infants diet indicated by arrows: ›, increase; fi, no change in the
incidence of disease/symptoms in infants having the diet as mentioned.
days of life, included low birth weight infants in *Premature infants.
one (149), and the outcome was based on data Low birth weight.
from medical files and questionnaires obtained at àIncluded diet only for the first few days.

16
High-risk infants. As reviewed in a position Table 7. Dietary intervention in `high-risk' infants. Prospective studies inclu-
ding control group. Infant diet – breastfeeding ‡4 months
paper of ESPACI (154) and a recent joint
statement of ESPACI and ESPGHAN (155) Follow-up
prospective studies on HR infants have shown a Study n (months) Diet Health effect
preventive effect of different dietary allergy
prevention programs on the cumulative inci- Chandra et al. (156)* 121 24 BF fl AD and wheeze
Miskelly et al. (158)* 487 12 BF fl Atopy
dence of FA especially CMA and atopic CMF ¼ Soy fi Atopy
dermatitis. An effect of dietary allergy preven- Burr et al. (160)* 440 7 yrs BF fl Wheeze in
tion has only been demonstrated in HR infants, non-atopics
i.e. infants with at least one first-degree relative CMF ¼ Soy fi Wheeze
(parent or sibling) with documented atopic Vandenplas et al. 45 4 BF fl Atopy
(159)* fl CMA
disease (doctor diagnosed), possibly combined Chandra et al. (157)* 221 18 BF fl AD
with elevated CB IgE in case of single atopic CMF ¼ Soy fi AD
predisposition. Due to great variations in study Lucas et al. (146) 160 18 BF fl Atopy
design and diagnostic criteria it is difficult to 777 fl CMA
compare the effect of these programs. pre-terms
Chandra et al. 263 18 BF fl AD and atopy
1. Breastfeeding: From previous studies (192)* CMF ¼ Soy fiAD and atopy
(Table 7) (100, 146, 156–161) it is presumed Halken et al. (100)* 141 18 BF fl CMA
that breastfeeding has an allergy preventive Schoetzau et al. (161)* 1121 12 Excl BF fl AD
effect compared with CMF feeding, but the (16 wk) AD in family:
› risk AD
extent of the preventive effect remains to be
AD: ·4 › risk of
determined. Meta-analyses (162–164) (Table 8) asp-CM-IgE
showed that exclusive breastfeeding for at least AD: ·8 › risk
3 months, in infants with atopic heredity resul- asp-egg-IgE
ted in a reduced odds ratio of 0.58 (95% CI:
AD, atopic dermatitis; CMA, cow's milk allergy; CMF, cow's milk formula; BF,
0.4–0.92) for atopic dermatitis and an odds ratio breastfeeding.
of 0.52 (95% CI: 0.35–0.79) for recurrent Effect of infants diet indicated by arrows: ›, indicate increase; fl, decrease;
wheezing in the first 5 yr of life. The only fi, no change in the incidence of disease/symptoms in infants having the diet
prospective, randomized study used banked as mentioned.
human milk vs. CMF in a preterm infant *Not randomized to breastfeeding.
cohort, and it was found that CMF feeding
increased the risk of developing eczema and
CMA by 18 months in the subgroup of neo- our intervention studies (100–102, 173) the
nates with an atopic heredity (146). mothers had unrestricted diets during pregnancy
In HR infants, exclusively breastfeeding dur- and lactation, and the effect as regards preven-
ing ‡4 months in combination with avoidance of tion of FA seemed not to be less than other
solid foods have resulted in a significant reduc- comparable studies. Thus, our results do not
tion of the cumulative incidence of CMA and support a recommendation of maternal diet
atopic dermatitis during the first 4 yr of life. In during pregnancy or during lactation.
our studies (100, 102) breastfed children were less The issue whether breastfeeding has an allergy
exposed to tobacco smoke, especially from their preventive effect remains controversial due to the
mothers, they were less exposed to pets, they had lack of evidence in some studies and due to the
complementary food introduced at a later age, fact that infants cannot ethically be randomly
they were admitted to day care outside home at a assigned to breastfeeding or formula feeding to
later age and they belonged to higher social enable a definitive study (155, 174).
classes (Table 9). Confounding factors may Low concentrations of food allergens especi-
therefore highly influence the results of compar- ally CMP are shown to be present in human milk
isons. when consecutive testing is carried out (175).
There is no conclusive evidence for a protective According to the low incidence of CMA in
effect of a maternal exclusion diet during preg- exclusively breastfed infants at 0.5% in unselect-
nancy (Table 10) (165–167). A few studies indi- ed infants (35), and 1.3% in HR infants (102) in
cate that the preventive effect of breastfeeding on prospective birth cohort studies, this low-degree
development of atopic dermatitis may be en- exposure seems to induce tolerance rather than
hanced by maternal avoidance of potential food disease.
allergens (milk, egg, and fish) while breastfeeding Recent studies indicate that variations in the
(157, 168, 169), whereas other studies do not composition of human milk – e.g. low levels of
confirm this finding (167, 170–172) (Table 10). In alpha-linolenic acid and relationship between the
17
Table 8. Results from three meta-analyses on the relationship between exclusive breastfeeding during the first 3 months of life and development of atopic disease

Population
Studies (n)
included/ Summary* Atopic heredity Combinedà
Effect measure period (years) OR (95% CI) OR (95% CI) OR (95% CI)

Gdalevich et al. (163) Atopic dermatitis 18/1966–2000 0.68 (0.52–0.88) 0.58 (0.41–0.92) )1.43 (0.72–2.86)
Gdalevich et al. (164) Asthma by 2–5 yr 12/1966–1999 0.70 (0.60–0.81) 0.52 (0.35–0.79) 0.99 (0.48–2.03)
Bloch et al. (162) Allergic rhinitis 6/1966–2000 0.74 (0.54–1.01) 0.87 (0.48–1.58) 0.68 (0.47–0.99)

*Analysis of pooled data.

Analysis of high-risk populations.
àAnalysis of combined high-risk and non-high-risk populations.

Table 9. Exposure to environmental factors in a birth cohort of atopic pre- protective effect of breastfeeding against allergic
disposed infants fed human milk or a hydrolyzed cow's milk-based formula.
disease. No association between nucleotide and
Breastfed high-risk infants differed from formula fed high-risk infants
regarding the following characteristics (102) polyamine levels in human milk and atopic
development during the first year of life has been
Breastfed Formula fed found (178). However, prospective long-term
follow-up studies with a proper sample size are
Age at introduction of solid foods (months) 5 4
Exposure to tobacco smoke at home (%) 46 46
desirable for confirmation of these possible
Exposure to tobacco smoking by mother (%) 13 29 relationships.
Exposure to pets (%) 33 42 2. Formulas: Some prospective studies have
Socio-economic class Higher – shown that soy formulas are as allergenic as
conventional CMF, and on this basis they should
not be recommended for the prevention of FA
Table 10. Dietary intervention in `high-risk' infants. Prospective studies (154, 157), but controversy still exists (93, 179–
including control group. Effect of maternal exclusion diet during pregnancy 182). One study (93) found no preventive effect of
and/or lactation
soy formula, whereas another (180) indicated a
Follow-up Maternal possible preventive effect of soy formula but only
Study n (years) diet Health effect to allergen-non-specific atopic symptoms. Fur-
ther studies may be useful to clarify the allerge-
FNlth-Magnusson 180 0 Pregnancy fi Total IgE
et al. (165) fi Spec. IgE
nicity of soy formula in infants who are prone to
FNlth-Magnusson 180 5 Pregnancy fi Atopy the development of allergy. Prospective interven-
and Kjellman (166) tion studies (93, 157, 180) have compared the
Lilja et al. (167) 63 1 1/2 Pregnancy fi Atopy preventive effect of soy formula with CMF in HR
Chandra et al. (169) 109 1 Pregnancy fl AD in BF children infants, but none included controlled elimin-
and lactation fi AD in CMF children
Zeiger et al. 225 4 Pregnancy fl FA (CMA)
ation/challenge procedures in order to diagnose
(185, 186) and lactation FA.
Lilja et al. (167) 107 1 1/2 Pregnancy fi Atopy Extensively hydrolysed formulas (eHF) have
and lactation been investigated in studies on prevention of FA
Businco et al. (168) 101 2 Lactation fl Atopy in HR infants. Several prospective studies
Chandra et al. (157) 225 1 1/2 Lactation fl AD
Lilja et al. (167) 107 1 1/2 Lactation fi Atopy
(Table 11) (100, 101, 157, 173, 183–188) show a
Sigurs et al. 115 4 Lactation fi Atopy preventive effect of eHF in combination with
(170)* fl AD at 3 months, avoidance of CMP and solid foods during
6 months and 4 yr ‡4 months in HR infants on the cumulative
Hattevig et al. 105 10 Lactation fi Atopy, AD at 10 yr incidence of atopic dermatitis and FA, especially
(171)* fi SPT, RAST at 10 yr
CMA until the age of 4 yr. Definition of HR
AD, atopic dermatitis; CMA, cow's milk allergy; FA, food allergy; CMF, cow's infants varies and diagnostic criteria differ con-
milk formula; BF, breastfeeding. Effect of maternal diet indicated by arrows: fl, siderably in the published studies. Some studies
decrease; fi, no change in the incidence of disease/symptoms in infants describe the development of possible atopic
having the diet as mentioned. *Groups assigned by hospital rather than
true randomization. Follow-up at different time points of the same study
symptoms rather than specific allergic disease.
population. The development of FA especially CMA has
been evaluated in some studies based on well
described controlled elimination/challenge pro-
n-3 and the n-6 fatty acids (176) or varying cedures (100–102, 159, 185–187, 189, 190). In a
concentrations of cytokines (177) may in part Danish controlled intervention study (101) we
explain some of the controversies regarding the found a significant reduction in the cumulative
18
Table 11. Dietary intervention in Ôhigh-riskÕ infants. Prospective studies groups. In all children with symptoms suggestive
including control group. Infant diet – hypoallergenic formula ‡4 months
of CMA controlled elimination/challenge proce-
Follow-up dures were performed. In this study (100) more-
Study n (years) Diet Health effect over a significant reduction in the cumulative
incidence of documented CMA from 20% in the
Vandenplas et al. (159)* 45 4 pHF fl CMA, atopy control group to 3.6% in the prevention group
months
Vandenplas et al. (189)* 67 1 1/2 pHF vs. CMA 15.6%, atopy
until the age of 18 months was found. No
CMF 21.8% vs. CMA difference between two eHFs: an extensively
42.8%, atopy 48.6% hydrolyzed casein product (Nutramigen) and an
Vandenplas et al. (190)* 58 5 pHF vs. CMA 29% vs. 60% extensively hydrolyzed and ultrafiltrated whey
CMF (cumulated) formula (Profylac), was found. Although differ-
Chandra and 263 1 1/2 pHF fl Eczema, atopy
Hamed (192)*
ences in study design these results were compar-
Chandra (193)* 216 5 pHF BF fl Eczema, atopy, able with another intervention study (185–187) in
FA, asthma which the dietary restrictions were much more
Chan et al. (194) 110 30 pHF fl Atopic dermatitis extensive and for a longer duration – up to 3 yr
months for some foods. In our studies (100, 173) the
Chandra et al. (157) 221 1 1/2 eHF fl Eczema
Mallet and 177 4 eHF fl Eczema cumulative incidence of FA and CMA was
Henocq (188) significantly reduced at follow-up at the age of
Zeiger et al. 225 1 1/2, 4, 7 eHF fl FA/CMA 5 yr, and in the study by Zeiger (185–187) the
(185–187) 165 (cumulated) cumulative incidence of FA and CMA was
at 1 1/2 and 4 yr
significantly reduced until the age of 4 yr. Thus,
Halken et al. (100) 141 1 1/2 (5) eHF fl CMA (3.6%)
Oldæus et al. (195) 50 1 1/2 eHF fl Atopic a real prevention, and not only a postponement of
symptoms 51% the onset of the disease, was documented. In none
45 pHF fl Atopic of these studies an effect as regards respiratory
symptoms 64% allergy was found at follow-up at 5 and 7 yr.
46 CMF fl Atopic
symptoms 84%
Partially hydrolysed formulas (pHF) (with
Halken et al. (102) 478 1 1/2 pHF vs. CMA 4.7% vs. moderately reduced allergenicity) have been
eHF 0.6% (p ¼ 0.05) investigated in randomized prospective studies
(Table 11) (159, 189–194) in HR infants, and an
CMA, cow's milk allergy; FA, food allergy; CMF, cow's milk formula; BF, allergy preventive effect has been reported.
breastfeeding; eHF, extensively hydrolyzed formula; pHF, partially hydrolyzed
formula.
Because of great variations in study design and
*Diagnostic criteria inclusive food challenge procedure and time for investi- diagnostic criteria, the relative efficacy of the
gation unclear. different interventions tested in the various stud-
Controlled challenges not performed. ies cannot be compared directly (159, 189, 190,
192, 193). One of these studies (189, 190)
reported a very high prevalence of CMA; the
incidence of atopic symptoms from 74% to 32% reason for this is unclear, but it may be due to
due to reduced cumulative prevalence of atopic less strict diagnostic criteria or selection bias.
dermatitis (31% vs. 14%, p < 0.01), recurrent Recent data from studies comparing the allergy
wheezing (37% vs. 13%, p < 0.01), vomiting/ preventive effect of pHF and eHF indicate a
diarrhea (20% vs. 5%, p < 0.01), infantile colic greater effect with eHF in two (102, 195) of three
(24% vs. 9%, p < 0.01) and FA from 17% to studies (102, 195, 196) with well-defined diag-
6% until the age of 18 months in the prevention nostic criteria. A Swedish study (195) reported a
group when compared with a control group. The lower cumulative incidence of atopic symptoms
infants in the prevention group were recom- up to the age of 18 months with both an eHF
mended and fed breast milk and/or an eHF and a pHF diet, compared with a CMP-based
exclusively, combined with avoidance of solid formula; a greater effect was reported with eHF.
foods for the first 4–6 months of life, and they We performed a prospective randomized, dou-
were compared with a historical, but identically ble-blind study from birth to 18 months of age
defined control group from the same area having comparing the allergy preventive effects of two
no dietary restrictions. Due to ethical reasons we eHFs (Nutramigen and Profylac ) and one
were not able to randomize HR infants to a pHF (NanHA ) (102). This study included a 1-yr
control group having ordinary cow’s milk-based birth cohort of HR infants (n ¼ 478) randomized
formula at that time. The same experienced at birth to one of the three hydrolyzed formulas
pediatricians using the same well-defined diag- if breastfeeding was not possible or sufficient.
nostic criteria, as described in ÔdefinitionsÕ, Only a few infants were never breastfed, most of
investigated the intervention and the control the infants were breastfed exclusively (n ¼ 232)
19
or had varying amounts of supplement with 5. Duration of the diet: The duration and the
formula (n ¼ 246) until the age of 4 months. dietary restrictions vary in different studies. All
Introduction of complementary foods was not studies showing a preventive effect have included
recommended until the age of 4 months. After solely breastfeeding or eHF and avoidance
the age of 4 months no dietary restrictions were of cow’s milk and solid foods for at least
recommended, and all mothers had an unre- 4–6 months. Studies including restrictive diets
stricted diet during pregnancy and lactation. In for a long period >12–24 months and studies
this study the overall incidence of confirmed with dietary restrictions for only 4–6 months
CMA was low (1.3%) and significantly lower in have shown comparable results. In our interven-
infants fed eHF (0.6%) when compared with tion studies the infants were recommended diet-
pHF (4.7%). Thus, the study shows a better ary restrictions for the first 6 months in the first
allergen-specific preventive effect of eHF, but study (100, 101, 173) and 4 months in the last
does not exclude an effect of a pHF also. one (102). After that period the children were fed
3. Combined dietary and environmental inter- normal infant diets without any restrictions
vention: In two properly conducted studies including a conventional CMP formula when
(Table 12) combined dietary and environmental formula was needed. Both these regimens resul-
preventive measures have been applied not ted in a very low incidence of CMA and other
allowing evaluation of the causative measure of food allergies until the age of 18 months (100–
effect (183, 184, 197, 198) (Table 12). 102, 173). In another recent study (199) no
4. Solid foods: The introduction of comple- significant effect of supplement with hydrolysate
mentary foods during the first 4–6 months of life formula (eHF) compared with CMF after the age
has been associated with a higher risk of atopic of 6 months in breastfed HR infants was
dermatitis (55). A preventive effect of breastfeed- found. Controlled studies concerning the poss-
ing or hydrolyzed formulas has only been shown ible preventive effect of avoidance of other
in studies including avoidance of complementary potential food allergens, e.g. egg, fish etc. after
foods during at least the first 4 months of life. In the age of 4–6 months of life have not been
our studies (100–102, 173) the infants were published. Thus, there is no evidence of allergy
recommended to avoid introduction of supple- preventing effect of restrictive diets after
mentary foods until 4–6 months of age. After 6 months of age.
this period no dietary restrictions were recom- 6. Probiotics: One recent prospective study
mended and the parents introduced solid foods (135) has investigated probiotics in primary
gradually and initially in small amounts. Thus, at prevention of atopic disease. This study showed
the age of 12 months most fruits, vegetables, a preventive effect of supplementing the diet of
meat, cow’s milk, egg and fish were introduced HR infants by probiotics 2–4 wk prenatal and in
successfully into the children’s diet. Only few and the first 6 months of life. Meanwhile, the effect
mild reactions, primarily to egg, were registered. was only shown as regards point prevalence of
mild atopic dermatitis at the age of 2 yr and no
effect was shown as regards sensitization/proven
Table 12. Combined dietary and environmental intervention in Ôhigh-riskÕ in- allergic disease. This theory needs confirmatory
fants. Prospective studies including control group
evidence.
Intervention Effect of
Follow-up intervention
Dietary Environmental Environmental intervention
Study n I/C (years) (I vs C)
Unselected/non high-risk infants. Whilst there is
Arshad et al. 120 2 and 4 9 months Mattress fl HDM SPT
(183), and 58/62 exclusive encasing +
no direct evidence for the increase in allergen
Hide et al. BF/eHF acaracide exposure, the indirect evidence is overwhelming.
(184, 197) 5.2 vs. 24%* Most people with so-called ÔWestern life-styleÕ
flAllergy spend more than 95% of their time indoors and
Chan-Yeung 493 1 12 months Mattress fl A/AR children spend more time indoors than ever
et al. (198) 251/242 BF/pHF SF encasing + RR 0.66
after benzoate (0.44–0.98)
before. The indoor environment of homes (intro-
6 months duction of central heating, wall-to-wall carpet-
ing, etc.) has changed over the last 3 decades,
I, intervention group; C, control group; A, asthma; AR, allergic rhinoconjunc- making it more suitable for dust mite population
tivitis; HDM, house dust mite allergen; BF, breastfeeding; eHF, extensively growth. The number of indoor pets has in-
hydrolyzed formula; pHF, partially hydrolyzed formula; RR, relative risk (95%
confidence interval). creased, resulting in increased community expo-
*p < 0.02. sure. Houses have become better insulated, with
Allergy ¼ asthma, allergic rhinitis, atopic dermatitis, food allergy + pos SPT. lower air-exchange rates, and a consequent
20
substantial increase in concentration of poten- symptoms at the ages 1, 2, 3 and 4 yr were found,
tially harmful substances in indoor air (e.g. as well as significant reduction in number of
allergens, air pollutants). children who were sensitized against HDM. A
Based on the concept that pillows with syn- reduction (not statistically significant) was found
thetic filling are non-allergenic compared with as regards the incidence of asthma at 4 yr.
feather pillows, the use of pillows with synthetic However, the small number of children and the
filling has increased over the past few decades difficulty of diagnosing asthma in this age group
(200). Meanwhile, recent studies have shown that may explain this finding. In another prospective
synthetic pillows accumulate HDM allergens randomized study (198) in HR infants avoidance
faster (201), and contain more HDM allergen of pets, HDM avoidance measures (mattress
(201) and cat and dog allergen (202) than feather encasing and benzyl benzoate powder for carpets
pillows. The prevalence of asthma is negatively and furniture’s) and dietary measures (breast-
associated with use of feather pillows when feeding supplemented with pHF when necessary
compared with synthetic pillows (200). up to 1 yr) resulted in a modest, but significant
The relationship between allergen exposure reduction in the risk of possible or probable
and development of allergic disease is confoun- asthma or rhinitis at the age of 12 months. As
ded by a number of important factors and most children in the intervention group and the
individuals are exposed to a mixture of several control group were breastfed for a long period
allergens, irritants and pollutants, which may act and had only little supplement, the effect was
and interact in different ways by several mech- ascribed to the environmental measures. Re-
anisms. Moreover, the measures of reservoir cently, a large prospective, prenatally random-
allergen measured in most studies are at the best ized, cohort study indicated that mite avoidance
surrogate measures of personal inhaled exposure. measures can achieve and maintain a low mite
Several cross-sectional and prospective studies allergen environment during pregnancy and in
documents that there is a close dose–response the first year of life in homes of infants at risk of
relationship between HDM allergen exposure in atopy resulting in a 50% reduction of airway
the home and development of IgE-mediated atopic symptoms during the first year of life,
sensitization and subsequent asthma. Concerning most pronounced for attacks of severe wheeze
pets, especially cat allergen, the results are much with shortness of breath, prescription of medi-
more contradictory, but prospective studies indi- cation for wheezy attacks, and wheeze after
cate that early life exposure to cat is associated exertion (204, 205). Moreover, cat ownership
with an increased risk of sensitization to cat and was significantly associated with sensitization to
increased risk of developing asthma symptoms in cats (205). As the diagnosis of asthma is difficult
HR children. in this age group, and sensitization to inhalant
allergens most often occurs at a later age further
High-risk infants. The effect of exposure to follow-up of these studies is necessary.
tobacco smoke and to indoor allergens seems to A recent prospective, randomized but open
be most pronounced in children with atopic study (203) included infants less than 1 yr of age
predisposition and in children with exposure with atopic dermatitis and sensitization to egg/
during the first months/year of life. There seems milk/soy but not HDM. In this study it was
to be a synergistic effect of several co-existing found that reduction of exposure to HDM
environmental factors (70, 103). allergens with encasing of mattresses significantly
So far, a few prospective, randomized studies reduced the risk of sensitization to HDM aller-
have investigated the efficacy of the avoidance of gens after 1 yr.
indoor allergens (HDM) (197, 198, 203). These Thus, in homes of HR infants, current evi-
studies have produced the first indication that a dence supports measures to reduce the level of
reduction in HDM allergen levels in homes of indoor allergens, such as HDM and pets. Fur-
HR infants may reduce the prevalence of sensi- thermore, as for non-HR infants, exposure to
tization to HDM and recurrent wheezing during tobacco smoke, damp housing conditions and
the first years of life. One prospective, random- indoor pollutants should be avoided.
ized study (183, 184, 197) has investigated the
efficacy of avoidance of indoor allergens (HDM) Children with allergic symptoms (secondary pre-
in HR infants followed from birth until the age vention).
of 4 yr. The intervention included dietary avoid- 1. Allergen avoidance: Avoiding exposure to
ance measures and HDM avoidance measures relevant allergens is a logical way to treat allergic
with encasing of mattresses and acaracides. A diseases (e.g. allergic asthma) when the offending
significant reduction in sensitization and allergic allergen can be identified and effective avoidance
21
is feasible. Allergen avoidance in a mountain been shown to be effective in allergic asthma in
environment improves lung function and nor- randomized controlled trials with extracts of
malizes markers of allergic inflammation in HDM, pollen, and animal dander (especially
children with allergic asthma (206–210). Several cat). A significant reduction in asthma symptoms
controlled randomized studies have shown that and medication, and a reduction in both non-
allergen (especially HDM allergens and animal specific as well as allergen-specific airway hyper
dander) avoidance measures are effective both in responsiveness has been documented (235–240).
reducing the level of allergens and in improve- Rhinitis frequently precedes the onset of
ment of disease control (203, 210–230). Some asthma, and patients who also have bronchial
efficacy in allergen reduction has been reported hyper responsiveness are more likely to develop
by washing, steaming and vacuum cleaning asthma (241–244). Up to 50% of patients with
procedures (231–233). Meanwhile, most of the hay fever show bronchial hyper responsiveness
previous studies included small number of during the season (245, 246). Previous studies
patients, a short follow-up period and only a indicate a potential preventive effect of SIT as
small degree of evaluation of changes in the regards bronchial hyperresponsiveness in children
severity of the asthma symptoms and asthma with asthma and allergy to cat (247, 248) and
medication. In a large prospective, double-blind HDM (240, 249) and the development of asthma
placebo-controlled study (234) we were able to in patients with allergic rhinoconjunctivitis (250,
show that encasing of mattresses and pillows, 251). In the European multi-center Preventive
with semi permeable polyurethane encasings Allergy Treatment Study (PAT study) (252) we
(Allergy Control ) when compared with placebo aimed at investigating the possible preventive
encasings, resulted in a significant perennial effect of SIT in children aged 7–13 yr with allergic
reduction in HDM allergen concentrations in rhinoconjunctivitis and grass and/or birch pollen-
mattresses and a significant reduction of the allergy as regards development of asthma and
needed dose of inhaled steroids by approximately new sensitivities. The children were randomized
50% (mean dose: 408 lg fi 227 lg/day) in to SIT for 3 yr or a control group. Children in
children with physician-diagnosed asthma and both groups received optimal symptomatic treat-
documented HDM allergy after 1-yr follow-up. ment and followed prospectively for 5 yr. A 10-yr
Despite the reduction in pharmacologic treatment follow-up is planned. Treatment with local ster-
the children were well treated with few symptoms oids was avoided. Before start of SIT 20% had
and a normal lung function during the follow-up mild asthma during the pollen season(s). Among
period. The HDM allergy was documented by a those without asthma significantly fewer in the
positive bronchial challenge with HDM allergen at immunotherapy group developed asthma when
inclusion. This is the first study documenting a compared with the control group (19/79 ¼ 24%
clinical relevant steroid sparing effect of allergen vs. 32/72 ¼ 44%) after the first 3 yr; and meth-
avoidance by means of mattress encasings in acholine bronchial provocation test results
children with asthma and HDM allergy. More- improved significant in the active group. The
over, the study confirms the clinical importance of results after 5 and 10 yr are awaited. This is the
allergen exposure in children with allergic asthma. first study showing that SIT has the potential for
2. Other environmental measures (avoidance of preventing the development of asthma in children
irritants, especially tobacco smoke): The associ- with hay fever and pollen allergy, and that it may
ation between parental smoking and recurrent be possible to interfere with the natural course of
wheezing and asthma in children is well docu- allergic diseases.
mented, with severity and frequency of symp- Other studies indicate that SIT may have a
toms related to the extent of exposure. preventive effect as regards development of new
Avoidance of passive smoking reduces morbidity sensitivities (253–255), but long-term follow-up
and use of medication and improves lung func- of good prospective studies inclusive of the PAT
tion in asthmatics. Tobacco smoke appears to be study are awaited.
one of the most important preventable asthma
inducers and triggers.
Conclusion and perspectives
The development and phenotypic expression of
Specific immunotherapy
atopic diseases depends on a complex interaction
Specific immunotherapy (SIT) has been demon- between genetic factors, environmental exposure
strated in many studies to be an effective treatment to allergens, and non-specific adjuvant factors,
for patients with allergic rhinoconjunctivitis. such as tobacco smoke, air pollution and infec-
Recently, SIT with subcutaneous injections has tions.
22
 According to present knowledge from pros- registered in countries with a so-called Ôwestern
pective non-interventional studies, atopic predis- lifestyleÕ, and there has been an eager search for
position is associated with a significantly Ôthe responsible factorÕ. However, atopic diseases
increased risk for development of atopic disease are multifactorial, and it appears unlikely that
in childhood. However, the majority of children one or a few factors are responsible for the
who develop atopic disease, particularly recur- changing prevalence and pattern of atopic dis-
rent wheezing and asthma, during early child- eases. At present data show evidence of the effect
hood do not belong to HR groups for of dietary allergy preventive measures as regards
development of atopic disease. FA, especially CMA and atopic dermatitis.
In the evaluation of the clinical significance of There is no evidence for prenatal dietary inter-
different environmental factors it is important to vention during pregnancy.
be aware of the existence of different phenotypes In planning intervention to prevent the devel-
of the allergic diseases, e.g. there is compiling opment of allergic diseases we need to target the
evidence of at least two different phenotypes of factors for which there is valid evidence of their
asthma – a so-called infectious type triggered by effect and for which the preventive measures can
viral infections, and allergic asthma associated be controlled. It is obvious that an attempt to
with atopic predisposition and sensitization to make an allergy prevention strategy should
particularly indoor allergens. include environmental as well as dietary meas-
Breastfeeding and late introduction of solid ures. Moreover, it seems reasonable to act on the
foods (>4 months) are associated with a reduced present evidence and give advice to the parents,
risk of FA (especially CMA), atopic dermatitis, while we continue to test intervention strategies
recurrent wheezing and asthma. A clear associ- both to evaluate their efficacy and to resolve the
ation between exposure to indoor allergens and components which are necessary and which
sensitization as well as a clear association confer the greatest benefits.
between sensitization and development of asth- In all infants breastfeeding should be encour-
ma has been documented, especially in HR aged for at least 4–6 months, and likewise
infants. Several studies have documented a rela- exposure to tobacco smoke should be avoided
tionship between prenatal as well as postnatal during pregnancy as well as during early child-
exposure to tobacco smoke, and development of hood. In HR infants a documented eHF is
asthma as well as increased morbidity in asth- recommended if exclusive breastfeeding is not
matics. The first year(s) of life seems to be an possible for the first 4 months of life. In homes of
especially vulnerable period, where exposures to HR infants, current evidence supports measures
several risk factors such as tobacco smoke and to reduce the levels of indoor allergens, e.g. pets
indoor allergens [HDM and molds (often asso- and HDM.
ciated with high indoor humidity) and animal Some studies indicate that early allergen-
dander (especially cat)] seem to act in a syner- specific treatment reduces the need for pharma-
gistic manner. cologic treatment and may influence the natural
Many other factors have been incriminated, course of the disease in preventing development
mostly from cross-sectional and/or case–control of new symptoms and sensitivities. In children
studies. These factors include early infections, with allergic asthma and HDM allergy, HDM
vaccinations, intestinal flora, family size (number allergen avoidance measures, including encasing
of siblings and sibling order) and dietary factors of mattresses and possibly pillows and blankets/
such as low intake of n-3 fatty acids, antioxidants duvets should be an integrated part of the
or high sodium intake. At present there is no treatment. SIT may be effective in preventing
convincing evidence for the possible influence of development of asthma in children with allergic
these factors on the development of atopic rhinoconjunctivitis, and may therefore be a part
disease. As regards the influence of Ôindoor of the treatment at an early stage of the disease.
pollutionÕ (chemical vapors, gasses, formalde-
hyde and volatile organic compounds) and out-
Implementation of preventive measures
door pollution, there is evidence of a cause–effect
relationship between exposure to pollutants and Simple dietary recommendations for HR infants
induction of respiratory symptoms, whereas the have proven beneficial as regards reduction of the
role of pollutants for the development of asthma risk for development FA, especially CMA. Thus,
and atopic airway disease seems less important if exclusive breastfeeding for 4–6 months is not
and needs further elucidation. possible in HR infants, a documented hypoaller-
Generally, the increased prevalence of atopic genic formula and avoidance of solid foods are
diseases in childhood has particularly been recommended for the first 4 months of life.
23
 As direct evidence of the primary risk factors Secondary prevention: evidence-based recommendations
leading to the increase in asthma prevalence does
Avoidance of tobacco smoke.
not exist, it is necessary to test the hypothesis of Patients who have perennial asthma, rhinitis or atopic dermatitis and who are
changing the exposure to the risk factors for allergic to house dust mites or animal dander should try to reduce their
which there is a good evidence of an association exposure to the relevant allergens. Recommended measures include:
Reduction of indoor relative humidity below 50% if possible.
with asthma. Evidence for risk factors with a Encasing of mattresses with documented protective coverings.
direct causal role is most complete for indoor Washing of pillows in hot water (>55 C) regularly or encasing of pillows
allergens, especially HDM. General health pro- with documented protective coverings.
motion may address the needs of the general Washing of bedding in hot water (>55 C) regularly.
Removal of carpets in bedroom.
population whereas more focused and specialized Vacuum cleaning regularly.
intervention strategies may be appropriate for
those at high risk. As genetics and environment
differ in different parts of the world, prevention
measures may also differ. References
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