Food allergy

Scott H. Sicherer, MD, and Hugh A. Sampson, MD New York, NY

Adverse immune responses to foods affect approximately 5% of

young children and 3% to 4% of adults in westernized Abbreviations used
countries and appear to have increased in prevalence. Food- OFC: Oral food challenge
induced allergic reactions are responsible for a variety of OIT: Oral immunotherapy
symptoms and disorders involving the skin and gastrointestinal SPT: Skin prick test
and respiratory tracts and can be attributed to IgE-mediated
and non–IgE-mediated (cellular) mechanisms. Genetic
disposition and environmental factors might abrogate oral
tolerance, leading to food allergy. Disease outcomes are 1.4% for vegetables and less than 1% for wheat, soy, and ses-
influenced by the characteristics of the immune response and of ame. Although an allergy could be triggered by virtually any
the triggering allergen. Diagnosis is complicated by the food, ‘‘major allergens’’ responsible for most significant reac-
observation that detection of food-specific IgE (sensitization) tions include milk, egg, peanut, tree nuts, shellfish, fish, wheat,
does not necessarily indicate clinical allergy. Therefore and soy. Allergy to additives and preservatives is generally
diagnosis requires a careful medical history, laboratory studies, uncommon.4
and, in many cases, an oral food challenge to confirm a Food allergy rates vary by age, local diet, and many other
diagnosis. Novel diagnostic methods, including ones that focus factors. Studies in the United Kingdom and North America
on immune responses to specific food proteins or epitopes of focusing on peanut indicate that prevalence rates in children have
specific proteins, are under study. Currently, management of increased, essentially doubling, and exceed 1% in school-aged
food allergies consists of educating the patient to avoid ingesting children.5 A 2008 Centers for Disease Control and Prevention re-
the responsible allergen and to initiate therapy (eg, with port indicated an 18% increase in childhood food allergy from
injected epinephrine for anaphylaxis) in case of an unintended 1997 to 2007, with an estimated 3.9% of children currently af-
ingestion. Improved therapeutic strategies under study include fected.6 Extrapolation from US studies indicates approximately
oral and sublingual immunotherapy, Chinese herbal medicine, 125,000 emergency department visits7 and 53,700 episodes of an-
anti-IgE antibodies, and modified vaccines. (J Allergy Clin aphylaxis8 from foods each year. Fatalities are primarily reported
Immunol 2010;125:S116-25.) from allergic reactions to peanuts and tree nuts, appear to be as-
sociated with delayed treatment with epinephrine, and occur
Key words: Food allergy, food hypersensitivity, oral tolerance, gas-
more often in teenagers and young adults with asthma and a pre-
trointestinal food hypersensitivity, food allergens, anaphylaxis
viously diagnosed food allergy.9 The determination of accurate
food allergy prevalence rates is hampered by the lack of studies
The term food allergy is used to describe an adverse immune applying reliable diagnostic methodologies, such as supervised
response to foods.1 Considering allergy to milk, egg, peanut, OFCs, to large unselected populations. Table I presents estimated
and seafood in a meta-analysis of 51 studies, self-reported al- rates of food allergies in North America based primarily on data
lergy ranged from 3% to 35%, whereas estimates from 6 studies from studies conducted there when possible.2,3,10
using oral food challenges (OFCs) estimated rates of 1% to Although prior studies indicated childhood food allergies typ-
10.8%.2 In a meta-analysis including 36 population-based stud- ically resolved by age 3 years, recent studies, albeit possibly
ies focusing on allergy to fruits and vegetables (excluding pea- affected by selection bias because of referral patterns, indicated
nut),3 only 6 included OFCs, and estimates of allergy varied only 11% resolved egg and 19% resolved milk allergy by age 4
widely from 0.1% to 4.3% for fruits and tree nuts to 0.1% to years; however, about 80% resolved these allergies by age 16
years.11,12 Peanut allergy, which is typically considered a persis-
tent allergy, can resolve for about 20% of young children by school
From the Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and age, although recurrence of peanut allergy has also been described
Immunology, Department of Pediatrics, Mount Sinai School of Medicine. primarily in those who tolerated an OFC but did not continue to
Disclosure of potential conflict of interest: S. H. Sicherer is a consultant for the Food consume the food.5 Studies to address the reasons for increased
Allergy Initiative and a medical advisor for the Food Allergy & Anaphylaxis Network
and has received research support from the National Institutes of Health/National
prevalence and persistence of food allergies, focusing primarily
Institute of Allergy and Infectious Diseases. H. A. Sampson is a consultant for and on peanut, have included the hygiene hypothesis; changes in the
holds shares in Allertein Pharmaceuticals, LLC; is a consultant and scientific advisor components of the diet, including antioxidants, fats, and nutrients,
for the Food Allergy Initiative; and has received research support from the Food such as vitamin D; the use of antacids, resulting in exposure to
Allergy Initiative and the National Institutes of Health/National Institute of Allergy
more intact protein; food processing, such as for peanut roasting
and Infectious Diseases.
Received for publication July 20, 2009; revised August 18, 2009; accepted for publica- and emulsification to produce peanut butter compared with fried
tion August 21, 2009. or boiled peanut; and extensive delay of oral exposure, thus in-
Reprint requests: Scott H. Sicherer, MD, Division of Allergy/Immunology, Mount Sinai creasing topical (possibly sensitizing) rather than oral (possibly
Hospital, Box 1198, One Gustave L. Levy Place, New York, NY 10029-6574. E-mail: tolerizing) exposure to food allergens.5,13 Evidence supporting
scott.sicherer@mssm.edu.
0091-6749/$36.00
this latter hypothesis is supported by one study showing peanut al-
Ó 2010 American Academy of Allergy, Asthma & Immunology lergy rates in a school-aged cohort of Israeli Jewish children to be
doi:10.1016/j.jaci.2009.08.028 0.17% compared with those in a cohort of Jewish children in the

S116
J ALLERGY CLIN IMMUNOL SICHERER AND SAMPSON S117
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United Kingdom, where the rate was about 10-fold higher (1.85%, TABLE I. Estimated food allergy rates in North America
P < .001), in the context of data showing consumption of peanut at Prevalence Infant/child Adult
ages 8 to 14 months was 7.1 g in Israel compared with 0 g in the
United Kingdom (P < .0001).14 A case-control study additionally Milk 2.5% 0.3%
Egg 1.5% 0.2%
found that peanut allergy was associated with household peanut
Peanut 1% 0.6%
consumption rather than maternal or infant peanut consumption.15 Tree nuts 0.5% 0.6%
However, randomized controlled trials are needed to confirm the Fish 0.1% 0.4%
hypothesis that earlier ingestion of peanut is protective. Shellfish 0.1% 2%
Wheat, soy 0.4% 0.3%
Sesame 0.1% 0.1%
PATHOGENESIS Overall 5% 3% to 4%
Oral tolerance induction and immune response to
food proteins
The gastrointestinal tract encompasses the largest surface area population of CD41 cells that secrete IL-10; CD41 and CD251
in the human body and is comprised of a single-cell layer of regulatory T cells; CD81 suppressor T cells; and gd T cells.16
columnar intestinal epithelial cells separating the internal sterile In addition, intestinal epithelial cells can process luminal antigen
environment from the external world.16 Its main function is to and present it to T cells on an MHC class II complex but lack a
process ingested food into a form that can be absorbed and used ‘‘second signal,’’ thus leading to anergy and suggesting their
for energy and growth, while at the same time preventing the pen- role in tolerance induction to food antigens as nonprofessional an-
etration of harmful pathogens into the body. An intricate ‘‘gastro- tigen-presenting cells. Despite the evolution of this elegant gas-
intestinal mucosal barrier’’ has evolved that consists of trointestinal barrier, about 2% of ingested food antigens are
physiologic and immunologic components to accomplish this. absorbed and transported throughout the body in ‘‘immunologi-
The physiologic barrier includes a single layer of epithelial cells cally’’ intact forms, even through the normal mature gut.21 In a se-
joined by tight junctions and covered with a thick mucus layer that ries of experiments performed more than 75 years ago, Walzer
traps particles, bacteria, and viruses. Trefoil factors are secreted and colleagues22,23 passively sensitized volunteers with sera
by mucus-secreting cells of the stomach and intestine to help from patients with food allergy and demonstrated that immuno-
strengthen and promote restoration of the mucosal barrier. In ad- logically intact antigens cross the mucosal barrier and dissemi-
dition, luminal and brush border enzymes, bile salts, and extremes nate rapidly throughout the body to activate local mast cells.
of pH serve to destroy pathogens and render antigens less immu- Several nonhost factors can influence the development of oral
nogenic. The immunologic component consists of innate (poly- tolerance, such as physical properties of the antigen and the dose
morphonuclear neutrophils, macrophages, natural killer cells, and frequency of exposure. Studies in murine models indicated
epithelial cells, and Toll-like receptors) and adaptive immune (in- differences in immune responses depending on the dose of
traepithelial and lamina propria lymphocytes, Peyer patches, se- antigen ingested: high-dose tolerance involves deletion of effec-
cretory IgA, and cytokines) cells and factors, which also tor T cells, and low-dose tolerance is the result of activation of
provide an active barrier to foreign antigens. However, the effi- regulatory T cells with suppressor functions.16
ciency of this mucosal barrier in infants and young children is Ongoing studies indicate that commensal gut flora also likely
not optimal because of the developmental immaturity of various play a role in oral tolerance induction, as initially suggested by the
components of the gut barrier and immune system (eg, the activity observation that mice raised in a germ-free environment do not
of various enzymes is suboptimal in the newborn period and the have normal tolerance.24 In one study mice treated with antibi-
secretory IgA system is not fully mature until 4 years of age).16 otics or lacking Toll-like receptor 4–recognizing bacterial LPSs
Consequently, this immaturity might play a role in the increased and then exposed to a sensitizing regimen of peanut were more
prevalence of both gastrointestinal tract infections and food aller- prone to peanut allergy than wild-type control animals.25 Popula-
gies seen in the first several years of life. Recently, studies in both tion-based observational studies relating the presence of atopic
murine models and human subjects have suggested that alteration dermatitis to stool bacterial patterns and interventional studies ad-
of the physiologic barrier function (eg, decreased gastric acidity ministering probiotics suggest a potential for allergy prevention
caused by potent antacids) can lead to increased IgE sensitization by creating a tolerogenic bacterial milieu, although clinical stud-
in both children and adults.17 Additionally, altered intestinal per- ies are conflicting.26
meability leading to increased exposure to intact proteins might IgE-mediated hypersensitivity responses are attributed to the
promote sensitization and might enhance the severity of food- generation of TH2 cells that produce IL-4, IL-5, and IL-13. Mu-
induced allergic reactions.18 rine models demonstrate a role of TH2 skewing at the time of
Whereas the systemic immune system is typically confronted gut antigen presentation by dendritic cells.27,28 To explore the rel-
with relatively small quantities of foreign antigen and mounts a ative role of a TH2- or TH1-biased immune response in food al-
brisk inflammatory response, the mucosal immune system regu- lergy, Turcanu et al29 expanded human peanut-specific T cells
larly encounters enormous quantities of antigen and must sup- in vitro from the peripheral blood of patients with peanut allergy
press immune reactivity to food and harmless foreign commensal using peanut antigen and then stimulated the cells with phorbol
organisms (ie, develop oral tolerance). Antigen-presenting cells, 12-myristate 13-acetate and ionomycin to maximize cytokine se-
including intestinal epithelial cells and dendritic cells, and cretion. Expanded T cells from 9 subjects with peanut allergy
regulatory T cells play a central role in the development of oral were found to be TH2 biased. However, Thottingal et al30 mea-
tolerance.16,19,20 Several types of regulatory T cells have been sured peanut allergen–driven cytokine responses in short-term
identified in conjunction with intestinal immunity: TH3 cells, a primary cultures of PBMCs from adults with peanut allergy and
population of CD41 cells that secrete TGF-b; TR1 cells, a peanut-tolerant adults with or without peanut-specific IgE.
S118 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
FEBRUARY 2010

Subjects with positive skin test responses had more frequent or in- However, it is clear that additional aspects, such as food
tense IL-5 and IL-13 responses than those without, irrespective of preparation, can affect allergenicity. One theory proposed to
whether they had clinically symptomatic peanut allergy. Surpris- explain a higher rate of peanut allergy in westernized countries,
ingly, the 3 groups were not distinguishable based on IFN-g re- where peanut is consumed roasted, compared with lower preva-
sponses, which were absent, suggesting that a protective TH1 lence rates in China, where peanut is primarily boiled or fried,
bias does not explain the distinction in clinical outcomes, whereas regards the differential effect of these preparation methods.5 The
a spectrum of TH2 responses might. high temperature of roasting (180 8C) peanuts leads to a Maillard
In susceptible hosts oral tolerance might not develop after reaction that appears to increase stability and allergenicity.41,42
antigen ingestion, or it might be bypassed altogether by presen- Another theory posits that emulsification (peanut butter) in-
tation of proteins through alternate routes, such as the respiratory creases allergenicity through an adjuvant effect.5 Additional char-
tract or skin. Oral allergy syndrome/pollen-food–related syn- acteristics of the manner in which foods are ingested might be
drome is an example in which oral tolerance is bypassed because relevant. For example, recent studies suggest that 70% to 80%
sensitization occurs through the respiratory route.31 Respiratory of young children allergic to milk or eggs can tolerate baked
sensitization to Bet v 1 in birch pollen might lead to oral pruritus (heat-denatured) forms of the protein but not the unbaked
in allergic patients when eating raw apples because of cross-reac- form.43,44 It is suggested that these children make IgE antibodies
tivity to a homologous apple protein, Mal d 1. Application of food primarily to conformational epitopes on the food proteins and rep-
proteins to the skin of mice has been shown to result in systemic resent the children who will naturally outgrow their food
allergic symptoms after oral exposure.32,33 As described above, allergies.
there are epidemiologic studies from Israel and the United King- Two recent studies suggest that the carbohydrate moiety of
dom that support the notion that environmental, rather than or per- certain glycoproteins might play a significant role in the allerge-
haps in the absence of, oral exposure to peanut might promote nicity of food proteins. Shreffler et al45 showed that glycosylated
sensitization and allergy.13,15 The loss of skin barrier provides a Ara h 1, a major peanut allergen, but not the deglycosylated form,
portal for sensitization to food allergens in the environment and acted as a TH2 adjuvant by activating dendritic cells to drive the
is increasingly being considered a potential route by which food maturation of TH2 cells. Additionally, Ara h 1 acts as a ligand
allergens can evade oral tolerance.13 for DC-SIGN (dendritic cell–specific intercellular adhesion mol-
The immunopathophysiology of non–IgE-mediated gastroin- ecule 3–grabbing nonintegrin, an ITAM I [immunoreceptor tyro-
testinal food allergy disorders are also being evaluated. In infants sine-based activation motif–containing type II member of the C-
with food protein–induced enterocolitis syndrome, detection of type lectin family]), which also has been shown to interact with
TNF-a from PBMCs cultured in vitro with food proteins respon- schistosome glycoproteins and induce TH2 responses.46 Com-
sible for the reaction has been shown.34 Chung et al35 found in- mins et al47 identified 24 adults who reported urticaria, angioe-
creased staining for TNF-a and decreased staining for the dema, or anaphylaxis 3 to 6 hours after ingesting beef, lamb, or
regulatory cytokine receptor TGF-b1 in duodenal biopsy speci- pork. These patients were all found to have positive skin test re-
mens of affected infants. More work is clearly needed to elucidate sults and serum IgE antibodies to galactose-a-1,3-galactose, the
the immunologic basis of this disorder, but these studies suggest carbohydrate moiety of these glycoproteins. This is the first dem-
that a deficit in TGF-b1 response and excessive TNF-a response onstration of IgE antibodies directed at a carbohydrate epitope
might be important pathogenic factors. leading to clinical symptoms.
Healthy subjects without food allergy frequently have low
concentrations of food-specific IgG, IgM, and IgA antibodies in
their serum. Food protein–specific IgG antibodies tend to increase CLINICAL DISORDERS
in the first months after the introduction of a food and then In addressing possible food-induced allergic disease, the
generally decrease, even though the food protein continues to be clinician must consider a variety of adverse reactions to foods
ingested.36 Subjects with various inflammatory bowel disorders that are not food allergies, especially because more than 20% of
(eg, celiac disease, inflammatory bowel disease, and food allergy) adults and children alter their diets for perceived adverse reac-
frequently have high levels of food-specific IgG and IgM anti- tions/allergies.2 Adverse reactions that are not classified as food
bodies, but there is no evidence that these antibodies are allergies include host-specific metabolic disorders (eg, lactose in-
pathogenic.37 tolerance, galactosemia, and alcohol intolerance), a response to a
pharmacologically active component (eg, caffeine, tyramine in
aged cheeses triggering migraine, and histaminic chemicals in
The role of food proteins spoiled dark-meat fish resulting in scombroid poisoning
Allergic reactions to egg, milk, peanut, tree nuts, fish, shellfish, masquerading as an allergic response), or toxins (eg, food poison-
wheat, and soy account for most significant food allergies in ing). Additionally, psychologic (food aversion and anorexia nerv-
the United States, although any food can trigger an allergic osa) or neurologic (eg, auriculotemporal syndrome manifested by
response.38 However, relatively few protein families account a facial flush from tart foods or gustatory rhinitis manifested by
for the vast majority of allergic reactions.39 In a study by Jenkins rhinorrhea from hot or spicy foods) responses can mimic food
et al40 comparing animal food allergens and their human homologs allergies.
(considering protein families, sequence analysis, and evolutionary It is conceptually and diagnostically helpful to categorize food-
relationships), they noted that sequence identities to human homo- induced allergic disorders based on immunopathology among
logs of greater than 62% typically excluded the protein from being those that are and are not mediated by IgE antibodies. Disorders
allergenic in human subjects. Major food allergens share a number with an acute onset of symptoms after ingestion are typically
of common features; they are water-soluble glycoproteins, 10 to 70 mediated by IgE antibody. Food-specific IgE antibodies arm
kd in size, and relatively stable to heat, acid, and proteases. tissue mast cells and blood basophils, a state termed sensitization.
J ALLERGY CLIN IMMUNOL SICHERER AND SAMPSON S119
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On re-exposure, the causal food proteins bind to the IgE anti- essentially confirm the absence of IgE-mediated allergic reactiv-
bodies specific for them and trigger the release of mediators, ity (negative predictive accuracy, >90%). However, a positive test
such as histamine, that cause the symptoms. Another group of response does not necessarily prove that the food is causal (spec-
food hypersensitivity disorders are subacute or chronic and are ificity, <100%). Consideration of the clinical history and disease
mediated primarily by T cells. A third group of chronic disorders pathophysiology is required to maximize the utility of test results.
attributed to food allergy are variably associated with detectable For example, a positive SPT response can be considered confirma-
IgE antibody (IgE-associated/cell-mediated disorders). Table II tory when combined with a recent clear history of a food-induced
lists the features of a spectrum of the most common food-induced allergic reaction to the tested food. Additionally, increasing SPT
allergic disorders categorized by pathophysiology.4,48 The table wheal size is correlated with an increasing likelihood of clinical
does not include disorders such as recalcitrant childhood gastro- allergy.4,52 Studies have attempted to define wheal sizes above
esophageal reflux, constipation, and irritable bowel syndrome, which allergy is virtually confirmed based on the test result
which are sometimes attributed to food allergy.49 Detection of alone53,54; however, these studies have been limited to a few foods
IgG antibodies to foods is not considered diagnostic of food al- in infants using specific techniques in only a few populations.4 In
lergy.1,4,37 However, Heiner syndrome, a rare infantile disorder one study of 140 children evaluated for peanut allergy, 64 had pos-
characterized by pulmonary hemosiderosis triggered by milk pro- itive SPT responses, and 18 reacted during oral peanut chal-
tein, is associated with increased milk-specific IgG antibodies. lenge.55 Of 17 children with an SPT wheal of greater than
Celiac disease and the related skin disorder dermatitis herpetifor- 10 mm, only 8 reacted during the challenge. Thus additional stud-
mis can be considered food allergies because an immune response ies are needed to continue to define the diagnostic accuracy of
to gluten in grains, such as wheat, rye, and barley, is responsible, skin test wheal sizes for different foods, ages, disease, and popu-
but these disorders are not discussed further here. Dietary (food) lations; wheal size has not been correlated to severity of out-
protein–induced enteropathy is another malabsorption syndrome, comes. When evaluating allergy to many fruits and vegetables,
but unlike celiac disease, it is usually caused by cow’s milk, is commercially prepared extracts are often inadequate because of
transient, is not associated with malignancy or dermatitis, and, the lability of the responsible allergen, and therefore the fresh
for unclear reasons, has been rarely described in the past decade. food might be used for testing.
Although symptoms of mucous and bloody stools in breast-fed in- Serum immunoassays to determine food-specific IgE antibodies
fants have typically been attributed to dietary proctitis/proctoco- (the term RAST is now antiquated) provide another modality to
litis caused by immune responses to maternal ingestants, such as evaluate IgE-mediated food allergy.56 Increasingly higher concen-
cow’s milk, studies have recently emphasized that alternative trations of food-specific IgE levels correlate with an increasing
causes, such as infection or other inflammatory disorders, should likelihood of a clinical reaction but do not generally correlate
be considered.50,51 Thus empiric maternal dietary interventions very well with reaction severity.57-62 Different predictive values
should be undertaken with consideration that alternative explana- are being generated from emerging studies, which might represent
tions might exist, and retrials of the avoided allergen can be con- nuances of diet, age, disease, and challenge protocols.60,61,63 Par-
sidered shortly after resolution of symptoms if other signs of ticular values associated with a high likelihood of clinical allergy
allergy are absent. Lastly, contact dermatitis has also been attrib- (eg, >95%) are often referred to as diagnostic values. Undetectable
uted to foods, particularly with occupational exposure. serum food-specific IgE might be associated with clinical reactions
for 10% to 25%.57,64 Consequently, if there is a suspicion of possi-
ble allergic reactivity, a negative SPT response, negative physi-
DIAGNOSIS cian-supervised food challenge result, or both are necessary to
The evaluation requires a thorough history and physical exam- confirm the absence of clinical allergy. Nomograms are available
ination to consider a broad differential diagnosis, to ascertain where prior probabilities can be used along with likelihood ratios
possible trigger foods, and to determine a likely general patho- (determined from studies evaluating the diagnostic utility of tests)
physiologic basis, specifically whether the food-induced allergic to predict a diagnosis; however, there are few studies providing
disorder is likely IgE mediated, which guides testing. The history likelihood ratios, and results vary.4 A decrease in specific IgE con-
should determine the possible causal food or foods, quantity centration is associated with an increasing chance of allergy reso-
ingested, time course of reaction, ancillary factors (exercise, lution.65 A complete primer of food allergy diagnosis is beyond the
aspirin, and alcohol), and reaction consistency.4 The history also scope of this review, but Table III provides additional insights and
focuses on details that might contribute to estimating the prior information that are key to accurate diagnostics.57-62,66-68
probability of an allergic reaction to a specific food. For example, Although not commercially available, determination of spe-
reasoning dictates that a food ingested infrequently is more likely cific IgE-binding epitopes on an allergen might provide increased
responsible for an acute reaction than one previously tolerated; diagnostic utility.69 The specific profiles of epitopes bound might
that contamination of a meal by a previously diagnosed allergen reflect distinctions in binding to areas of an allergen that are de-
should be considered ahead of a less likely explanation, such as de- pendent on protein folding (conformational epitopes) and are a
velopment of a new allergy to a previously tolerated food; and that feature of mild/transient allergy versus areas that represent linear
major allergens are inherently more likely to be triggers than other binding regions that are stable, reflecting a severe persistent al-
foods. To arrive at a diagnosis, the clinician should consider the lergy. Additionally, IgE responses to specific proteins in foods
epidemiologic aspects of the disease (eg, common triggers and might account for particular outcomes.70 For example, identifica-
common associations) and the details of the specific history and tion of IgE binding to labile birch pollen–related proteins is asso-
then consider appropriate testing that can be evaluated in the con- ciated with mild reactions, whereas binding to stable lipid transfer
text of these prior probability estimates.4 proteins in the same foods is associated with more severe reac-
For IgE-mediated disorders, skin prick tests (SPTs) provide a tions. This observation forms the basis for an approach termed
rapid means to detect sensitization.4 Negative SPT responses component-resolved diagnostics.
S120 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
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TABLE II. Food-induced allergic disorders (also see text)

Additional Most common Natural
Immunopathology Disorder Key features immunopathology Typical age causal foods course

IgE antibody
dependent
(acute onset)
Urticaria/ Triggered by Children > adults Primarily major Depending
angioedema ingestion or direct allergens on food
skin contact
(contact urticaria);
food commonly
causes acute (20%)
but rarely chronic
(2%) urticaria
Oral allergy Pruritus, mild edema Sensitization to Onset after pollen Raw fruit/vegetables Might be
syndrome confined to oral pollen proteins by allergy established Cooked forms long-lived
(pollen–food cavity the respiratory (adult > young tolerated Examples and vary
related) Uncommonly route results in IgE child) of relationships: with seasons
progresses beyond that binds certain birch (apple,
mouth (;7%) or homologous, peach, pear,
anaphylaxis (1% to typically labile carrot), ragweed
2%) food proteins (in (melons)
Might increase after certain fruits/
pollen season vegetables (eg,
apple Mal d 1 and
birch bet v 1)
Rhinitis, asthma Symptoms might Infant/child > General: major Depending
accompany a food- adult, except for allergens on food
induced allergic occupational Occupational:
reaction but rarely disease (eg, wheat, egg, and
an isolated or baker’s asthma) seafood, for
chronic symptom example
Symptoms might also
be triggered by
inhalation of
aerosolized food
protein
Anaphylaxis Rapidly progressive, Massive release of Any Any but more Depending
multiple organ mediators, such as commonly peanut, on food
system reaction can histamine, although tree nuts, shellfish,
include mast cell tryptase fish, milk, and egg
cardiovascular levels not always
collapse increased
Key role of
platelet-activating
factor
Food-associated, Food triggers Exercise is Onset more Wheat, shellfish, Presumed
exercise-induced anaphylaxis only if presumed to alter commonly later and celery are persistent
anaphylaxis ingestion followed gut absorption, childhood/adult most described
temporally by allergen digestion,
exercise or both
IgE antibody
associated/cell-
mediated
(delayed
onset/chronic)
Atopic dermatitis Associated with food Might relate to Infant > child Major allergens, Typically resolves
in ;35% of homing of > adult particularly
children with food-responsive egg and milk
moderate-to-severe T cells to the
rash skin
(Continued )
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TABLE II. (Continued )

Additional Most common Natural
Immunopathology Disorder Key features immunopathology Typical age causal foods course

Eosinophilic Symptoms vary on Mediators that Any Multiple Likely

gastroenteropathies site(s)/degree of home and activate persistent
eosinophilic eosinophils play a
inflammation role, such as
Esophageal: eotaxin and IL-5
dysphagia and
pain
Generalized: ascites,
weight loss, edema,
and obstruction
Cell-mediated
(delayed onset/
chronic)
Dietary protein Primarily affects Increased TNF-a Infancy Cow’s milk, Usually
enterocolitis infants response, soy, rice resolves
Chronic exposure: decreased and oat
emesis, diarrhea, response to
poor growth, and TGF-b
lethargy
Re-exposure after
restriction: emesis,
diarrhea, and
hypotension (15%)
2 hours after
ingestion
Dietary protein Mucus-laden, bloody Eosinophilic Infancy Milk (through Usually
proctitis stools in infants inflammation breast-feeding) resolves

Increasingly, studies are evaluating the utility of the atopy patch minimized.78 If the blinded challenge result is negative, it must
test for disorders in which symptoms are delayed after food be confirmed by means of an open supervised feeding of a typical
ingestion, such as atopic dermatitis,71 eosinophilic esophagitis,72 serving of the food in its natural form to rule out a false-negative
and food protein–induced enterocolitis syndrome.73 The test is per- challenge result (approximately 1% to 3%). A number of reviews
formed by placing foods under Finn chambers in a manner akin to have outlined the procedures involved for OFCs,78,79 and a
testing for contact allergens. Although the atopy patch test shows comprehensive clinically oriented guide has been recently
promise, there are currently no standardized reagents, methods published.80
of application, or interpretations, and the additional diagnostic in-
formation in some studies appears marginal.71,72 Additional future
diagnostic modalities might include the basophil activation test.74 MANAGEMENT
Various tests and procedures (eg, endoscopy/biopsy and breath hy- The primary therapy for food allergy is to avoid the causal food
drogen tests) might be required to evaluate possible gastrointesti- or foods. Education about avoidance includes careful attention to
nal allergy.75 Unproved or disproved tests, such as the pulse test, label reading, care in obtaining foods from restaurants/food
applied kinesiology (muscle strength tests), cytotoxic tests, elec- establishments, and avoidance of cross-contact of foods with an
trodermal tests, and IgG testing, should not be used.76 allergen during meal preparation, such as avoiding shared cutting
The OFC is comprised of a gradual feeding of a possible boards, slicers, and mixers. Food-labeling laws in the United
allergen under medical supervision to determine tolerance or States require simple English terms, such as ‘‘milk’’ instead of
clinical reactivity. Severe reactions could be elicited, and there- ‘‘casein,’’ to indicate the presence of specific regulated food
fore the procedure is undertaken by properly trained personnel allergens, including only milk, egg, wheat, soy, peanut, tree nuts,
with medications and equipment to treat anaphylaxis on hand. fish, and crustacean shellfish. Patients and caregivers should be
Feeding is generally stopped when objective or persistent sub- encouraged to obtain medical identification jewelry, taught to
jective symptoms are elicited.62 For chronic disorders in which an recognize symptoms, and instructed on using self-injectable
ingested food is currently a part of the diet, diagnosis typically in- epinephrine and activating emergency services. Comprehensive
cludes a period of elimination of the possible trigger food or foods educational materials are available through organizations such as
to determine whether symptoms resolve before an OFC. Caution the Food Allergy & Anaphylaxis Network (Fairfax, Va; 1-800-
is advised because acute severe reactions are sometimes noted af- 929-4040 or http://www.foodallergy.org).
ter reintroduction of a potential allergen (eg, positive test result Various medications can provide relief for certain aspects of
for IgE or suspicion of allergy) after prolonged dietary elimina- food-induced disorders. Antihistamines might partially relieve
tion.77 Open or single-blind OFCs are often used to screen for re- symptoms of oral allergy syndrome and IgE-mediated skin
actions. The double-blind, placebo-controlled OFC is the gold symptoms. Anti-inflammatory therapies might be beneficial for
standard for the diagnosis of food allergies because bias is allergic eosinophilic esophagitis or gastroenteritis.81 It is
S122 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
FEBRUARY 2010

TABLE III. Pearls and pitfalls regarding the diagnosis of food allergy
Pearl/observation Additional details Clinical application

A positive skin test or serum food-specific IgE test Screening with indiscriminate panels of tests is The history and epidemiologic considerations
result indicates sensitization but not necessarily poorly informative should guide test selection
clinical allergy Tolerated foods generally need not be tested
Differential diagnosis should include alternative
allergen triggers (environmental aeroallergens)
and nonallergic diseases (eg, intolerance)
Dose, manner of preparation, and ancillary Alcohol, NSAIDs, and exercise are among The history should focus on amounts triggering a
(eliciting) factors might alter reaction outcomes eliciting factors that might facilitate a reaction reaction and ancillary factors
Heating can alter allergenicity (eg, bakery The history should explore the types of foods
products with egg/milk might be tolerated when tolerated or not tolerated
whole forms are not, and cooked fruits might be
tolerated when raw fruits are not)
A low dose might be tolerated, whereas larger
amounts might not
IgE binding to homologous proteins among food Care should be used in not overtesting
groups and between foods and pollens might For some categories and foods, avoidance of the
have variable clinical relevance entire group might be prudent, especially to
avoid cross-contact in preparation, but
Rates of clinical cross reactivity: individualization might be possible

Approximate
Allergy clinical
to: reaction rate
Related food

Peanut Most beans 5%

A tree Other tree nut 35%
nut Higher for:
walnut-pecan,
almond-hazel,
cashew-pistachio
A fish Other fish 50%
Shellfish Another 75%
shellfish
Grain Another grain 20%

Cow’s Goat/sheep milk >90%

milk Mare’s milk 5%
Beef 10%
Tests for serum food-specific IgE might not In the United States there are 3 major test Care must be taken in evaluating test results over
provide comparable results among manufacturers time when different manufacturers are used
manufacturers
Serum/skin tests might be negative despite clinical Might be due to reagent lacking relevant protein Do not discount a convincing history because of a
reactivity Might be because reaction is not IgE mediated negative test result
Consider testing with fresh food (prick-prick test)
Be cognizant of non–IgE-mediated allergic
reactions
Increasingly high serum food-specific IgE levels Correlation of tests with outcomes vary by centers, Tests should not be viewed solely as positive/
or increasingly larger skin test wheal sizes age, and disease (equivalent results are negative
indicate greater chances of clinical allergy generally more predictive of allergy in a Results can be followed over time to monitor
younger patient) allergy persistence/resolution
Results are not strongly reflective of severity Specific correlative values might not be applicable
over all patient groups
At specific high levels of IgE or large skin tests, Age Oral food challenges might be deferred,
Mean Mean
clinical reactivity is highly likely; however, particularly if there is a clinical history
age 5 y, age 5 y, <2 y, 95%
studies are limited, and variations in diagnostic 50% react 95% react react
cutoff values are reported Food

Egg (kUa/L) 2 7 2
Milk (kUa/L) 2 15 5
Peanut 2/5 14
(kUa/L)

NSAIDs, Nonsteroidal anti-inflammatory drugs.

J ALLERGY CLIN IMMUNOL SICHERER AND SAMPSON S123
VOLUME 125, NUMBER 2

TABLE IV. Selected immunotherapeutic strategies

Therapy Immune rationale Benefits Observations to date

Standard subcutaneous Antigen presentation in nonmucosal Proved for venom and respiratory Primarily avoided for risk of
immunotherapy (native allergens) site results in TH1 skewing allergy, possible benefit (pollen) anaphylaxis (eg, peanut)
for oral allergy syndrome
Sublingual/OIT Antigen presentation to mucosal site Natural foods, reduced risk of Mounting evidence for
provides desensitization and might systemic anaphylaxis compared desensitization and relative safety;
induce tolerance with injections unclear effect on tolerance
Modified protein vaccine Reduced IgE activation by mutation A safer form of immunotherapy Murine models show promise,
of IgE-binding epitopes compared with injection of native human studies are planned
protein
Peptide vaccine (overlapping Peptides are less likely to cross-link No requirement for IgE epitope Limited
peptides) IgE, avoiding mast cell activation mapping/mutation
Conjugation of immune stimulatory Enhance TH2 response by activating Increased efficacy, possibly improved Preclinical studies
sequences to allergen and innate immune receptors (using safety
additional adjuvant methods specific sequences or whole
bacteria)
Plasmid DNA-encoded vaccines Endogenous production of allergen Possible 1-dose treatment Murine models reveal strain-specific
might result in tolerance response
Anti-IgE antibodies Targeted toward Fc portion of Not food specific Preliminary study showed improved
antibody, can inactivate IgE with Some response in eosinophilic threshold overall but did not show
reduced risk for activating mast gastroenteropathy (pilot study) uniform protection
cells
Chinese herbal medicine Mechanism unknown Not food specific Murine models show efficacy
Human safety studies are underway
Cytokine/anti-cytokine To interrupt inflammatory signals Might allow directed interruption of Preliminary study shows benefit for
(eg, anti–IL-5) inflammatory processes without eosinophilic esophagitis.
need for food restriction

important to recognize that the key treatment for food-induced an- and are not food specific.48,84,85Table IV summarizes some of the
aphylaxis is prompt administration of epinephrine. current strategies. Of note, immunotherapeutic approaches now
under study attempt to avoid serious adverse effects that would
otherwise be triggered by injection of native allergens, as noted
PREVENTION in a study of injection immunotherapy for peanut allergy,86 by
There are limited data on primary prevention of food allergy changing the route of administration or by modifying (engineer-
through dietary means, although numerous studies possessing ing) the treatment proteins. The approach undergoing the most
various limitations have addressed outcomes of atopic disease, current research is oral immunotherapy (OIT), in which doses
such as atopic dermatitis and asthma. Based on review of the of the food protein are given in gradually increasing amounts to-
available literature, professional organizations82,83 have gener- ward a maintenance dose. Jones et al87 enrolled 39 children with
ally concluded that there is insufficient evidence regarding re- peanut allergy in an open study of OIT; the study did not use initial
duced atopic disease to recommend maternal avoidance of OFCs, but after therapy for 4 to 22 months, initially aiming for
allergens during pregnancy or lactation, although there is some 300 mg as a maintenance dose, 27 of 39 children completing
evidence that allergen avoidance during lactation might be related the maintenance phase tolerated the targeted 3.9-g open peanut
to reduced atopic dermatitis. For infants with a family history of food challenge (18 of them without symptoms). Immune param-
atopy placing them at increased risk, data primarily support the eters followed during the study revealed a decrease in skin test and
practice of exclusive breast-feeding for at least 4 months com- basophil activation, a decrease in peanut-specific IgE levels, and
pared with feeding intact cow’s milk formula to decrease the cu- an increase in IgG levels.4 In a first double-blind trial of milk OIT
mulative incidence of atopic dermatitis and cow’s milk allergy in by Skripak et al,88 20 children (12 completed active treatment and
the first 2 years. Similarly, avoidance of solid foods for the first 4 7 received placebo) underwent a regimen of an initial escalation
to 6 months is associated with reduced risk of atopic dermatitis. day (aiming for 50 mg), 8 weekly updosings to a final dose of
Additionally, for infants not being exclusively breast-fed, whole 500 mg, and maintenance for 3 to 4 months. The median dose
protein formula (cow’s milk or soy) compared with the use of eliciting a reaction at baseline was 40 mg, which increased to
studied extensively or partially hydrolyzed formulas in the first 5,140 mg (range, 2,540-8,140 mg) in the treated group but was
few months appears to be associated with increased risks for unchanged in the placebo group. OIT is presumed to restore or in-
atopic dermatitis. After 4 to 6 months, there are insufficient stud- duce a tolerant state. However, a distinction must be made be-
ies/data that specific allergen avoidance alters atopy outcomes. tween desensitization, in which the allergen is ingested without
symptoms during treatment but requires daily ingestion, and tol-
erance, in which the food might be ingested without allergy symp-
FUTURE THERAPIES toms despite periods of abstinence. Studies to date indicate that
Future therapeutic options for food allergy include strategies OIT induces desensitization, but it remains unclear whether toler-
that target specific foods and ones that block allergic responses ance is achieved.89 Staden et al90 randomized children to egg or
S124 SICHERER AND SAMPSON J ALLERGY CLIN IMMUNOL
FEBRUARY 2010

milk OIT (n 5 25) or observation during dietary elimination 19. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat
Rev Immunol 2003;3:331-41.
(n 5 20); after OFCs at about 21 months on therapy, the treatment
20. Strobel S, Mowat AM. Oral tolerance and allergic responses to food proteins. Curr
group discontinued daily therapy for 2 months and were rechal- Opin Allergy Clin Immunol 2006;6:207-13.
lenged. Although 64% of the treatment group had a good or at 21. Husby S, Jensenius J, Svehag S. Passage of undegraded dietary antigen into the
least partial response to OIT while on treatment, food challenges blood of healthy adults. Quantification, estimation of size distribution and relation
performed 2 months off treatment revealed only 36% continued to of uptake to levels of specific antibodies. Scand J Immunol 1985;22:83-92.
22. Brunner M, Walzer M. Absorption of undigested proteins in human beings: the ab-
have true tolerance, a percentage that exactly matched tolerance sorption of unaltered fish protein in adults. Arch Intern Med 1928;42:173-9.
achieved in untreated control subjects. More studies are required 23. Walzer M. Allergy of the abdominal organs. J Lab Clin Med 1941;26:1867-77.
to assess safety,91 efficacy, and mechanisms. 24. Sudo N, Sawamura S, Tanaka K, Aiba Y, Kubo C, Koga Y. The requirement of in-
testinal bacterial flora for the development of an IgE production system fully sus-
ceptible to oral tolerance induction. J Immunol 1997;159:1739-45.
SUMMARY 25. Bashir ME, Louie S, Shi HN, Nagler-Anderson C. Toll-like receptor 4 signaling by
intestinal microbes influences susceptibility to food allergy. J Immunol 2004;172:
Food allergies are common, result in both acute and chronic 6978-87.
disease, might be increasing in prevalence, affect quality of life, 26. Prescott SL, Bjorksten B. Probiotics for the prevention or treatment of allergic dis-
and can be severe and potentially fatal. Diagnosis currently relies eases. J Allergy Clin Immunol 2007;120:255-62.
on a careful history and an appreciation of epidemiologic aspects 27. Blazquez AB, Berin MC. Gastrointestinal dendritic cells promote Th2 skewing via
OX40L. J Immunol 2008;180:4441-50.
of the disorder, the role and limitation of simple diagnostic tests,
28. Yang PC, Xing Z, Berin CM, Soderholm JD, Feng BS, Wu L, et al. TIM-4 expressed
and, if needed, the use of an OFC to confirm allergy or tolerance. by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differ-
Treatment currently relies on avoidance of triggers and appro- entiation and intestinal allergy. Gastroenterology 2007;133:1522-33.
priate prompt response to allergic reactions, such as using 29. Turcanu V, Maleki SJ, Lack G. Characterization of lymphocyte responses to pea-
epinephrine for anaphylaxis. Insights on pathophysiology are nuts in normal children, peanut-allergic children, and allergic children who ac-
quired tolerance to peanuts. J Clin Invest 2003;111:1065-72.
leading to the development of improved methods for prevention, 30. Thottingal TB, Stefura BP, Simons FE, Bannon GA, Burks W, HayGlass KT. Hu-
diagnosis, and management, including clinical studies that are man subjects without peanut allergy demonstrate T cell-dependent, TH2-biased,
currently underway that might reduce risks for allergic subjects or peanut-specific cytokine and chemokine responses independent of TH1 expression.
possibly cure these allergies. J Allergy Clin Immunol 2006;118:905-14.
31. Fernandez-Rivas M, Bolhaar S, Gonzalez-Mancebo E, Asero R, van Leeuwen A,
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