Cross-reactivity occurs when the immune system mistakes a similar protein or chemical composition for an allergen, causing an adverse reaction. The immune system may
react to foods or plants in the same botanical family. For example, a person who cannot tolerate peach may not be able to eat apricots; or a person allergic to
birch will often get oral symptoms from eating fresh apples.
Clinical implications of cross-reactive food allergens
(Adapted from Current reviews of Allergy & Clinical Immunology by Scott H Sicherer, MD, JACI, Dec. 2001)
The Allergist is called on to determine the risk of reaction to related foods among legumes, tree nuts, fish, shellfish, cereal grains, mammalian and avian
food products, and a variety of other plant-derived foods that may share proteins
with pollens, latex, and each other. Clinical evaluation requires a careful
history, skin prick tests and RAST-type blood tests, and in some cases oral
food challenges. The pitfalls in evaluation are interpreting the clinical relevance
of a positive skin prick test or RAST and deciding when it is a false-positive
Cross-Reactions Among Various Foods
It is common to find positive responses for IgE to several beans in individuals
who are clinically reactive to one type. Using RASTs, Barnet et al screened
sera from 40 patients with peanut allergy against 10 other legumes and demonstrated
IgE binding to multiple legumes for 38% of patients. Bernhisel-Broadbent and
Sampson studied 62 children with allergy to at least 1 legume and found that
79% had serologic (positive RAST) of IgE binding to more than 1 legume, and
37% binding all 6 legumes.
Despite the high rate of cross-sensitization, clinical cross-reactions are
uncommon, as demonstrated by studies of allergenic legumes, such as peanut and
soy. Among 113 children with atopic dermatitis evaluated with DBPCFCs only 1
(0.8%) had clinical allergy to both foods, despite 19% reacting to peanut and
5% to soy. Bock and Atkins studied 32 children with peanut allergy confirmed
by DBPCFC and found that 10 (32%) had a positive skin test response to soy,
but only 1 (3% of those with peanut allergy) had a clinical reaction.
In considering a wide variety of legumes, only 3 (1.8%) of 165 children with
atopic dermatitis evaluated with DBPCFCs reacted to more than 1 legume, despite
19% reacting to at least 1 legume. Bernhisel-Broadbent and Sampson specifically
addressed the issue of legume cross-reactivity by performing open tests or DBPCFCs
in 69 highly atopic children with at least 1 positive skin response to a legume.
Oral challenge to the 5 legumes (peanut, soybean, pea, lima bean, and green
bean) resulted in 43 reactions in 41 patients (59%). Only 2 (5%) of 41 with
any 1 positive challenge reacted to more than 1 legume. The authors concluded
that elimination of all legumes in individuals with clinical reaction to 1 legume
was unwarranted, despite the high prevalence of patients with multiple legume-positive
skin prick tests (SPT) responses.
These studies did not include large batteries of legumes, and it may be that
particular types are more allergenic or cross-reactive. In an evaluation of
children with peanut allergy in France, 11 (44%) of 24 had positive skin prick
test response to lupine, and of 8 subjects who underwent DBPCFC (6 children)
or labial challenge (2 children) to lupine, 7 reacted.
Regional dietary habits and pollen exposure may influence the epidemiology
of legume allergy. In Spain, for example, allergy to lentil was more common
than allergy to peanut, and of 22 children with lentil allergy evaluated for
reactions to other legumes, 6 had a history of reacting to chickpea, 2 to pea,
and 1 to green bean. These findings raise suspicion for multiple legume allergy
on those reacting to lentil, lupine, and chickpea, but more studies in a variety
of geographic settings are needed to quantify the risk.
Assessment of cross-reactivity among tree nuts is complicated by shared allergens
among the nuts and between nuts and other plant-derived foods and pollens. Clinical
reactions to tree nuts can be severe, potentially severe and can occur from
a first exposure to a nut in patients allergic to other nuts. Studies have indicated
a high degree of IgE binding to multiple tree nuts.
In the authors study of children with tree nut allergy, 92% of 111 patients
with peanut allergy, tree nut allergy, or both had IgE antibody to more than
1 tree nut, and 37% of 54 had experienced convincing reactions and had specific
IgE antibody to more than 1 nut.
Bock and Atkins performed challenges to 1 or more nuts in 14 children, and
at least 2 reacted to multiple nuts (as many as 5 types). Several studies have
reported coallergy to multiple tree nuts. In Ewans study coallergy was
seen in over a third of 34 patients evaluated for tree nut allergy. Considering
the potential severity of the allergy and issues with accurate identification
of particular nuts in prepared foods, caution would seem sensible, and total
elimination of the nut family is suggested. Several clinicians (including the
author) suggest that if a nut, eaten in isolation, is previously tolerated by
a nut- allergic individual it would be OK to continue eating this nut. Other
clinicians (including myself) take a more restrictive approach, to avoid
accidents and also, because there are reports of nut allergic individuals becoming
allergic to nuts that they previously tolerated. It is known that some nuts
are homologous and cause reactions (eg, in pistachio-cashew), whereas others
may be homologous but rarely elicit clinical cross-reactivity (eg, proteins
in coconut and walnut).
Legumes, tree nuts and seeds
Cosensitization to allergenic foods, such as peanut, tree nuts, and seeds (sesame,
poppy & mustard) is common. In a study of 731 subjects in the UK, 59% sensitised
to peanut were sensitised to hazelnut, Brazil nut, or both. Although clinically
significant cross-reacting proteins have not yet been described, coallergy to
peanut and tree nut has been reported between 23% and 50% in referral populations
of atopic patients. The rate of coallergy is much lower in unselected populations
(2.5%). The clinician must consider the age of the patient, history, and perhaps
sensitisation in considering categoric elimination of these allergenic foods.
Reactions to seeds, such as sesame, mustard, and poppy, are reported, and cross-reactivity
with foods (hazel, kiwi, and other seeds) and pollens is potentially important,
but the full clinical implications are far from established.
Several reports demonstrate that isolated allergy to a single species of fish
(eg, tropical sole and swordfish) occurs and usually does so in the relative
absence of IgE antibody to common fish allergens (Gad c 1). However, positive
skin test responses to multiple fish in subjects with fish allergy is almost
the rule, and clinical cross-reactivity is also common. In 61 children with
a history of fish allergy exposed to 2 to 8 species, 34 (56%) reacted to all,
and 27 (44%) tolerated some types.
Summary: A patient with fish allergy is at high risk for reactions to other
fish but may tolerate some fish species and may deserve further evaluation with
supervised oral challenges if desirous of ingesting other fish. The fact that
fish allergy can be severe and that cooking-canning and other processing can
alter allergenicity must be considered during these evaluations.
Invertebrate tropomyosin is a panallergen with significant sequence homology
identified in Crustacea, such as shrimp, crab, and lobster; molluscs, such as
oyster, scallop, and squid; parasites, such as Anisakis and insects, such as
cockroach, grasshopper, and dust mite, with less homology to vertebrate tropomyosin.
Although the clinical impression is that reactions to multiple crustaceans are
fairly common, there are few clinical studies addressing this issue. In 16 atopic
patients with shrimp allergy, greater than 80% had positive SPT responses to
crab, crayfish, and lobster. In 11 patients with immediate reactions to shrimp
ingestion, the reaction rate to crab, lobster, and crayfish was 50% to 100%
per species. On the other end of the spectrum is a report of several individuals
with reactions to only particular species of shrimp. Overall, Crustacea represent
an increased risk of cross-reactivity, with a potential for severe reactions.
Even les well defined is the risk for mollusk allergy for individuals with
allergy to Crustaceae or mollusk. Even though the studies are not conclusive,
the overall impression is that the risk of mollusk cross-reactivity is common
in patients allergic to Crustacea.
Tropomyosin is found in house dust mite, an aeroallergen, which raises the
possibility of sensitisation by the respiratory route. In a report of asthma
induced by snail consumption in 28 patients, RAST inhibition studies indicated
that house dust mite sensitisation was the likely sensitising event. There are
several reports linking immunotherapy (IT) with house dust mites to the development
of severe reactions to molluscs and crustacea.
Cereal grains (eg, wheat, barley, rye, and oat) share homologous proteins with
grass pollens and each other. This may account for the high rate of cosensitization
to these foods, but among 145 children with positive Skin prick test responses
to cereal grains, only 21% exhibited clinical reactivity during challenges.
In addition, among those with reactions to 1 grain, 80% were tolerant of all
other grains. Caution is warranted, but clinical reactivity to multiple grains
Mammalian and avian food products
Cross-sensitization is more common within than between mammalian meats, but
clinical correlation with sensitisation is generally under 50%. For avian foods,
sensitisation has been described to a-livetin found in feathers, egg and meat,
and associated with reaction to chicken meat in 22% to 32%. When chicken meat
allergy is present without egg allergy, the risk of reaction to multiple species
of avian meats (turkey, pheasant, and quail) may be increased.
A study with oral challenges showed that 9.7% of 62 children with cows
milk allergy (CMA) reacted to beef. Heating reduces the allergenicity of beef,
and therefore, well-cooked beef is less likely to cause a problem with those
In vitro studies shows extensive cross-reactivity among sheeps, cows,
and goats milk and among cows, ewes, goats, and buffalos
milk, with no significant binding to camels milk. 92% of 26 patients with
cows milk allergy reacted to goats milk during oral challenge. However,
only 4% of 25 children with cows milk allergy rteacted to mares
Fruit, Pollen and Latex
Oral allergy syndrome (OAS) is classically described as isolated oral symptoms
caused by labile proteins in fresh fruits and vegetables that share homology
with proteins in pollens (the initial source of sensitisation). Several clinical
associations have been described (eg, birch pollen with Rosaceae fruits, ragweed
with melon, and mugwort with celery). The number of foods reported to be involved
in the syndrome is ever increasing. Cooked forms of the foods are typically
tolerated. The epidemiology varies by the exposure to pollens. 23% to 76% of
patients with allergic rhinitis experience OAS. More than70% of patients with
OAS react to more than 2 foods. Peach is the dominant allergenic fruit.
In a review of several studies with a total of 1,361 patients allergic to food
pollen with OAS, 8.7% experienced associated systemic symptoms outside of the
gastrointestinal tract, 3% at some time experienced systemic symptoms without
oral symptoms, and 1.7% experienced anaphylactic shock. Hence the term pollen-food
syndrome may be more appropriate than OAS. There is evidence that when fruit
allergy develops in the absence of pollen allergy, reactions are directed tolipid
transfer proteins (LTPs). Reactions involving fruits with homologous LTPs are
more likely to be severe. One study compared patients with Rosaceae fruit allergy
with and without pollinosis (hay fever) and found that systemic reactions occurred
in 82% without compared with 45% with pollinosis. Anaphylactic shock was also
more common in the former (36% vs 9%, respectively). A similar theme was noted
for hazelnut, in which patients without pollinosis experienced severe reactions
and had IgE binding to hazelnut that were heat stable. One study found that
individuals with positive skin prick test responses to commercial Rosaceae food
extracts (presumably enriched for stable allergens) were more likely to experience
systemic reactions than those with responses positive only to fresh extracts.
Foods commonly reprted to cross-react with latex include banana, avacado, kiwi,
chestnut, potato, and papaya. In a study of 136 patients with latex allergy
evaluated by means of RAST to 12 foods reported to be involved in latex-food
reactions, 69% of responses were positive to at least 1 food, and 49% were positive
to more than 1 food. In one study of 47 patients with latex allergy, 100 of
376 food skin test responses were positive, but only 27 (7.2%) were associated
with clinical reactions. In patients with isolated latex allergy, reactions
are more likely to banana, avacado and kiwi, whereas those with latex allergy
& pollinosis are more likely to react to Rosaceae foods and celery.
Approximate rate of clinical reactivity to at least 1 other