Immunol Allergy Clin N Am

25 (2005) 149 – 167

Food allergy and additives: triggers in asthma

Jonathan M. Spergel, MD, PhD*, Joel Fiedler, MD
Department of Pediatrics, Division of Allergy and Immunology,
The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine,
34th Sreet and Civic Center Blvd, Philadelphia, PA 19104, USA

Food allergies are increasing in occurrence in Westernized societies. Approxi-

mately 8% of children less than 3 years of age endure food allergies, and about 2%
of adults are affected [1,2]. Cow’s milk, egg, peanut, soy, wheat, fish, shellfish, and
tree nuts are responsible for the majority of allergic reactions to foods in the
United States. Adverse food reactions or food allergies can be broadly divided into
immunologic and nonimmunologic responses. Nonimmunologic food reactions are
subdivided into metabolic, pharmacologic, toxic, and infectious etiologies. Immu-
nologic reactions occur after a food is absorbed, processed, and presented to an active
immune system that reacts to the food. Food antigens can cause three types of
immune responses: (1) IgE-mediated reactions, (2) non-IgE–mediated reaction, and
(3) tolerance (ie, no reaction). IgE-mediated are the most common food allergies.
The most frequently observed clinical manifestations of IgE-mediated food
allergies are cutaneous and gastrointestinal (GI) symptoms [3,4]. Foods can in-
duce respiratory reactions with various consequences: (1) food-induced ana-
phylaxis, (2) food-induced rhinitis, (3) oral allergy syndrome, (4) food-induced
asthma, (5) food-induced exercise-dependent anaphylaxis, (6) food-additive
reactions, (7) occupational asthma due to foods, and (8) inhalation of food vapor
particle (Box 1). This article discusses these scenarios and food allergy as a risk
factor for precipitating an asthmatic response or episode.

Food allergy as risk factor for asthma

Longitudinal studies of patients with atopic dermatitis and food allergies have
found that a history of food allergy increases the risk of asthma. Investigators

* Corresponding author.
E-mail address: Spergel@email.chop.edu (J.M. Spergel).

0889-8561/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.iac.2004.09.012
150 spergel & fiedler

Box 1. Respiratory-induced food reactions

Respiratory symptoms: 25% of food challenges

Isolated respiratory symptoms: 2% to 5% of food challenges
Isolated rhinitis symptoms: b 1% of food challenges
Respiratory reactions to food additives: b 0.5% of population
Occupational asthma: Up to 25% of grain workers

from the Isle of Wight reported in their 4-year follow-up of a birth cohort of
1218 children that 29 (2.4%) children developed egg allergy [5]. Rhinitis and
asthma were associated with egg allergy, with an odds ratio (OR) of 5.0 compared
with the population in general. Similarly, Gustafusson [6] found, in 94 children
with atopic dermatitis, that a history of egg allergy increased the risk for the
development of asthma. Kotaniemi-Syrjanen [7] identified 80 children with
wheezing in the first 2 years of life and followed the subjects to school age; 40%
(32 patients) developed persistent asthma. Persistent asthma was significantly
associated with elevated specific IgE to egg and wheat, duplicating earlier obser-
vations. In the study with the longest follow-up (22 years), 100 atopic children
were enrolled, and 63 were followed until 22 years of age. In those 63 adults, egg
or milk allergy in the first year of life was a major risk for adult asthma [8]. These
studies confirm that food allergy, and egg allergy in particular, in early infancy
increases the risk for developing asthma later in life.

Food allergy as risk factor for severe asthma

Food allergy can be a risk factor for life-threatening asthma. A case-control

study by Roberts et al [9] found that patients with asthma and food allergy had an
OR of 8.58 for life-threatening asthma compared with allergic diseases (4.42) or
frequent admissions (14.2). This study indicates that food allergy is a risk factor
for life-threatening asthma but is not as significant a risk as multiple hospitali-
zation or previous severe reactions.

Food-induced anaphylaxis

Foods can induce a wide spectrum of allergic response from mild isolated
urticaria to life-threatening anaphylaxis with severe respiratory compromise. Egg,
milk, peanut, soy, fish, shellfish, and tree nuts are the most common food aller-
gens confirmed in well-controlled, blinded food challenges [4,10]. Food-elicited
reactions with respiratory symptoms include difficulty breathing, wheezing,
throat tightness, and nasal congestion, and these symptoms are significantly more
likely in patients with underlying asthma. These respiratory reactions are
 food allergy and additives: triggers in asthma 151

typically more severe than GI or cutaneous reactions. This finding is consistent

with the observation that patients with respiratory symptoms are more likely to
have a fatal or near-fatal reaction after accidental ingestion of food to which they
are allergic [11,12]. In a survey of six fatal and seven near-fatal anaphylactic
reactions after food ingestion, all patients experienced asthma and respiratory
symptoms as manifestations of their clinical presentation [11]. Furthermore,
patients with asthma are at greater risk for severe and fatal anaphylaxis compared
with patients with no history of asthma, allergic rhinitis, or atopic dermatitis. One
study reported that in 31 of 32 cases of food-related fatalities, the patients had
asthma in a physician-reported registry in the United States [13]. This finding was
confirmed in a UK study, where eight out of eight patients with fatal anaphylaxis
had a history of asthma [14].
The foods responsible for these serious reactions were peanut, tree nuts, egg,
and cow’s milk in the United States [11]. The causative food varies by region; for
example, in Asia, the Chinese delicacy bird’s nest soup (double-boiled edible nest
of swift, Collocalia spp.), crustacean seafood, egg, and cow’s milk are the most
common reported foods to cause anaphylaxis [15]. In summary, patients with
asthma are at greater risk for a life-threatening allergic reaction to foods, and
experiencing respiratory symptoms as part of a food reaction increases the risk for
severe reaction.

Food-induced rhinitis

Nasal symptoms are on occasion attributed to food ingestion, and roughly

20% of the children who underwent double-blind, placebo-controlled food chal-
lenges experienced nasal symptoms [16]. Rhinitis typically occurs in association
with other clinical symptoms and rarely occurs in isolation [16].
Many patients associate the ingestion of cow milk and other dairy products
with an increase in the production and thickness of nasal secretions or mucus.
This association, although often anecdotally reported, cannot be ascribed to a
specific allergic type reaction. Pinnock et al [17] investigated the relationship
between milk intake and mucus production in adults. They found that milk and
dairy product intake was not associated with an increase in upper or lower
respiratory tract symptoms of congestion or increased amount nasal secretions
whether patients were asymptomatic or symptomatic with rhinovirus infection.
The amount of nasal secretions in tissue was not significantly related to overall
milk consumption.

Oral allergy syndrome

Oral allergy syndrome represents a cross-reaction of plant proteins with

airborne environmental allergens. The designation of the syndrome is derived
from the fact that symptoms occur primarily, if not exclusively, in the oropharynx
152 spergel & fiedler

and do not involve other organ systems. The term ‘‘pollen food allergy’’ has also
been proposed to reflect the clinical scenario of oral symptoms provoked by a
food sensitivity as a response to previous exposure to a respiratory allergen with
sensitization to a pollen [18]. Local IgE-mediated mast cell activation provokes
sudden onset of pruritus affecting the oropharyngeal cavity. The symptoms often
affect the lips, tongue, palate, and throat, with occasional reports of throat
tightness. The symptoms are generally of short duration and respond well to
antihistamines or can self-dissipate without medications.
The oral allergy syndrome can be elicited by a variety of plant proteins and
occurs with the ingestion of various fresh fruits and fresh vegetables. The reac-
tions do not occur when the fruit or vegetable is cooked or the antigenic form is
altered. Often, removing the skin or peel of the fruit or vegetable can eliminate or
reduce the tendency for the reaction.
The environmental allergens that have been most commonly reported to cross-
react with the plant proteins often referred to as pathogenesis-related proteins are
birch tree, ragweed, mugwort, and grasses [19]. Cross-reactivity occurs when two
or more allergens share common epitopes and bind to the same IgE antibody.
Sensitivity to pollens usually occurs before sensitivity to provoking foods. Oral
allergy syndrome can begin as early as in the young school-age child.
The most common reported cross-reactivities include melons and banana with
ragweed; apple, hazelnut, carrot, potato, kiwi, cherry, and pear with birch pollen;
and celery and carrot with mugwort. The major apple allergen, Mal d 1, has 63%
homology with the major birch pollen, Bet v 1 [20]. The birch pollen profilin, Bet
v 2, cross-reacts with profilin found in pear, celery, and potato [19]. Because of
cross-reactivity, patients with oral allergy syndrome with melons and ragweed
allergy may experience more pronounced symptoms during the ragweed season
due to the rise in ragweed-specific IgE.
The diagnosis of oral allergy syndrome is based on suggestive history in a
patient with significant allergic rhinitis. The skin test with commercially prepared
extracts can be negative because the responsible food allergen is often altered in
the manufacturing process [21]. Use of the pure fresh fruit or vegetable for skin
testing via a prick test often elicits a positive response when testing to the com-
mercial extract is negative. Three studies [22–24] suggest that treatment of
pollen-induced allergic rhinitis with immunotherapy can abate the oral allergy
syndrome, but the natural history of this entity has not been well studied or
characterized. However, Moller [25] was not able to demonstrate a change in oral
allergy symptoms in patients undergoing desensitization to birch pollen.
There is no consensus among allergists regarding recommendations for these
patients. A recent survey of board-certified allergists revealed that 50%
recommended complete avoidance of the offending fruit or vegetable and that
9% never recommended avoidance [18]. The survey showed that 3% of allergists
always prescribed an Epi-pen (Epinephrine, Dey Pharmaceutical), kit and 30%
never prescribed one. The difficulty lies in defining the patient who may be at
risk for a more severe type of reaction. Although oral allergy syndrome is not a
typical food allergy, it should be considered a food-related allergic reaction. As
 food allergy and additives: triggers in asthma 153

with other food allergies, the treatment remains avoidance of the offending fruit
or vegetable, especially during ‘‘cross-reacting’’ pollen season.

Food-allergy–induced asthma

Food sensitivities causing isolated asthma or lower airway symptoms are rare.
Studies of food challenges suggest overall rates between 2% and 5%. Onorato
et al [101] examined 300 asthmatic patients from a pulmonary clinic. Only
12% had a history of food allergy suggested by clinical symptoms and positive
skin testing. Food-induced wheezing was confirmed in only 2% of cases, com-
pared with 25% suggested by history alone. This substantially lower rate on
direct challenge compared with history and a positive skin test is a common
finding; positive skin testing is only about 50% predictive for food reactions. In a
larger study of almost 600 pulmonary patients at the National Jewish Research
and Medical Center in Denver, Colorado, 68% had a clinical history of food-
induced allergic reactions. Subsequent food challenges were positive in 60% of
the patients, with 25% of the patients experiencing wheezing on challenge but
only 2% with isolated wheezing. Similar to our studies and others, wheezing
occurs in about 25% of challenges in combination with cutaneous or GI
symptoms [10,26]. These studies cite wheezing occurring often in combination
with other systemic symptoms. Isolated asthma symptoms from food allergic
reactions are rare, occurring in 2% of the patients.
Several studies have examined children with undefined food allergies. These
children underwent food challenges to determine if they were clinically sensitive
to the food. The rate for isolated lower airway symptoms in these studies ranged
from 1% to 13% [27,28]. The highest rate occurred in patients with milk allergy
[28]. In our study of over 1000 open food challenges in pediatric patients in a
tertiary care center with food allergies, we documented isolated respiratory
symptoms in less than 5% of our patients [10].
In a subset of food-allergic children, the chronic ingestion of an allergic food
may result in increased airway hyper-responsiveness in the absence of acute
symptoms on ingestion. In one study, 26 children with asthma and food allergy
were evaluated for changes in their airway hyper-responsiveness [29] during
methacholine inhalation challenges before blinded food challenges and 4 hours
after the food challenge. Twelve out of 22 positive food challenges involved
lower airway symptoms, including cough or wheezing. Significant increases in
airway hyper-responsiveness occurred in 7 of the 12 patients who experienced
chest symptoms during positive food challenges. Decreases in FEV1 were not
generally observed in these seven patients during the food challenges. These data
indicate that food-induced allergic reactions may increase airway hyper-
responsiveness, as demonstrated by increasing responsiveness to methacholine
in a subset of patients with moderate to severe persistent asthma after ingestion of
specific foods.
154 spergel & fiedler

One small pilot study of milk and egg avoidance for 8 weeks found an
improvement in asthmatic children with avoidance measures. The 13 children
in the avoidance group had improvement in peak flow rate compared with
nine children in the control group who did not show improvement in peak flow
reading [30]. In contrast, Wood et al [31] investigated a high-risk population of
20 adults to assess whether milk consumption had an effect on asthma control
and flares. They used a randomized, crossover, double-blind, placebo-controlled
trial to examine the effects of dairy products in patients who perceived that their
asthma worsened with the ingestion of milk products. Subjects complied with a
dairy-free diet throughout the study. The active challenge was a single-dose drink
equivalent to 300 mL of cow’s milk. They found no difference in symptoms or in
lung function after a milk challenge. Nguyen et al [32] found similar results with
no effect of milk ingestion on FEV1 and FVC 20 minutes after a milk challenge
in 25 asthmatic adults. The latter two studies were done in more rigorous scien-
tific manner compared with the pilot study of Yusoff [30] on milk and egg
avoidance. Pinnock et al [33] examined 60 adult volunteers who were challenged
with rhinovirus and had nasal mucus production measured over a 10-day period
and assessed milk and total diary consumption. Pinnock found no evidence of in-
creased mucus production with milk consumption. Therefore, dairy products are
unlikely to cause isolated rhinitis or bronchoconstriction in patients with asthma.
A study in adults with asthma concluded that food allergy is an unlikely cause
of increased airway hyper-responsiveness [34]. In eleven adults with asthma, a
clinical history of food-induced wheezing and positive prick skin tests to the
suspected foods were evaluated. Results demonstrated that an equal percentage of
patients had increased airway hyper-responsiveness, which was determined by
methacholine inhalation challenges, after blinded food challenges to food aller-
gen or placebo. Therefore, it is unlikely that food allergy causes isolated in-
creased airway hyper-responsiveness in a significant number of patients.

Food-dependent, exercise-induced anaphylaxis

Food-dependent, exercise-induced anaphylaxis (FDEIA) is a subset of

exercise-induced anaphylaxis that is characterized by urticaria, airway obstruc-
tion, and hypotension after physical exercise. In some cases of FDEIA, the food
ingestion can be any nonspecific meal, and in other cases the FDEIA occurs with
exercise after ingestion of specific inciting foods [35,36]. In specific FDEIA, an
IgE-mediated mechanism is likely because patients have positive testing for the
causative foods [36].
FDEIA was first described in 1979 by Maulitz [37]. Numerous foods
(eg, shrimp; shellfish; chicken; wheat; nuts; fruits such as apples, peaches and
grapes; and vegetables such as celery, tomatoes, fennel, lettuce, and potatoes)
have been implicated in this clinical entity [38,39]. Wheat is the most commonly
identified allergen in many studies from Europe and Japan; in particular, the a-
and g-gladin–like peptides have been postulated to be the causative allergen [40].
 food allergy and additives: triggers in asthma 155

In the United States, FDEIA is more common in females than males by 3 to

1 ratio, with shellfish as the most common specific food [41].
The mechanism of FDEIA has not been elucidated, but it has been hy-
pothesized that exercise triggers allergic reactions in patients who have low-grade
type I allergies specific for certain foods. Because serum histamine and tryptase
levels are increased during symptomatic attacks, this finding supports a
mechanism that indicates degranulation of mast cells in a probable IgE-mediated
fashion [42]. Many other factors may play a role, including autonomic nervous
system dysfunction, medication use, weather, humidity, stress, family tendency,
and menstruation cycle in females [35,36]. It is hypothesized that rigorous
exercise increases food allergen absorption by changes in splanchnic blood flow.
FDEIA is rare but is a known cause of food-related wheezing and anaphylaxis.

Food-additive–induced asthma

Food additives have been thought by many people, including physicians, to be

a precipitating cause of exacerbations of asthma and a cause of acute allergic-type
reactions. Despite this common perception, there is a relative paucity of well-
controlled, double-blinded studies to support this view.
There are more than 2500 substances that the FDA lists as food additives in
the United States [43]. There are relatively few additives that have been linked to
provoking bronchoconstriction in asthmatic patients, and in this article the most
common additives that have been purported to trigger asthma are discussed.
The incidence of reactions to food additives is unknown but is generally
overestimated by the public. European studies have extrapolated the prevalence
as b0.5% of the total population and only as high as 2% in an atopic population
[44]. A large British survey of more than 15,000 patients with self-reporting of
challenges listed prevalence of adverse reactions as 0.01% to 0.23% [45].
The prevalence of allergic reactions to foods (2% to 8% in pediatric popu-
lations) [1,2] is much higher than the incidence of reactions to any of the food
additives. Asthmatic responses to a variety of additives are not as prevalent as
once suspected. Diets restricted in food additives have not been shown to be of
benefit in asthmatic patients and should not be routinely recommended.
The most well known of the additives for which evidence exists to support
an association of sensitivity and asthmatic responses are sulfating agents. The
sulfating agents include sulfur dioxide, sodium sulfite, sodium and potassium
bisulfite, and metabisulfites. These agents have long been used in food processing
and have been used as preservatives and antioxidants [46]. Sodium metabisulfite
is the most commonly used chemical preservative, and it has been estimated that
1 to 3 mg of sulfites are consumed per person per day, with an additional amount
in those that consume beer and wine [47]. Sulfites have also been used as
preservatives for inhalation and parenteral medications (including Epi-pen kit).
Their main function is to delay the oxidation of foods and medications by being
preferentially oxidated before the food or the medication. In 1986, the FDA
156 spergel & fiedler

moved to regulate the use of sulfites in fresh fruits and vegetables, and the
previously common practice of using these agents in salad bars is no longer in
practice. In addition, the FDA regulation requires specific labeling on products
that exceed 10 parts per million. Foods that are highest in sulfite content include
dried fruits, wine, molasses, sauerkraut, and white grape juice. Other foods that
are relatively high in sulfite content include dried potatoes, gravies, fresh shrimp,
pectin, corn syrup, pickles, and relishes.
The prevalence of adverse reactions to sulfating agents is not known, and few
studies have been conducted in children. The reactions to sulfites have been
reported primarily in patients with underlying asthma. The mechanism of action
has not been clearly defined, but a number of hypotheses have been advanced,
including IgE-mediated processes (skin testing by prick and intradermal methods
have identified some individuals with positive skin test results and positive
challenges) [48]. Another possible mechanism is So2-induced bronchospasm.
So2 is a by-product of metabisulfite in an acidic environment and can produce
bronchospasm in patients with asthma in concentrations as low as 1 ppm. A third
possible mechanism of action is deficiency of the enzyme sulfite oxidase. Evi-
dence for this mechanism is limited [49].
The diagnosis of sulfite sensitivity requires a specific challenge because
history alone usually cannot establish the diagnosis. Patients may be challenged
with various forms of the additive, such as capsules, neutral solutions, or acidic
solutions of a sulfite preparation. Toxicity studies in normal individuals have
shown that ingestion of up to 400 mg per day can be tolerated [50]. The role of
sulfating agents in the production of nonasthmatic adverse reactions is contro-
versial. Simon [51] conducted a challenge using potassium metabisulfite on
61 adult asthmatic patients and demonstrated a 25% decrease in FEV1 in 5 of the
61 patients (8.2%). The largest study reported is that of Bush [52], in which
203 adult asthmatics (not preselected for sulfite sensitivity) were challenged with
capsules and neutral solutions of sulfite; 3.9% had a 20% drop in FEV1. The
positive response rate was 8.4% in the group that was being treated with steroids
(oral or inhaled) but was only 0.8% in the group that did not require steroids for
the control of asthma. This observation suggests that the risk of reacting to
sulfites may be much higher in the subgroup of patients with more severe asthma.
Observations have been made that the prevalence of sulfite sensitivity may
increase with age in children with severe asthma. Towns and Mellis [53]
performed challenges on 29 children with moderate to severe asthma (age range
5–14 years). Although two thirds of the children showed a fall in FEV1 on
challenge, none of the asthma symptoms improved on elimination and avoidance
of sulfites. Other studies in children have shown reaction rates of 3.5% in
asthmatic children challenged with sulfiting capsules or oral metabisulfite [54].
Differences in challenge procedures, such as capsule versus acidic beverage, may
account for the discrepancies in reports of prevalence of reactions. The inhalation
of metabisulfite may reflect a heightened bronchial sensitivity to inhaled So2 and
may not indicate a concomitant risk of asthma episode from the ingestion of food
containing a sulfiting agent [55].
 food allergy and additives: triggers in asthma 157

The role of other food additives as precipitating agent for asthma is less clear.
This is particularly true for tartrazine. The cause and effect of tartrazine
sensitivity in triggering asthma has not been established. In an early textbook on
childhood asthma, it was postulated that tartrazine precipitated asthma in some
children [56]. Stevenson [57], in his review of tartrazine sensitivity, concluded
that tartrazine does not induce asthma even among the group that was aspirin
sensitive. Interpretation of many of the studies on the role of tartrazine sensitivity
and asthma is difficult due to flaws in the study designs, such as withholding
asthma medications during challenges. The most extensive study was performed
by Stevenson [57]. In 240 patients, of whom 190 patients were aspirin intolerant,
there was no asthmatic response in any of the patients who were challenged with
tartrazine up to doses of 50 mg [57]. There is no compelling evidence that
tartrazine induces asthmatic responses.
Tartrazine is also known as yellow dye #5, and other food colorants, including
yellow dye #6 (sunset yellow), amaranth (red dye #2), and erythrosine (red dye
#3), have been linked in sporadic case reports to triggering asthmatic responses,
but conclusive evidence is lacking. Many natural colorants, such as annatto,
carmine, carotene, and tumeric, have been added to foods and have been linked to
an asthmatic response. IgE-mediated reactions, including asthma, have been
reported in patients upon ingestion of carmine-containing foods and beverages
[58]. Carmine has a red color and is a protein derived from an insect that lives as
a parasite on the pear cactus.
Monosodium l-glutamate (MSG) is a popular flavor enhancer, and there are a
few anecdotal reports of MSG sensitivity linked to asthma [59,60]. Woessner [61]
found, in a study of 100 asthmatic patients (30 with a clinical history of asthma
flare after MSG ingestion), that none of the 100 patients had a drop in FEV1 after
MSG challenges up to 2.5 mg. Thus, even in history-positive patients, the exis-
tence of MSG-induced asthma has not been reproducible. There is a report of
delayed fall in pulmonary function beginning 6 hours after ingestion of MSG and
not associated with Chinese restaurant syndrome [59,60]. This may be a separate
entity. In most of the anecdotal reports, the quantity of MSG required to elicit a
positive response was in the range of 2.5 to 3 mg, also in the absence of other
foods eaten concurrently. This quantity is much higher than that usually ingested
in typical Chinese restaurant syndrome. Studies examining the Chinese restaurant
syndrome did not find consistent results in patients reacting to MSG, also sug-
gesting that Chinese restaurant syndrome is not a clinically relevant syndrome
for precipitating asthmatic responses [62].
Food additives are typically minor ingredients or components of the food. A
few additives are allowed to be listed collectively, such as natural flavors, but a
recent bill (The Food Allergen Labeling and Consumer Protection Act, S. 741)
was approved by the House Energy and Commerce Committee, and the Senate
will require stricter labeling guidelines [63].
Suspected food additive sensitivities are best studied by performing oral
challenges (skin testing is not helpful). Challenges in asthmatic patients need to
be done while patients are on their routine medications to avoid false-positive
158 spergel & fiedler

tests (a flaw in many studies). Challenges are also best performed in a double
blind manner.

Protective roles of food in asthma (omega-3-fatty acids)

Foods that are rich in omega-3-polyunsaturated fatty acids may be protective

of asthmatic response by virtue of their anti-inflammatory effects. High dietary
levels of foods rich in omega fatty acids have been associated with a lower
incidence of inflammatory diseases. However, only limited effects have been
demonstrated in asthma, and few clinical studies have been done. Most of the
evidence derives from in vitro work. A Japanese study was performed in a long-
term hospital setting in which subjects received fish oil capsules containing
eicosapentaenoic acid or control capsules with olive oil [64]. Asthma symptom
scores and methacholine response decreased in the fish oil group but not in the
olive oil control group. The results suggest that dietary supplementation with fish
oil rich in omega fatty acids may be beneficial for children with asthma in a
strictly controlled environment. The children in this 10-month study had minimal
exposure to environmental inhaled allergens.
In the ongoing Childhood Asthma Prevention study, dust mite avoidance and
dietary supplement of omega-3-fatty acids had a beneficial effect on childhood
asthma. In the preliminary results of 700 mothers and their offspring, children in
the dietary intervention group at 18 months of age had fewer wheezing episodes
[65]. There was also a recent report from Salam in which asthmatic mothers who
ate fish high in omega-3-fatty acids during pregnancy had offspring who were
70% less likely to develop asthma before age 5 than the mothers who never ate
fish high in omega-3-fatty acids while pregnant [66]. These findings suggest that
the omega-3-fatty acid consumption by pregnant asthmatic mothers may decrease
the tendency for asthma in offspring who are predisposed to develop asthma.
These results suggest that dietary intervention may play a role in preventing
airway disease.
It has been suggested that anti-oxidants, especially vitamin C, may have a
protective function for lung parameters [67]. In patients with asthma, diets high in
antioxidants may decrease bronchial reactivity and may thereby have an affect in
the prevention and treatment of asthma [68]. This is based on observations of
lower levels of vitamin C in asthmatics than nonasthmatics because oxidant stress
is thought to contribute to the pathogenesis of airway obstruction. Despite studies
that have shown that ascorbic acid supplementation is associated with improved
lung function [69], studies have not documented that the use of vitamin C has a
beneficial effect on wheezing or asthma control [70]. Pretreatment with vitamin C
has not been effective in preventing histamine- or allergen-induced bronchocon-
striction [71,72], and no definitive study has documented the usefulness of
vitamin C in the treatment of asthma. However, a recent report from Mexico City
that looked at children with a genetic deficiency of glutathione transferase
showed a decrease of asthma symptoms with supplementation with antioxidants
 food allergy and additives: triggers in asthma 159

vitamin C and E in a clinical trial [73]. This was in a group of children with high
ambient ozone exposure, and it was hypothesized that asthmatic children
genetically lacking in the glutathione enzyme have a greater susceptibility to
deterioration of lung function with ozone exposure and greater benefit from
antioxidant supplementation. Glutathione peroxidase, which is a component of
the body antioxidant system, has been found to be reduced in asthmatic children
compared with a control group. These children were given a supplement of
250 mg/d of vitamin C and 50 mg/d of vitamin E. It cannot be claimed that the
routine use of antioxidant vitamin C or vitamin E is helpful in controlling asthma
symptoms or asthma exacerbations. Although the concept that antioxidants can
prevent free radical inflammatory damage to lung tissue is intriguing, clinical
evidence to support the routine use of antioxidants is lacking.

Occupational asthma

Occupational asthma as a response to many low- and high-molecular-weight

antigens has been well described. Airway hyper-reactivity can develop due to
exposure to an occupational agent via inhalation in patients without pre-existing
asthma. Numerous chemicals have been shown to cause occupational asthma on
an IgE and a non-IgE basis. The list of agents includes a number of food
products, with baker’s asthma being one of the more commonly identified causes.
This entity can be caused and mediated by specific IgE sensitization to a number
of flours, including wheat, rye, barley, buckwheat, and soy. Significant cross-
reactivity has been demonstrated among those grains because exposed workers
often develop IgE antibodies to a number of different cereal proteins [74]. In
addition to common food antigens, sensitivity has been noted to enzymes con-
tained in the flour [75]. There is a family of alpha amylase inhibitor compounds
(these compounds inhibit insect and mammalian alpha amylase and have a role
in defending plants against parasitic infection) that have been shown to be sen-
sitizers, and a recent report on limiting exposure to amylase has shown an overall
decrease in symptomatic sensitization in bread workers over a 10-year period
in a UK food company [76]. In addition to alpha amylase, other additives can be
sensitizers that include hemicellulose, cellulase, and glucoamylase, all of which
are enzymes derived from aspergillus mold. Bakers can also become sensitized to
a number of contaminants, such as storage mites, fungi, and insect debris, which
can be contained in the flour [77].
Wheat consists of four major protein fractions: albumin, gliadin, globulin, and
gluten. Sensitivity can develop to a single fraction or a combination of proteins.
Wheat allergens can also become antigenic after alteration during the processing
of wheat. Studies on patterns of crossed immunoelectrophoresis show that
40 different wheat antigens have been identified when water-soluble extract was
analyzed [78]. In most cases, baker’s asthma is caused by IgE-mediated responses
to a specific allergen.
160 spergel & fiedler

Asthma and rhinitis have been described in bakers dating as far back as 1713
in a narrative by Ramazzini reporting that grain handlers were almost always
short of breath [79]. A typical history for baker’s asthma would begin as rhinitis
followed by asthma occurring after exposure in the workplace. Flour allergy has
been reported as high as 30% in bakers [76,80]. In a review by Popp [80], a
combination of positive skin test and RAST to a cereal antigen and elevated IgE
was predictive of developing baker’s asthma; the diagnosis was confirmed with
bronchial provocation. A recent report from Spain documented four bakery
workers whose work-related allergic respiratory symptoms were induced upon
exposure to egg aerosols [81]. Elucidating the specific antigen as cause for each
case of baker’s asthma remains difficult because a significant number of antigens
have been reported to induce asthma.
Grain dust exposure has been linked to the development of asthmatic
symptoms. A survey of farmers in England who engaged in harvesting grains
showed that 25% complained of respiratory symptoms including cough, wheeze,
and dyspnea after working on combine harvesters [82]. A 40-year-old Canadian
study examined particle size of airborne dust collected during oat and wheat
loading and found dust particles to be in the respirable range [83]. Another risk
factor is a history of atopic disease for the development of baker’s asthma [84].
A number of workers in various food industries have been described who have
developed asthma in response to inhalation of specific food antigens. Occupa-
tional asthma has been described in garlic workers on the basis of developing
specific IgE to inhalation of garlic dust [85]. All of the 12 patients in that report
had allergy to pollens, and in all cases the asthma was preceded by rhinitis. It was
postulated that atopic status increased the susceptibility of these patients to garlic
dust sensitization.
Allergic sensitization has been reported in workers who process seafood. The
prevalence of occupational asthma is higher in workers exposed to crustaceans
than those exposed to mollusks and bony fish. One longitudinal study of crab-
processing workers demonstrated that 25% of exposed workers developed new
onset of asthma-like symptoms [86].
A careful and thorough history is of paramount importance in the evaluation of
any patient thought to be manifesting occupational asthma. Symptom pattern may
not always be obvious when there is delay in onset of symptoms or when
exposure is intermittent. Variables may include duration and type of exposure and
the patient’s underlying atopic status. Skin testing and RAST testing may be
helpful when a suitable agent is available. Specific inhalation challenges must be
performed in specialized laboratory facilities and may not be readily available.
Once occupational asthma has been diagnosed, the ideal treatment is to re-
move the patient from that exposure, but this can be difficult. Specific levels of
airborne exposure to some allergens that can cause asthma symptoms have been
defined, and industrial hygiene measures can often help to minimize exposure
[87]. However, once hypersensitivity to an agent develops, asthmatic responses
may occur at low levels of exposure that are unavoidable in the workplace. The
treatment is the same as for other types of asthma. Follow-up studies of patients
 food allergy and additives: triggers in asthma 161

with occupational asthma have suggested that a significant percentage of these

individuals have ongoing symptoms [88]. The factors that affect long-term
prognosis probably include duration of symptoms and disease severity.
The ideal treatment remains prevention. In many industries, prospective em-
ployees may undergo skin testing (eg, in the seafood industry) before beginning
work. Compliance with protective devices to prevent aerosolized inhalation is
often low due to the cumbersome nature of the masks. Occupational asthma
remains a major concern and cost burden to the health care system and an eco-
nomic and emotional burden for the patient who may be in a situation in which
he may be forced to change occupation.

Inhalation of food particles triggering asthma

Exposure to airborne food particles can cause respiratory symptoms in a

susceptible individual with known IgE-mediated symptoms to the food. These
reactions have been reported most commonly with fish and shellfish. Patients
with known fish allergy can develop wheezing or rhinitis when exposed to food
particles during cooking or manipulation of the food [89]. Similar reactions have
been reported to rice [90], legumes [91,92], and milk [93].
The best controlled study examining this problem was done by Roberts et al
[94], who identified 12 children with reported reaction on inhalation of a food.
Nine children and families agreed to be challenged to the causative food by
inhalation in a double-blind placebo challenge. Five children had positive chal-
lenges with acute symptoms of asthma; two children had late-phase reactions
with a decrease in lung function. The foods that the patients reacted to were fish,
chickpea, and buckwheat. However, in a study of 30 children with peanut allergy,
no reactions were noted on just smelling peanut butter or casual contact with
peanut butter [95]. These studies indicate that only if a food protein can be
aerosolized can a patient with known sensitivity to that particular food react if the
food particles are inhaled.

Food testing

Prick skin tests to food extracts are a useful screening method as initial
assessment. They are the quickest, most reliable, least costly, and best-studied
screening method. Controls used include the glycerinated saline diluent (to rule
out nonspecific or dermatographic reactions) and histamine (to screen for the
presence of residual antihistamines in the tissues).
A positive prick skin test with appropriate controls strongly supports the
diagnosis of immediate hypersensitivity to a food in patients with a compatible
clinical history. Positive skin tests are defined as wheal 3 mm greater than a
negative control. A patient with a positive skin test but a questionable clinical
history should undergo a formal food challenge to clarify the diagnosis because
162 spergel & fiedler

the positive predictive accuracy of an isolated prick skin test is b 50% [96]. A
negative prick skin test excludes an IgE-mediated food reaction, with a negative
predictive accuracy of N 90% expected for all allergy syndrome. False-negative
skin tests are possible but rare. When a false-negative test is suspected, testing
should be repeated with fresh food, particularly for fruit and vegetables. When
testing to fresh foods is performed, a control subject is helpful to rule out
nonspecific irritant reactions.
In vitro tests such as CAP-RAST FEIA (Pharmacia) measure absolute values
of food-specific IgE and are less sensitive than prick skin tests. RAST tests are
useful in the following circumstances when skin tests cannot be performed:
(1) patients who cannot discontinue antihistamines because of severe ongoing
allergic symptoms, (2) patients who have significant dermatographism, and
(3) patients with severe atopic dermatitis with little available surface area for
appropriate skin testing. A major limitation of RAST testing is that interpretation
can be difficult because sensitivity and specificity vary by each food. CAP-RAST
tests are an improved in vitro measurement of specific IgE with less nonspecific
IgE binding that can occur with standard RAST. However, similar to other RAST
tests and skin tests, there are limitations in interpretation because sensitivity and
specificity are not 100%. Knowledge of particular test characteristics (and the
illness being evaluated) is required for appropriate application and interpretation
of each method.
Various studies of the CAP-RAST FEIA (Pharmacia) in children have
established 90% positive predictive values milk, egg, peanut, and fish [97–100].
These values varied by population studied and the age of the patient. A 90%
predictive value could not be established for soy or wheat.

Summary

Exposure to food allergens can cause a varied pattern of respiratory symptoms

as allergic responses (Table 1). Food allergy in a patient presenting with asthma

Table 1
Foods causing respiratory reactions
Food implicated Reactions
Fish and shellfish Occcupational asthma
Inhalation of food particles triggering asthma
Wheat and other grains Baker’s asthma
Melons, banana, apple, hazelnut, carrot, potato, Oral allergy syndrome
kiwi, cherry, pear, celery, and carrot
Shrimp, chicken, wheat, nuts, apples, peaches, Food-dependent exercise-induced anaphylaxis
grapes, celery, tomatoes, fennel, lettuce,
and potatoes
Peanut, tree nuts, and many others (including Food-induced anaphlyaxis
many of the foods above)
 food allergy and additives: triggers in asthma 163

tends to indicate a more severe disease constellation. Patients with underlying

asthma may experience more severe and life-threatening allergic food reactions.
When a food reaction involves respiratory symptoms, it is almost always a more
severe reaction compared with reactions that do not involve the respiratory tract.
Susceptible patients may react to a causative food on inhalation without in-
gestion. Patients can react to food particles in work environments (eg, baker’s
asthma). However, isolated asthma or rhinitis symptoms without concomitant
cutaneous or GI symptoms are rare events. Additionally, reactions to food
additives can involve respiratory symptoms but are more unusual than reactions
to foods.

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