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Asthma is one of the most common respiratory manifestations in children and sometimes is provoked by food allergens with two mechanisms: ingestion or inhalation Clinical evidence acquired in recent years shows that the role of foods in asthma is far from being clear, while food allergy (FA) is well known as one of the leading causes of atopic disease. FA-induced manifestations range from urticaria, abdominal pain and anaphylaxis, but above all FA can trigger atopic dermatitis (AD). It may be speculated that, as in AD, food allergens could induce a cutaneous hyperreactivity comparable to the bronchial hyperreactivity (BHR) reported in allergic children with asthma. Eosinophils, as in asthma, seem to have a major role in inducing and maintaining skin lesions. These observations suggest that the characteristic AD chronic skin lesions can be initiated, amplified and perpetuated by immunologic and non immunologic factors acting in various ways and at different levels, thus starting a vicious circle, resulting in different, though synergistic, reactions.
Studies have suggested a possible link between inflammatory mediators and food-induced asthma, that can be distinguished from asthma with FA. Nonspecific stimuli can have a role in triggering and worsening skin lesions, however they may play a first part in the induction of BHR. Epidemiologic studies should investigate both facets of the problem, such as asthma with FA and food-induced asthma in children. Personal data on the prevalence of respiratory symptoms in children with FA will be analyzed. We suggest considering in young children food as one of causes of asthma.
Although FA is accepted as one of the causes of a number of atopic disorders, such as AD, acute urticaria, vomit-ing, diarrhea, and systemic anaphylaxis, its role in asthma appears to be less clear. In this paper we shall briefly review the current knowledge on food induced asthma, and we shall present some personal data on the prevalence of respiratory symptoms in children with FA.
Correct definition of FA is a prerequisite for effective communication in scientific circles, and for comparison of the results of different studies. Appropriate definition of FA is mandatory to establish both the prevalence of hypersensitivity to a given food and the role of FA in asthma. There is a general agreement that FA is defined as a group of symptoms occurring locally, in the gastrointestinal tract, or in remote organs as a result of an immunologic reaction. Different immunologic reactions may be involved in the clinical manifestations of FA, but the immunologic reaction easiest to demonstrate routinely is the IgE-mediated reaction. Immune complexes, as well as neutrophil chemotactic factor, have been detected in some patients with food induced asthma following the challenge test with the relevant allergen [1,2]. Allergen extracts currently available for skin testing to foods are not standardized, and their stability is usually poorly determined.
For allergen extracts that are rapidly degraded like those of fruits and legumes, skin tests may be falsely negative in food-allergic patients. Conversely, some extracts may contain irritating substances, causing false positive skin tests. The titration of food-specific IgE is available only for certain foods, and in contrast with better characterized inhalant allergens, the sensitivity of the test is not yet known for most unpurified food allergens. Moreover, as in inhalant allergen sensitivity, the presence of food IgE in serum does not always correlate with symptoms . Symptomatic hypersensitivity is present when symptoms occur during food ingestion and a specific immune
response can be shown. Asymptomatic hypersensitivity exists
when no symptom occur during food ingestion but a specific
immune response can he shown (Table 1). Double-blind
placebo-controlled oral food challenge (DBPCFC) is considered
the “golden standard” for the diagnosis of FA in patients enrolled
in research studies or in clinical trials .
The epidemiology of asthma triggered by FA has not been
fully investigated. Several authors have examined FA in general
as opposed to food-induced asthma specifically. Even in studies
in which food ingestion and asthma have been associated
with every suboptimal methodology has been used to confirm
the relationship. The number of subjects with proven foodinduced
asthma by DBPCFC has been rather small. Anyway, the
prevalence and incidence of children with food-induced asthma
has not been entirely studied. FA may trigger allergic respiratory
symptoms through two main routes: ingestion or inhalation.
Exceptionally, life-threatening systemic reactions, including
asthma, have been shown in children with FA after inhalation
of the offending food. Recently, an Italian teenager girl, allergic
to cow’s milk (CM), suddenly died for a severe asthma attack
following CM inhalation when she entered into a diary product
factory, with no indication of CM selling .
Respiratory symptoms as the only manifestation of FA or
even in concert with cutaneous and gastrointestinal symptoms
are not common . According to several studies, children
with asthma, who are allergic to foods, present some particular
features. More frequently they are children or adolescents,
furthermore, they have AD and a significantly high mean level of
total serum IgE (Table 2). The reason for this high IgE level is not
completely known, but could be related to the presence of AD in
these patients. High IgE levels, in fact, were reported in subjects
with asthma with AD. Alternatively, FA may occur in patients who are “high IgE responders” and more prone to become sensitive
towards many allergens, including foods. Therefore children
with asthma with a history of AD and/or elevated total serum
IgE level should be carefully assessed for a possible FA (Table
In reviewing the presentation of food-associated symptoms
in 367 children with asthma, evaluated at the National Jewish
Center, Bock et al.  showed that 257 children (70%) had a
history of specific foods being as-sociated with the onset of
asthma symptoms. Of these 257, 163 (63%) had some symptoms
produced during positive DBPCFC. Fifty-seven out of 257
children (22%) with positive DBPCFC exhibited wheezing as one
of the symptoms. Five out of 257 patients (2%) had wheezing
as the only symptom. In addition, 203 children underwent
DBPCFC because of a history of food-associated symptoms
since wheezing was not suspected of being precipitated by food
ingestion. Six out of 203 children (3%) had wheezing as one of
the elicited symptoms, but in 5 out of 6 the wheezing was quite
mild. None of the children had wheezing as the only symptom of
a food allergic reaction .
To determine the prevalence of FA as a cause of exacerbation
of asthma, Onorato et al.  studied 300 patients with asthma
(7 months-80 years). They confirm that asthma induced by FA
has a low prevalence (2%), even in a population attending a
speciality clinic. A similar prevalence is reported by Novembre
et al. , who studied 140 children with asthma. The presence
of specific IgE was investigated with prick skin tests (PTC)
and, in some cases, with RAST (radioallergosorbent test). The
patients were divided into 2 subgroups on the basis of clinical
history: in 92 patients asthma was the only symptom, in 48
patients asthma was associated to other symp¬toms of FA. Using
open food challenge tests, these authors observed symptoms
related to FA in 16 out of 140 (11.4%) children. Respiratory
symptoms were observed in 13 out of 140 children (9.2%), and
one of these 13 had asthma as the only symptom. Moreover,
12 out of 13 children with asthma had associated symptoms
(cutaneous, gastrointestinal), and 8 of out 140 (5.7%) children
had immediate or delayed onset asthma .
The association between FA and chronic asthma has been
studied by Zimmerman et al. . These authors showed that
food allergic children with asthma had more often AD, high IgE
serum levels, multiple positive RAST, and chronic wheezing in comparison to non food-allergic children. In addition, it was
shown that highly atopic children (multiple positive RAST and
high IgE serum level) had a significantly higher prevalence
of chronic asthma. The authors conclude that highly atopic
children are more prone to develop bronchial inflammation
which induces chronic persisting symptoms.
In a previous study  we studied seventy-nine children,
(aged 6 months- 10 years, median age 24 months), fulfilling the
criteria of Hanifin & Rajka  for the diagnosis of AD, underwent
the challenge test. In all children PTCs and RAST for CM protein
and egg were performed. Following 4-6 weeks of a CM and eggfree
diet, 113 open challenge tests were perform¬ed in the
hospital. Nine out of 70 children had asthma at the challenge test
with CM (13%). Three children out of 9 (33%) presented asthma
within 2 hours following food challenge. In particular, 2 out 3
children presented asthma associated with pruritus, urticaria
and erythema and 1 out of 3 children presented isolated asthma.
None of 38 children presented asthma fol¬lowing the challenge
test with egg.
Moreover, 42 children (median age 20 months) attending
our clinic, with proven IgE-mediated CM allergy (CMA) were’
included in a prospective study to investigate the prevalence of
CM-induced asthma (Table 4). All children presented positive skin-tests and RAST to CM proteins and immediate reactions
following DBPCFC with CM. Eleven children out of 40 (27%)
developed asthma 10 to 120 minutes after the challenge: of the
11 children, 6 experienced asthma as the only symptom, and
5 presented vomiting, erythema, urticaria, angioedema and
lip edema associated with asthma, respectively. In 3 out of 11
children asthma occurred for the first time after the challenge.
In addition, 5 children out of 11 experienced asthma even
following the challenge with some hydrolyzed formulas (HF); in
particular, in 4/5 children asthma occurred with a partly whey
HF and one with an extensively casein HF. Interestingly, 3 out
of 5 children had asthma only with a HF, thus suggesting that
hidden allergenic epitopes may be exposed during hydrolysis
In a study on 94 children with asthma using clinical history,
PTC, radioallergosorbent test (RAST) and double-blind food
challenge (DBFC) we have shown that food is one of the causes of
asthma. Out of 94 asthmatic children we found that 23 also had
AD (24.6%); 14/23 children (8 boys and 6 girls aged 2-6 years)
had positive PTC, RAST and DBFC. In all 14 patients the main
symptom after DBFC was asthma, however associated in 5 cases
with erythema, urticaria, vomiting, lip edema and angioedema.
In 9 children asthma was provoked by CM, in 2 by partly HF,
in 2 by extensively HF and one by fish, Moreover in 3 children
asthma appears with very little doses of CM: one drop in one
case and 2 ml in two cases . Completely different, but similar
in the conclusion, are the respiratory reactions induced by food
challenges in children with AD or pulmonary disease (Table 5)
The relationship between FA and asthma is based on several
considerations. First, inhaled food allergens may reach the
respiratory tract directly. On the contrary, food allergens, raw
or cooked, may reach the target organ after a number of steps
such as ingestion, digestion, uptake through the intestinal
mucosa, absorption into the blood stream, etc. All these steps may significantly interfere with the immunogenicity and
allergenicity of foods, as a consequence allergenic determinants
may be destroyed or hidden allergenic epitopes may be exposed.
As a result, the immunogenic and allergenic potency of foods
may be reduced or even increased. Moreover, patients with FA
may have coexisting inhalant allergy and other specific factors,
besides allergens, (such as pollutants, smoking, or emotions, can
increase bronchial reactivity (Table 6). Foods may also induce
respiratory symptoms involving non reaginic mechanisms.
For instance, substances as egg, milk, nuts, chocolate and food
additives (sulphites, benzoate, tartrazine) may cause wheezing
in patients with asthma but do not elicit a reaction when ingested
(oral challenge test).
It has been demonstrated that these substances may enhance
airway reactivity instead of provoking airways obstruction
directly . Once airway reactivity is enhanced, other common
triggers of asthma, such as cold air or drinks, exercise  or
other environmental factors, could readily precipitate acute
bronchoconstriction. It has been reported that no specific airway
reactivity increased after DBPCFC with cold drinks but not after
challenge with soda or water .
There is not doubt that foods may induce FA in children.
However, at present, there are no definite data on the prevalence
of such association. According to our studies, children with
asthma and AD, have a significantly higher prevalence of food
induced asthma. Mechanisms, cells and mediators involved
in food induced asthma are not completely known. Moreover,
whether airway reactivity increases following a positive
challenge test with the offending food, or, daily, if the child has
not a good compliance to the diet, is a crucial point which should
be investigated in future (Table 7), Similar phenomenon has
been demonstrated to occur in patients with asthma when they
are daily exposed to the relevant inhalant allergens.