Food allergy and asthma—what is the link? Graham Roberts and Gideon Lack

PAEDIATRIC RESPIRATORY REVIEWS (2003) 4, 205–212
doi: 10.1016/S1526–0542(03)00058-7
SERIES: DIFFICULT ASTHMA
Food allergy and asthma—what is the link?
Graham Roberts1 and Gideon Lack2*
1
Paediatric Respiratory Medicine, Royal London Hospital, Whitechapel, London E1 1BB, UK; 2Paediatric Allergy,
Asthma and Immunology, Imperial College at St Mary’s Hospital, Praed Street, London W2 1NY, UK
KEYWORDS
asthma; food allergy
Summary Food allergy and asthma are both atopic diseases and therefore frequently
co-exist. Food allergy is common in childhood, affecting approximately 8% of infants. The
diagnosis is based on a suggestive history supported by skin-prick testing, serum specific
IgE or food challenge. The role of diet in the aetiology of asthma and as a precipitant of
exacerbations has been investigated extensively. Many people perceive diet as being an
important precipitant of their asthma but objective testing suggests that it is only
important in a minority. Meanwhile, there is considerable epidemiological evidence to
suggest that there is a link between asthma and food allergy. Food can induce
bronchospasm and food allergy has been implicated as a risk factor for life-threatening
asthma. Additionally, asthma also seems to be a risk factor for life-threatening food allergy.
The mechanism underlying this connection is unclear. The co-existence of food allergy
should be considered in any child with asthma. Where food allergy is confirmed, steps
should be taken to avoid these foods as this may considerably improve asthma control.
ß 2003 Elsevier Science Ltd. All rights reserved.
INTRODUCTION
Food allergy and asthma are both atopic diseases and
therefore frequently co-exist. Given this relationship, there
has been much interest in recent years in the role of diet in
the development of asthma and as a precipitant of exacerbations. Additionally, there is now evidence to suggest that
food allergy may be a risk factor for life-threatening asthma
and asthma may be a risk factor for life-threatening food
allergy. This statistical association between these two
allergic diseases may be due to their common atopic
basis or may reflect a close inter-relationship in their
pathogenesis.
FOOD ALLERGY
Defining food allergy
Food allergy is a common childhood manifestation of atopy.
It is most common in early life, affecting up to 8% of infants.1
Food allergies are defined as any immunologically mediated
adverse reaction to food which is reproducible under blinded
*
Correspondence to: Gideon Lack. Tel.: þ44 (0) 20 7886 6384;
Fax: þ44 (0) 20 7886 1129; E-mail: [email protected]
1526–0542/$ – see front matter
conditions.1 Only a minority of adverse reactions to food
constitute food allergies. Other mechanisms relate to toxins,
pharmacologically active chemicals, enzymatic deficiencies or
psychological reactions. Food allergy can itself be divided into
IgE- and non-IgE-mediated reactions. IgE-mediated reactions
involve the release of mediators (e.g. histamine) from mast
cells and result in symptoms within 2 h of exposure.1 Other
mediators (e.g. prostaglandins) attract a local infiltrate of
inflammatory cells which may lead to the onset of late-phase
symptoms after 4–8 h. Symptoms from non-IgE-mediated
food allergy typically take 12–24 h to develop and consist of a
cell-mediated hypersensitivity reaction.1
Presentation and natural history of food
allergy
The usual allergenic foods are hens’ eggs, cows’ milk, soy,
wheat, tree nuts, peanuts, fish and shellfish.1 The age of onset
of food allergy depends on the individual food and the age at
which it is typically introduced into the child’s diet. Cows’
milk, egg, soy and wheat allergy all usually present in the first
year of life. Fish, peanut and tree nut allergy typically present
later. The presenting features of food allergy usually involve
the skin (urticaria, angioedema, eczema) or gastrointestinal
ß 2003 Elsevier Science Ltd. All rights reserved.
206
tract (nausea, vomiting, abdominal pain, diarrhoea). Frequently though, there is upper airway (sneezing, rhinorrhoea,
nasal congestion, change in voice, stridor), pulmonary
(cough, wheeze) and cardiovascular (collapse due to hypotension) involvement.1 The natural history of food allergy in
childhood can be divided into two groups: cows’ milk, egg,
soya and wheat, where resolution of the allergy is seen in
most children by 5 years of age; and peanuts, tree nuts, fish
and shell fish where the problem is thought to be generally
life-long.1,2
Diagnosing food allergy
The diagnosis of food allergy can be difficult as presenting
symptoms have many potential causes and there is often
not a clear temporal link between the ingestion of a single
food and the development of symptoms. It is further
complicated in that almost all young children outgrow
their food allergy. Skin-prick testing is performed by puncturing the skin through a drop of allergen using a lancet with
the weal diameter being measured after 15 min. It is
important that the results are interpreted in the light of
a negative saline control (ruling out dermatographism) and
positive histamine control (ruling out the presence of any
antihistamine). The predictive value of weal diameter of
3 mm or larger for food allergy is only approximately 50%,
although the negative predictive value of a negative result is
in the order of 99%.3 Recent work though has suggested
that larger weal diameters give better predictive values.4 A
weal diameter of at least 7 mm for egg and 8 mm for cows’
milk or peanuts had a 100% positive predictive value for
clinical allergy.
When skin-prick testing is impossible due to extensive
eczema, antihistamine use in the previous 72 h, or nonavailability of relevant allergen preparation, specific serum
IgE can be measured. The best validated system is the
Pharmacia CAP method. Again the level of specific IgE has
been shown to be related to probability that a child is
clinically allergic.5,6 Values at or above which there is a 95%
chance of clinical allergy are 6 kU/l for egg, 32 kU/l for milk,
15 kU/l for peanut and 20 kU/l for fish.
A number of tests are often promoted as being useful
for diagnosing food allergy. Examples are food-specific
IgG or IgG4 antibodies, provocation–neutralisation testing and applied kinesiology. None of these tests are
supported by any scientific testing and therefore should
be avoided.7
The gold standard for diagnosing food allergy is the
double-blind, placebo-controlled food challenge.1 Increasing amounts of the disguised food or a suitable placebo are
given at 15–30 min intervals under careful supervision. The
placebo is used to ensure against a false-positive outcome.
Assuming that the maximum dose given is equivalent to a
normal meal size portion, there is a low false-negative
rate.8,9 Open challenges are also clinically useful when
subjects present with objective symptoms.
G. ROBERTS AND G. LACK
ROLE OF DIET IN ASTHMA
The role of diet in the aetiology of asthma has become
a popular avenue of speculative research in recent
years.10,11 Investigators have focused on a number of the
constituents of our diet including potassium, magnesium, antioxidants such as vitamins C and E, and fatty acids. Results
from cross-sectional epidemiological studies have suggested that wheeze or increased bronchial reactivity
are related to low magnesium, potassium, vitamin C or
fatty acid intake.12–14 However, when an effect on lung
function is seen, it is very small.10,11 Additionally, there is
limited convincing interventional data examining the effect
of dietary manipulation of asthma. For example, a
Cochrane review of the effect of marine n–3 fatty acid
supplementation in asthma examined nine randomised
controlled trials.15 The authors could not find any consistent beneficial effect of supplementation of fish oil over
placebo.
The other dietary target of investigators looking for links
between diet and asthma has inevitably been food additives. Many thousands of chemicals are added to foods to
enhance flavour or act as preservatives. As many as 50% of
asthmatics perceive that their asthma is exacerbated by
these.16,17 Monosodium glutamate is perhaps the best
known as the cause of the ‘Chinese restaurant syndrome’
of paraesthesia, palpitations and a burning sensation of the
neck, chest and limbs. The relationship between monosodium glutamate and asthma is less clear. There are studies
both confirming and ruling out the association.18 There is
also some evidence to suggest that adverse reactions to
both tartrazine19 and sulphites20,21 may induce lower airway symptoms. Food additives would seem to be a problem for a few asthmatic subjects investigated in tertiary
clinics.18–21 However, there is no good epidemiological
data demonstrating that food additives play an important
role in community-based asthma.
While the role of diet and food additives in asthma
has attracted considerable interest, the inter-relationship
between food allergy and asthma has received scant
attention. The evidence that does exist suggests that there
is likely to be very important interplay between these
two diseases. The relationship between food allergy
and asthma will be discussed in the rest of this review.
First, we will examine the evidence that paediatric asthma
is an allergic disease, and then we will look at the association between asthma and food allergy and how they may
inter-relate.
ROLE OF ALLERGENS IN
CHILDHOOD ASTHMA
Over the last two decades, asthma has been increasingly
considered to be a disease which very often has an
important allergic component.22,23 This view is supported
by a number of lines of epidemiological evidence.
FOOD ALLERGY AND ASTHMA
207
Increased total IgE levels and cutaneous reactivity to
aeroallergens are both associated with an increased risk
of asthma.24 A number of case-controlled studies have
demonstrated a link between house dust mite reactivity
and asthma.25 Associations have been seen between
reactivity to indoor allergens and presentation to hospital
with asthma.26 There are seasonal changes in the rates of
asthma exacerbations related to seasonal increases in
levels of environmental aeroallergens such as grass pollen27 and Alternaria.28 Morphological studies of the asthmatic airways demonstrate an inflammatory infiltration,
hyperplasia of mucous-secreting goblet cells, disruption of
epithelial cells and marked thickening of the laminar
reticularis.23 These inflammatory changes are even seen
in mild paediatric asthma.29 The inflammation in asthma is
often but not invariably characterised by eosinophils, mast
cells and T lymphocytes.23 Lastly, perhaps the most
compelling line of evidence for the allergic nature of
asthma is the effect of anti-IgE on asthma. This agent is
a humanised mouse monoclonal antibody that binds to
free IgE. In recent randomised controlled trials in both
childhood30 and adult31 moderate to severe asthma, antiIgE has been shown to be a steroid-sparing agent and to
reduce the rate of exacerbations. The success of anti-IgE
treatment in asthma is a persuasive argument for the role
of IgE in the pathogenesis of asthma. However, recent
epidemiological data would suggest that there is not a
straightforward relationship between atopy and asthma,
and other additional factors may play an important role.
For example, rates of sensitisation to aeroallergens and
asthma, diagnosed using a symptom- and exerciseinduced bronchospasm, have been compared in Albania
and the UK.32 The prevalence of atopy was similar in
both countries but asthma was more than three times
more prevalent in the UK. A similar pattern was observed
when Nigerian and Australian children were compared.33
Additionally, rates of atopy have been shown to be
increasing in East Germany over the past few years,
whereas the prevalence of asthma has remained static.34
Thus while atopic status and allergen exposure are impor-
Table 1
tant factors in childhood asthma, there are other important genetic and environmental factors that remain to be
determined.
THE EPIDEMIOLOGICAL LINK
BETWEEN FOOD ALLERGY AND
ASTHMA
Epidemiological studies looking at the prevalence of asthma
are unfortunately complicated by the lack of a diagnostic
test, leading to non-specific questionnaire-based definitions
that are likely to overestimate rates.35 Similar problems
exist with food allergy, as the positive predictive value of a
history of an allergic reactions is only 50%.1 Cross-sectional
epidemiological studies involving double-blinded, placebocontrolled food challenges are expensive and time consuming, and therefore rarely attempted.
Co-existing asthma and food allergy
There is a perception amongst the general public that
foods are frequently implicated in precipitating exacerbations of asthma. In surveys of patients attending asthma
clinics in both Australia and the UK, over two-thirds
believed that food induced their asthma.16,36 Even in a
community sample, 21% of subjects considered diet as a
precipitant for their asthma.37 As can be seen in Table 1,
the real picture is very variable with 2–24% of asthmatics
experiencing food-induced bronchospasm within a challenge situation. The reason for the failure to substantiate
the link in so many individuals is apparent from some of
the items cited as inducing asthma: ice cream, cold water
and carbonated drinks.38 For these items, the mechanism
responsible for generating the bronchospasm is more
likely to be cold or acid than an allergic reaction.36 When
food challenges have been employed, the food implicated
in food-induced episodes of asthma were peanut, milk,
egg, tree nuts, soy, wheat, legume, bean and turkey.39,40
Such studies also suggest that food-induced asthma is
Prevalence of food allergy in asthmatic children.
Author (year)
Number
Subjects
Food allergy
Bock and Atkins 199042
410
Novembre et al. 198840
140
Oehling and Baena
Cagnani 198067
Onorato 198641
284
Children with asthma in an
allergy clinic
Children (2–9 years)
with asthma
Children and teenagers
with asthma
Children and adults with
asthma in a respiratory clinic
279 (68%) reported food-induced wheezing, 98 (24%)
confirmed in DBPC food challenge
32 (23%) reported history suggestive of food allergy,
eight (5.7%) had positive DBPC food challenges
Food-induced bronchospasm seen in 24 (8.5%)
300
DBPC, double-blind, placebo-controlled.
25 (8%) had a history of food-induced asthma;
food-induced wheezing seen in only six (2%)
challenges, all were children or teenagers
208
seen more frequently in children than adults.41 The rate of
food-induced bronchospasm in asthma is also very different in studies because of selection bias operating in
different clinical settings. Thus the higher rate of confirmed food-induced wheezing in the Bock and Atkins
paper42 compared with other studies may be explained
by the recruitment of these children from an allergy clinic.
Studies that have failed to detect an effect of foods on
pulmonary function could conceivably have shown effects
on other endpoints that were not measured. Thus exposure to food products in some subjects does not alter
their lung function but can result in increased bronchial
hyper-reactivity.43
It is possible that the link between asthma and food
allergy is merely a statistical association given that both have
a common atopic background. Alternatively, there may be a
causal pathophysiological link with clinical implications.
RESPIRATORY REACTIONS
ASSOCIATED WITH ALLERGIC
REACTIONS TO INGESTED FOOD
Respiratory reactions to ingested food
A number of investigators have looked at the extent to
which allergic reactions to food involve the lower respiratory tract. In one study, 100 small children with IgE- and
non-IgE-mediated milk allergy (mean age 16 months) were
challenged with milk.44 Regardless of the immunological
mechanism, one-fifth developed lower respiratory tract
symptoms during the challenge. In a larger study, 320
subjects (6 months to 30 years of age) with atopic dermatitis and possible food allergy underwent placebo-controlled, blinded food challenges. Food allergy was
confirmed in 205 (64%) with one-quarter experiencing
lower airway problems during the food challenge.39 These
respiratory reactions are typical early-phase responses seen
within 2 h of exposure.39 Late-phase asthmatic responses
have also been seen after ingestion of a food allergen.45
With a prolonged time interval between ingestion and the
onset of asthma, it has been suggested that this form of
allergic reaction to food is often misdiagnosed as asthma.46
This group also demonstrated that even when acute
asthma symptoms are not seen, there was an increase in
airway hyper-responsiveness. For example, when 26 children with asthma and food allergy were assessed before
and after placebo-controlled, blinded food challenges,
there were 22 positive reactions, 12 of which involved
lower respiratory symptoms. Seven of these 12 subjects
experienced an increase in hyper-responsiveness despite
the minimal decreases in lung function.47
The mechanism of food-induced asthma
The mechanism of food-induced asthma is unclear but
there are a few possibilities. Firstly, small particles of
G. ROBERTS AND G. LACK
ingested food may be inhaled into the airway during mastication. Alternatively, food may enter the airway within the
context of gastro-oesphageal reflux. In this way, food allergens would be able directly to stimulate airway mast cells
inducing a lower airway reaction. Secondly, potentially allergenic proteins may also be able to reach the lungs via the
circulation, having been absorbed intact from the gut. A last
possibility is that allergenic protein may act indirectly on the
lower respiratory tract via inflammatory mediators released
from the skin or gastrointestinal tract and circulating in the
blood. These mechanisms require further elucidation.
RESPIRATORY REACTIONS
ASSOCIATED WITH
AEROSOLISED FOOD
Aerosolised food as a cause of asthma
There are many case reports in the literature of bronchial
reactions associated with aerosolised food proteins, for
example aerosolised fish.48 It would seem that fish protein
can become aerosolised though boiling, frying or simply by
being exposed to the atmosphere. Thus, Taylor et al. have
been able to detect fish allergen using a competitive IgE
immunoassay from air samples collected in a fish market.49
It has also been reported that peanuts and tree nuts can
become aerosolised within a confined space, causing both
mild and severe symptoms in allergic subjects.50 Many
airlines have now stopped including nuts within snacks.
Lastly, food allergens have been known to behave as more
general aeroallergens. For example, in the past, Barcelona
has been affected by episodic epidemics of sudden, severe
and, in some cases, fatal asthma. Affected individuals
showed evidence of specific IgE to soya. Careful investigation concluded that these episodes were related to
unloading soya at the port, and were abolished when
unloading practices were altered.51
Occupational asthma in the food industry
The issue of aerosolised food allergens as precipitants of
asthma in childhood has not been examined systematically.
There are, however, observations about occupational asthma
in adults that have implications for the role of environmental
exposure to food allergens in children with asthma. Occupational exposure to aerosolised food can lead to the development of asthma in adult life. An example is baker’s asthma
caused by occupational exposure to airborne cereal grain.52
Workers with this problem cough and wheeze only in
association with exposure to aerosolised wheat proteins
and have positive skin prick or serum specific IgE to wheat
proteins. Other examples of occupational asthma are milk
powder,53 egg54 or carob bean flour.55 Overall, the food
industry accounts for 10% of occupational asthma.56 Data
reported by occupational physicians suggest that the annual
risk of a baker developing baker’s asthma is approximately
FOOD ALLERGY AND ASTHMA
0.3%, which represents a considerable risk over a 30-year
career as a baker.56 The pathophysiology of occupational and
allergic asthma are very similar. Histologically, an inflammatory eosinophilic infiltrate, oedema and airway smooth muscle hypertrophy are seen in both.57 The possibility of
occupational exposure must always be considered in any
adult with persistent asthma. Although children do not suffer
from occupational exposure to food allergens, they may be
exposed to aerosolised food allergens at school and home,
particularly in the kitchen.
Bronchial challenges with aerosolised
foods
We investigated a group of 12 children who presented to
our clinic over a 2-year period.58 All had proven IgEmediated food allergy in addition to asthma that seemed
to worsen on environmental exposure to the food to
which they reacted. The implicated foods were fish, milk,
chickpeas, buckwheat and eggs. Although the children
were practising dietary avoidance, the families continued
to cook the foods and the children continued to have
symptoms of chronic asthma. Nine subjects consented to a
bronchial challenge. Five of these developed an earlyphase response characterised by objective asthmatic signs
and lung function changes on bronchial food challenge. The
early-phase response is normally associated with specific
IgE-mediated release of mediators, such as histamine and
tryptase, from mast cells. Two subjects also developed
late-phase responses which are known to be related to an
influx of inflammatory cells, oedema and increased mucous
secretion. When the families of these children stopped
cooking the food in the house, there was a considerable
reduction in both their child’s symptoms and inhaled
steroid requirements.
IS THERE A LINK BETWEEN SEVERE
ASTHMA AND FOOD ALLERGY?
Food allergy as a risk factor for
life-threatening asthma
In a cohort study of peanut-allergic children, four of the 46
subjects in the cohort died of an exacerbation of asthma over
the 2–14-year follow-up period.59 This is a substantially
higher fatality rate than one would expect in any high-risk
asthmatic population. This suggests that subjects with food
allergy may have a greater risk of dying from asthma than
from anaphylaxis and that food allergy may be a risk factor for
life-threatening asthma. This is an important issue; despite the
improvement in therapies for asthma, there continue to be
approximately 50 childhood deaths a year in the UK.60
It has been reported that half of adults with brittle asthma
report co-existent food allergies.11 This risk factor for lifethreatening asthma in adults has been investigated in a
number of studies. In one, Ernst et al. aimed to investigate
209
whether frequent inhaled beta-agonist use was associated
with life-threatening asthma. In their study, the second most
significant factor associated with life-threatening asthma
was a history of asthma attacks being precipitated by food
(odds ratio, 5.1; 95% CI, 2.4–11.1).61 We examined this
issue in a group of children ventilated for a life-threatening
exacerbation of asthma. Using a case–control design, 19
cases were compared with 38 matched controls with
milder exacerbations. Subjects and controls were matched
for age, gender and ethnicity. Half the cases had persisting
food allergy compared with only 10% of the controls. Even
after logistic regression analysis for all potential risk factors,
food allergy remained a significant factor.62
Asthma as a risk factor for anaphylaxis
Asthma also seems to be a key factor associated with poor
outcome in children with food allergy. In published series of
subjects with fatal anaphylaxis, almost all subjects had
asthma.45 Respiratory rather than cardiovascular problems
were responsible for the severity of these reactions. The
foods responsible for these reactions were tree nuts,
peanuts, egg and milk.1,45 The results of these case series
have led many paediatric allergists to prescribe a selfinjectable epinephrine device (e.g. EpiPen) to any patient
with both asthma and food allergy.1
Explanations for the association between
severe asthma and food allergy
There are a number of possible explanations for the association between severe asthma and food allergy. The first
possibility is that anaphylaxis is misdiagnosed as asthma. This
is plausible since food-induced bronchospasm is often seen in
anaphylaxis, and there may be a delay between allergen
exposure and the development of respiratory symptoms.46
Studies have also documented life-threatening asthma symptoms within an hour of the onset of the exacerbation,63 a
short time frame that is consistent with anaphylaxis. In this
study, no subject had a history suggestive of anaphylaxis as a
cause of the asthma exacerbation. A second explanation for
the observed association is that food allergy may be a marker
for severe asthma. The persistence of food allergy in this
group of children suggests that they may be more atopic than
other asthmatics. Lastly, chronic inhalation of aerosolised
food may worsen asthma in subjects with food allergy.
IS THERE ANY ROLE FOR DIETARY
MANIPULATION IN MANAGING
ASTHMA?
The place of exclusion diet in the
management of asthma
There seems to be no universal role for a standard exclusion diet in most asthmatics. For example, despite the
210
popular thought that dairy products are associated with
increased mucous, exclusion of cows’ milk in adults with
asthma has no significant effect on their asthma.64 Additionally, exclusion diets in childhood may compromise a
child’s nutrition and therefore growth and development.1
However, there is a rationale for the rigorous and complete
removal of any food allergen that has a significant role in a
child’s asthma. The removal of such an allergen in subjects
with asthma will reduce their chance of experiencing a
severe allergic reaction and potentially improve their
asthma control.58,65
MANAGING AN ASTHMATIC WITH
POSSIBLE CO-EXISTING FOOD
ALLERGY
A history of unexplained sudden asthma exacerbations
suggests that there may be an allergic trigger. Although
foods are implicated in only a minority of cases of childhood
asthma, a high index of suspicion must be maintained as
elimination of a significant allergen can lead to a rapid
improvement in symptoms. A careful history will usually
point to the presence of food allergy in a child with asthma.
Detailed questioning may be required where patients are
avoiding a food to decide whether this represents allergy or
is due to cultural or psychological reasons. It is important
though that such a suspicion should be supported by
objective evidence given the high rate of false-positive
diagnoses based on history alone.1 The use of skin-prick
testing, serum specific IgE or food challenges are recommended. Also, it must be kept in mind that there are many
potential precipitants of asthma that can confound any
potential relationship between a food allergen and asthma
symptoms. Other diagnoses should also be considered;
examples are gastro-oeosphageal reflux, vocal cord dysfunction and exercise-induced anaphylaxis.66 Once food
allergy is confirmed, careful questioning is required to
determine whether continued hidden food exposure is
responsible for a subject’s continued exacerbations. The
help of a dietician is invaluable in these circumstances.
CONCLUSIONS
Food allergy may be an important factor only in a minority
of children with asthma. However, for these children, it is
important to identify the problem and take steps to avoid
direct and indirect exposure. This may lead to a significant
improvement in their asthma control. Furthermore,
this important minority may represent the more severe
end of the disease spectrum. Food allergy has been
implicated as a risk factor for life-threatening asthma
and asthma also seems to be a risk factor for life-threatening food allergy. These are further reasons why coexisting asthma and food allergy should be identified and
managed effectively.
G. ROBERTS AND G. LACK
PRACTICE POINTS
Generalised dietary exclusions do not have a
proven role in the majority of childhood asthma.
Foods should be considered as potential
precipitants of asthma when exacerbations are
sudden in onset, particularly when the child has a
known food allergy.
Removal of environmental food allergens may lead
to improvement in asthma control in selected
children.
Food allergy is a risk factor for severe asthma.
Asthma is a risk factor for life-threatening food
allergy.
RESEARCH DIRECTIONS
Clarification of the role of food allergens in lifethreatening asthma.
Definition of the mechanism by which food
allergens induce asthma.
Clarification of the significance of diet in asthma.
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