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FOOD ALLERGY

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FOOD ALLERGY Powered By Docstoc
					FOOD ALLERGY
Anna Nowak-Wegrzyn, MD, Mount Sinai School of Medicine, New York, NY

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Learning Objectives:
Upon completion of this activity, participants should be able to:
1. Explain prevalence of food allergy
2. Understand pathophysiology of food allergy
3. Be familiar with manifestations of food allergy
4. Be familiar with interpretation of diagnostic laboratory testing and utilization of oral food challenges
5. Understand the principles of managing food allergy
6. Be familiar with most promising future approaches to food allergy therapy

The content of this handout is based on the following review articles:
(1) Sicherer SH, Sampson HA. 9. Food allergy. J Allergy Clin Immunol 2006; 117(2 Suppl Mini-
Primer):S470-S475.
(2) Food Allergy: A Practice Parameter. Ann Allergy Asthma Immunol 96[3, Supplement 2]. 2006.
(3) Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004; 113(5):805-819.
(4) Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin
Immunol 2005; 115(1):3-12.
(5) Sicherer SH, Teuber S. Current approach to the diagnosis and management of adverse reactions
to foods. J Allergy Clin Immunol 2004; 114(5):1146-1150.
(6) Nowak-Wegrzyn A, Sampson HA. Food allergy therapy. Immunol Allergy Clin North Am 2004;
24(4):705-25, viii.
(7) Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of
atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of
introduction of complementary foods, and hydrolyzed formulas Pediatrics 2008; 121(1):183-191.
(8). Sicherer SH, Sampson HA. Peanut allergy: emerging concepts and approaches for an apparent
epidemic. J Allergy Clin Immunol 2007; 120(3):491-503.
(9). Sicherer S.H. Food allergy. Syllabus. Board Review Course 2007.

The following topics will be reviewed:
   • Definition / differential diagnosis
   • Prevalence
   • Pathophysiology
   • Specific food allergy disorders
   • Diagnosis and management
   • Natural history
   • Prevention of food allergy
   • Novel therapies for food allergy

                                                                              IgE-mediated food allergy reactions typically
            Food Allergy=                                                     start within minutes to 1 hour (rarely past 2
    Immune System-Mediated Adverse                                            hours) and may affect skin (urticaria,
            Food Reaction                                                     angioedema, morbilliform eruptions,
                                                                              flushing, pruritus), respiratory tract
IgE-Mediated                Mixed               Non-IgE-Mediated
                                                                              (sneezing, rhinorrhea, congestion, cough,
   Anaphylaxis; FDEIA
                                                                              wheezing, difficulty breathing), and
                                                                              gastrointestinal tract (pollen-food allergy
                                                Dermatitis herpetiformis
   Urticaria / Angioedema   Atopic dermatitis                                 syndrome, nausea, vomiting, diarrhea,
                                                                              crampy abdominal pain). Generalized
   Immediate GI symptoms    AEE/AEG             Celiac disease; Enteropathy   reactions, involving cardiovascular system
   PFAS
                                                FPIES                         (tachycardia, hypotension) are called
                                                Allergic proctocolitis
                                                                              anaphylactic shock. Mixed and cell-
                                                                              mediated mechanisms typically have
   Bronchospasm             Asthma              Heiner’s syndrome             delayed onset of symptoms (> 2 hours) and
                                                                              a chronic relapsing course.
                                                                 Food allergy must be distinguished from a
                Non-Immune Mediated                              variety of adverse reactions to foods that do
               Adverse Food Reactions                            not have an immune basis but may
                                                                 resemble food allergy in clinical
                                                                 manifestations.
      Toxic / Pharmacologic        Non-Toxic/ Intolerance
                                                                 Toxic reactions are host-independent and
                                                                 can be elicited in anyone who ingests a
                                  Lactase deficiency
       Food poisoning
                                  Galactosemia
                                                                 sufficient quantity of the tainted food. Non-
       Scombroid fish
                                  Pancreatic insufficiency       toxic reactions are dependent upon host
       poisoning
       Histamine
                                  Gallbladder / liver disease    factors and are referred to as intolerances.
       Tyramine
                                  Panic, anxiety                 Examples include lactose intolerance due to
                                  Depression, anorexia, bulimia
       Caffeine                   Hiatal hernia
                                                                 disaccharidase deficiency, metabolic
       Alcohol                    Gustatory rhinitis             disorders, pancreas or liver disease,
                                  Auriculotemporal syndrome      psychiatric disorders, anatomic defect,
                                  Blepharochalasis               neuronally-mediated disease (gustatory
                                                                 rhinitis-rhinorrhea from spicy foods), or
                                                                 auriculotemporal syndrome.*
*Frey’s syndrome: transient uni or bilateral facial flushing or sweating following ingestion of spicy or
flavored foods, infants and children with history of forceps delivery and damage to auriculotemporal
nerve.
                                                                 In spite of the tremendous diversity of the
                                                                 human diet, relatively few foods account for
                      Food Allergens                             the majority of food allergies. In the USA,
       Children              Adults                              milk, egg, peanut, wheat and soybean are
                                                                 the most common culprits in children;
       6-8% affected         2-4 % affected
                                                                 whereas peanut, tree nuts, fish and shellfish
            Milk
            Egg
                              Peanut                             are the most common culprits in adults.
                              Tree nuts
            Peanut
                              Fish
                                                                 Raw fruits and vegetables are responsible
            Soybean
            Wheat
                              Shellfish                          for pollen-food allergy syndrome that affects
            Tree nuts
                              Fruits/vegetables in PFAS (50-75%)
                                                                 approximately 50% of adults with rhinitis
            Fish                                                 caused by birch pollen.
               Shellfish




Modern diets that routinely include exotic foods as well as a variety of fresh fruits and vegetables have
resulted in an increase in allergic reactions to fruits such as kiwi and papaya, and seeds, such as
sesame, poppy, mustard, and rape (canola).
                                                                Food allergy affects about 6% of infants and
                                                                young children and approximately 3.5-4% of
       Prevalence of Food Allergy-                              adults. The most common food allergens in
           General Population                                   the pediatric population include cow’s milk,
                                                                egg, peanut, tree nuts, soy, wheat, fish and
                           Young children            Adults     shellfish, whereas peanut, tree nuts, fish
     Cow’s milk            2.5%                      0.3%       and shellfish prevail in adults. Recent
     Egg white             1.3%                      0.2%       studies reported doubling of peanut allergy
     Peanut*               0.8%                      0.6%       in young children. A 5-year follow up study
     Tree nuts             0.2%                      0.5%       of peanut and tree nut allergy utilizing a
     Fish                  0.1%                      0.4%
                                                                random digit dial telephone survey found
     Shellfish             0.1%                      2.0%
                                                                that in comparison with the 0.4%
     Overall               6%                        3.7%
                                                                prevalence of peanut allergy in American
     Prevalence doubled in the past decade in USA, Canada, UK
                                                                children 5 years of age or younger in 1997,
                                                                there was an increase to 0.8% in 2002.

Similarly, results reported from Isle of Wight in the UK indicated a doubling of clinical peanut allergy
and a tripling of IgE peanut sensitization in young children over a period of 10 years.
                                                                                   Food allergy remains the leading single
                                                                                   cause of anaphylaxis outside the hospital
            Prevalence of Food Allergy-                                            and an increasing trend has been noted in
                Specific Disorders                                                 recent years. More than 50% of adults with
                                                                                   birch pollen allergic rhinits report symptoms
                                                                                   of PFAS. Children with moderate to severe
                                                                                   persistent atopic dermatitis have a higher
     Anaphylaxis                         35-55%                                    prevalence of IgE-mediated food allergy,
     PFAS, adults                        25-75%
                                                                                   estimated at about 35%.
                                                                                   In addition, there is a significant increase in
     Atopic dermatitis, children         37% (moderate-severe, persistent)
                                                                                   reports of eosinophilic gastroenteropathies
     Atopic dermatitis, adults           Rare
                                                                                   such as allergic eosinophilic esophagitis
     Urticaria, acute                    20%                                       and allergic eosinophilic gastroenteritis,
     Urticaria, chronic                  Rare (4% children; 1.4% adults)           which in a subset of patients are due to
     Asthma, childhood, general          5-6%                                      dietary food protein hypersensitivity. Finally,
     Chronic rhinitis                    Rare                                      it has been recently appreciated that up to
                                                                                   50% of gastroesophageal reflux in infants
                                                                                   younger than 1 year may be caused by
                                                                                   hypersensitivity to dietary food proteins,
                                                                                   mainly cow’s milk and soybean.

                                                                                   Cooking can reduce the allergenicity of
                          Food Allergens                                           fruits and vegetables responsible for the
                                         • Class II
 • Class I                                                                         pollen-food allergy syndrome, and with
 • Water-soluble glycoproteins           • Plant-derived
                                         • Highly homologous with
                                                                                   cooked versus raw or undercooked egg and
 • 10-70 kDa
                                           pollen                                  fish, by destroying heat-labile
 • Resistant to heat, acid and
   proteases                             • Highly heat labile, cooking             conformational allergenic epitopes. In
                                           reduces allergenicity
 • Sensitization: G.I.                                                             contrast, high temperatures (e.g. roasting)
                                         • Sensitization: Respiratory to
      Protein             Nomenclature     cross-reactive pollen                   can increase allergenicity of certain
      Cow’s milk                                                                   allergens such as peanut through the
       Caseins
                                         Protein                    Nomenclature   induction of covalent binding that leads to
       Whey
       β-lactoglobulin    Bos d 5        Birch Bet v 1 homologous
                                                                                   new antigens or improved stability.
      Chicken egg white
       Ovalbumin          Gal d 1
                                         (PRP-10)                                  Traditional or class I food allergens induce
                                          Apple                     Mal d 1
       Ovomucoid          Gal d 2         Carrot                    Dau c 1        allergic sensitization via the gastrointestinal
      Peanut
       Vicilin            Ara h 1
                                          Celery
                                         Birch bet v 2 homologous
                                                                    Api g 1        tract and are responsible for systemic
       Conglutin          Ara h 2        (profilin)                                reactions (traditional or class I food allergy).
       Glycinin
      Wheat
                          Ara h 3         Latex
                                          Celery
                                                                    Hev b 8        Type I food allergens are typically heat- and
                                                                    Api g 4
       ω-5 gliadin        Tri a 19                                                 low pH- stable, water-soluble glycoproteins
                                                                                   ranging in size from 10 to 70 kD.


Type II food allergens are heat-labile and susceptible to digestion. Type II food allergens are highly
homologous with proteins in pollens and sensitization occurs in the respiratory tract as a consequence
of sensitization to the cross-reactive pollen allergens (pollen-food allergy syndrome or class II food
allergy).

A single food contains many proteins; areas of protein that bind IgE or interact with T cells are called
the epitope. Epitopes may be comprised of amino acid residues that are brought together by protein
folding are called “conformational”, whereas epitopes comprised of sequential amino acids and not
dependent on protein folding, are called “linear” epitopes.
                                                                       Immaturity of the immune system and
                  Gut Mucosal Barrier                                  gastrointestinal tract predisposes young
                                                                       infants to food allergy. Compared with older
     • Immaturity of gut barrier in infants and young children children and adults, infants and young
          – ↑ intestinal permeability                                  children have an immature glycocalyx,
          – ↑ gastric pH                                               decreased gastric acidity, as well as
          – ↓ activity of the proteolytic enzymes                      decreased intestinal and pancreatic enzyme
          – ↓ secretion of IgA                                         activity. The intestinal permeability is
          – ↑ T cell reactivity toward food Ags
                                                                       increased, resulting in higher concentrations
     • 2% of ingested food Ags are absorbed in an “intact              of intact food proteins in the circulation and
        form” → food-IgG in tolerant individuals                       likely leading to stimulation of the immune
                                                                       system and development of IgE-
     • Factors inreasing intestinal permeability associated            sensitization. The mucosal immune
        with FA                                                        response is immature; surface secretory IgA
          – ASA
                                                                       concentration is lower but T lymphocyte
          – Alcohol
          – Exercise
                                                                       reactivity to food proteins is increased. Early
          – Infection (virus)                                          introduction of food allergens have been
                                                                       shown to stimulate IgE antibody production
                                                                       and induce allergic conditions in
                                                                       predisposed infants.
Impaired mucosal gut barrier and the resulting increased intestinal permeability has been proposed as
one of the important factors contributing to the development of food allergy in infants and young
children. During the first two years of life, gradual maturation of the intestinal barrier corresponds to
decreased prevalence of food allergy and may be associated with the process of “outgrowing” food
allergy.
                                                                       Even in the mature gut, about 2% of
                  Oral Tolerance                                       ingested food allergens are absorbed and
                                                                       transported throughout the body in an
     • GALT largest secondary lymphoid organ, 5x1010                   immunologically intact form. However in
       cells in an adult
                                                                       most individuals these food proteins do not
     • Soluble antigens →specific non-responsiveness                   cause clinical symptoms because of oral
         – Low Ag dose: ↑ TGF-β, IL-10 and IL-4 in the Peyer’s patches tolerance-the physiological mucosal
         – High Ag dose: anergy or deletion of reactive T-cells and    immune response to soluble antigens such
           induction of allergen-specific CD8 suppressor T cells       as in foods, resulting in a state of
     • Endogenoues gut bacterial flora: animals in                     unresponsiveness. Oral tolerance is
       germ-free environment from birth fail to acquire                hypothesized to result from T cell anergy or
       normal tolerance                                                induction of regulatory T cells. Intestinal
                                                                       epithelial cells act as non-professional
     • Ingested Ag penetrates the gut barrier →immune                  antigen presenting cells and induce
       responses in the absence of food allergy                        tolerance. In addition, intestinal dendritic
         – PCA: rapid Ag uptake
                                                                       cells express interleukin-10 (IL-10) and
         – IgE receptor facilitates Ag uptake in sensitized mice
                                                                       interleukin-4 (IL-4) which favor the
                                                                       generation of tolerance in vivo.

The regulatory T cells that are potent sources of tumor growth factor- β (TGF-β) are generated in
mucosal lymphoid tissue in response to low-dose antigen. The gut flora is also believed to play a
significant role in the induction of normal mucosal immunity because animals raised in a germ-free
environment fail to develop normal tolerance. Childhood food allergy therefore can be viewed as a
failure to develop oral tolerance in the setting of immature gastrointestinal and immune systems.

When immune tolerance fails, sensitization to ingested food allergens occurs. In genetically
predisposed, atopic individuals, sensitization leads to the generation of allergic IgE antibodies that
facilitate immediate reactions such as food-induced anaphylaxis, urticaria, angioedema,
bronchospasm or gastrointestinal symptoms of emesis and diarrhea. In others, allergic sensitization
affects mainly T lymphocytes without generation of IgE antibody. Such non-IgE, cell-mediated food
allergic disorders are represented by allergic proctocolitis and food protein-induced enterocolitis
syndrome. Atopic dermatitis and allergic eosinophilic gastroenteritis are examples of disorders with
mixed mechanism, in which both IgE antibody and cell immunity may play a role.
     Antigen Sampling in the GI Tract                                                             Antigen-presenting cells, especially
                                                                                                  intestinal epithelial cells and regulatory T
                          Soluble Ag
                          uptake                                                                  cells play a central role in oral tolerance.
                                                                                                  Five regulatory T cells have been identified
                                                                                                  in conjunction with mucosal immunity:Th3
                                                                                                  cells, a population of CD4+ cells that secret
                                 Particulate Ag and                                               TGF-beta; TR1 cells, CD4+ cells that secret
                Lamina propria
                                 receptor mediated




                                                            Lamina propria
                                 uptake                                                           IL-10; CD4+ cells that secrete IL-1; CD4+,
                                                                              Intraepithelial
                                                                              lymphocytes
                                                                                                  CD25+ regulatory T cells; CD8+suppressor
                                                                                                  T cells, and gd T cells.
                                                                                                  Intestinal epithelial cells process luminal
                                                        M cell                                    antigen and present it to T cells on an MHC
                                                                             CD8 T cells          class II complex, but lack a “second signal”,
                                        PP                                   activation
            Th3 T cells                               sIgA B cells                                suggesting their potential to play a role in
            CD4 T cells                                                           Meyer L, 2000   tolerance induction.



Properties of antigens, dose and frequency of exposure also influence tolerance induction. Dendritic
cells residing in the lamina propria and non-inflammatory environment of Peyer’s patches express IL-
10 and IL-4, which favor the generation of tolerance. High dose tolerance involves deletion of effector
T cells, while low dose tolerance is mediated by activation of regulatory T cells with suppressor
function.
                                                                                                  Anaphylaxis represents the most severe
          Food-Induced Anaphylaxis                                                                form of IgE-mediated food allergy and is
                                                                                                  clinically defined as a food-allergic reaction
    • Rapid onset, multi-system, potentially fatal                                                involving two or more organ systems. In
                                                                                                  extremely sensitive individuals reactions
    • Course: may be biphasic in about 20%                                                        can be triggered by minute amounts of food
    • Tryptase level not elevated                                                                 proteins. Symptoms start within seconds to
    • Any food, highest risk: peanut and tree nuts                                                2 hours following allergen ingestion and
                                                                                                  include feelings of “impending doom”, throat
    • Risk factors for fatality:                                                                  tightness, coughing or wheezing, abdominal
       – Delayed epinephrine;                                                                     pain, vomiting, diarrhea, and loss of
       – Young adult/ teenager;                                                                   consciousness. Cutaneous symptoms of
                                                                                                  flushing, urticaria, and angioedema are
       – Underlying asthma;                                                                       present in the majority of the anaphylactic
       – Absence of cutaneous symptoms                                                            reactions; however, the most rapidly
    • FDEIA:                                                                                      progressive anaphylaxis may involve no
                                                                                                  cutaneous manifestations.
          – Specific food (wheat, celery, fish), or any food;
          – Severity increased with co-administration of alcohol and
            NSAIDs/ASA




                                                                                                  Acute urticaria and angioedema are the
        Food-Induced Urticaria and                                                                most common manifestations of acute
                                                                                                  allergic reactions to ingested foods in
               Angioedema
                                                                                                  children and adults. Onset of symptoms
   • ACUTE:                                                                                       may be rapid, within minutes of ingesting
        – <6 weeks duration                                                                       the responsible food. Skin involvement may
        – Onset within minutes to 1-2 hours following
          food ingestion
                                                                                                  be isolated or associated with other organ
        – The most common sign in immediate FA                                                    systems in food anaphylaxis. Acute IgE-
   • CHRONIC: >6 weeks duration                                                                   mediated urticaria can by induced by skin
        – Very unlikely to be associated with FA:                                                 contact with cow’s milk, raw egg white, raw
          children 4%, adults 1.4% confirmed with                                                 meats, fish, vegetables and fruits.
          DBPCFC
Skin contact reactions are typically local in nature but contact with oral mucous membranes (e.g.
kissing) or conjunctiva (e.g. eye rubbing) may lead to generalized reactions.
Chronic urticaria (symptoms lasting longer than 6 weeks) is rarely caused by food allergy.
                                                              Food allergy is frequently seen in children
                                                              with atopic dermatitis (AD) but infrequently
        Atopic Dermatitis and Food                            in adults. AD is a chronic inflammatory
                        Allergy                               disease of the skin characterized by marked
                                                              pruritus and a remitting and relapsing
     • 90% of children with food allergy have AD              course. The vesiculopapular rash of AD has
     • 30-40% of children with AD have skin                   a typical distribution, with generalized
       symptoms provoked by food hypersensitivity             involvement in infants and young children,
       (Eigenman et al, 1998)                                 and with localization to flexural areas in
     • Food allergy-related AD usually starts <1 year         older children. AD starts under age 5 years
       of age                                                 in over 95% of patients. In a study of
     • 90% of food allergy caused by egg, milk, soy,
                                                              patients with moderate to severe AD
       wheat, peanut, and fish                                referred to a pediatric dermatologist in a
                                                              tertiary medical center who underwent
     • Children have IgE antibody to foods                    1,613 double-blind placebo-controlled food
     • Food-allergen specific T cells have been               challenges, 37% of children were allergic to
                                                              at least one food.
In the presence of extensive chronic eczematous skin lesions, acute skin symptoms are not easily
appreciated and identification of the responsible food allergen is notoriously difficult, if not impossible.
However, following a 2-week strict dietary elimination period, reintroduction of the causative food
results in clear-cut immediate cutaneous reactions. In some adults with birch pollen sensitivity,
ingestion of birch pollen-related foods (e.g., apple, carrot, celery) causes immediate and /or late
eczematous reactions. Strict elimination of the causative food allergen results in significant
improvement in dermatitis.

                                                                           PFAS is a form of contact allergy to raw
     Pollen-Food Allergy Syndrome                                          fruits and vegetables that is confined to the
                                                                           oropharyngeal mucous membranes and
            (PFAS aka OAS)                                                 affects subjects allergic to pollens such as
   • Contact IgE-mediated reaction in the oro-pharyngeal                   birch (apple, cherry, peach, carrot), grass
     mucosa, onset <5 minutes                                              (tomato, kiwi), ragweed (melon, banana,
   • Rare cases my progress to systemic reactions (<1% risk of             tomato), or mugwort (carrot, celery). PFAS
     anaphylaxis)
                                                                           affects approximately 50% of birch pollen-
   • Caused by raw fruits or vegetables, cooked foods are well-            allergic adults and represents the most
     tolerated
                                                                           common food allergy in adults. It is due to
   • Cross-reactive allergens in pollen and plant foods (primary
     respiratory sensitization to pollen then reaction to food             the cross-reactivity between the allergenic
     ingestion)                                                            proteins in the pollens and plant foods.
   • Typical associations:                                                 Local IgE-mediated mast cell activation
   BIRCH         Apple, peach, apricot, hazelnut, potato, carrot, celery   provokes the rapid onset of pruritus, tingling
   RAGWEED Banana, cucumber, cantaloupe, watermelon, zucchini, cucumber    and angioedema of the lips, tongue, palate,
   MUGWORT Celery, onion, mustard, cabbage                                 and throat; and occasionally a sensation of
                                                                           pruritus in the ears, tightness in the throat or
                                                                           both. These symptoms resolve promptly
                                                                           when the food is swallowed or removed.
Patients typically tolerate cooked or baked forms of fruits and vegetables in which unstable allergens
are destroyed by high temperature. Symptoms of PFAS are typically mild but in a small subset of
patients allergy to fruits and vegetables may progress to systemic reactions. Risk factors for systemic
reaction are not well delineated but may involve sensitization to heat-stable and protease-resistant
lipid transfer proteins and storage proteins such as globulins (7S and 11 S) and albumins (2S); lack of
pollen allergy; peach hypersensitivity; positive allergy tests with commercial extracts (64% rate of
systemic reaction versus 6% (p<0.001); history of systemic reaction to one of the related foods; and
reactions to cooked foods.
                                                                                Food protein-induced enterocolitis
            Pediatric GI Syndromes                                              syndrome (FPIES) is most frequently seen
                                                                                in young infants who present with irritability,
                      FPIES                Enteropathy       Proctocolitis
                                                                                protracted vomiting and diarrhea. Twenty
 Onset                1 day-1 year         Up to 2 years     Newborn
                                                                                percent of cases may result in shock,
 Most common          Cow’s milk, soy      Cow’s milk, soy   Cow’s milk, soy    presumably due to intense intestinal
 Less common          Rice, oat, barley,   Wheat, egg
                      chicken, turkey,                                          inflammation leading to third-spacing and
                         fish                                                   intravascular volume depletion. Vomiting
 Multiple FA          >50% both cow’s      Rare              >50% both cow’s
                         milk and soy                           milk and soy    generally occurs 1 – 3 hours after feeding
                                                                                but continued exposure may result in bloody
 Feeding at onset     Formula              Formula           60% breast-fed
 Symptoms                                                                       diarrhea, anemia, abdominal distention, and
  Emesis              Prominent            Intermittent      No                 failure to thrive. FPIES is most frequently
  Diarrhea            Severe               Moderate          No
  Bloody stools       Severe               Rare              Yes                due to cow’s milk and soy, but other foods
  Edema               Acute, severe        Moderate          No                 such as grains (rice, oat), meats (turkey,
  Shock               15%                  No                No
  Failure to thrive   Moderate             Moderate          No or minimal      chicken) and vegetables (pea) have also
                                                                                been reported. Breast-feeding appears to
                                                                                have a protective effect.
The pathophysiology of FPIES may involve depressed TGF-alpha expression in intestinal mucosa and
increased secretion of TNF-alpha by circulating milk-specific T cells that result in increased intestinal
permeability.
Enteropathy syndrome occurs in infants and toddlers and resembles celiac disease in regard to
malabsorption and villus atrophy but is induced by cow’s milk or soy proteins and typically resolves by
age 2 years.
Allergic proctocolitis typically starts in the first few months of life, with blood-streaked stools in
otherwise healthy-looking infants and is considered a major cause of colitis under age 1 year, with
more than 50% of infants in published reports being exclusively breast-fed. Food protein-induced
proctocolitis typically presents in the first four months of life, usually at 1 to 4 weeks of age with
intermittent blood-streaked normal to moderately loose stools. Pathologic findings are limited to the
colon and include focal acute inflammation with epithelial erosions and eosinophilic infiltration of the
lamina propria, the epithelium and lamina muscularis. After 9-12 months of age, the infants typically
tolerate an unrestricted diet.

                                                                                Allergic eosinophilic esophagitis (AEE) and
             Allergic Eosinophilic                                              gastroenteritis (AEG) are characterized by
   Esophagitis (AEE) & Gastroenteritis (AEG)                                    infiltration of the gastrointestinal tract with
                                                                                eosinophils, basal zone hyperplasia,
   • Mixed IgE- and non-IgE-mediated disorders; 50% atopic
   • Clinical symptoms correlate with the extent of eosinophilic infiltration
                                                                                papillary elongation, and absence of
     of the bowel wall                                                          vasculitis. The eosinophilic infiltrates may
   • Symptoms: vomiting, anorexia, difficulty swallowing, pain, irritability,   involve the mucosal, vascular, and/or
     diarrhea, poor weight gain/weight loss, protein-losing enteropathy
   • Eosinophilic infiltrates resolve with elimination of the offending food    serosal layers of the esophagus, stomach
     (within 3-8 weeks) and recur with food reintroduction
   • Food-induced IgE-mediated reactions in a minority of patients;
                                                                                or small intestine. The underlying
     results of allergy tests correlate poorly with response to dietary         pathophysiology of these disorders is poorly
     restrictions; most common foods: cow’s milk, soybean, hen’s egg,
     wheat, fish                                                                understood, but both T lymphocyte and
   • Diagnosis: endoscopy and biopsy! Skin tests / IgE tests negative           food-specific IgE antibody are implicated.
   • IL-5 and Eotaxin-3 important for eos accumulation
   • Management: dietary avoidance, elemental (AA-based) diet,
                                                                                Data from animal models suggest important
     systemic steroids, topical steroids (inhaled-swallowed fluticasone);       role of IL-5 and Eotaxin-3 in the
     anti-IL-5 monoclonal AB
                                                                                pathophysiology of these disorders.
Clinical symptoms correlate with the extent of eosinophilic infiltration of the bowel wall. AEE is seen
most frequently in infants, children and adolescents and presents with symptoms of gastroesophageal
reflux, such as nausea, dysphagia, emesis and epigastric pain that fail to resolve with standard anti-
reflux therapy. Patients typically have a negative pH probe; on esophageal biopsy more than 10-20
eosinophils per 40X high-power field are seen. AEG can occur at any age, including young in infants
and failure to thrive is common. In young infants, AEG may cause gastric outlet obstruction with pyloric
stenosis. Patients also present with abdominal pain, emesis, diarrhea, blood loss in the stool, anemia,
and protein-losing gastroenteropathy.

Up to 50% of patients with these eosinophilic disorders are atopic and have detectable (by prick skin
test or RAST) IgE sensitization to food allergens. However, food-induced IgE-mediated immediate
reactions are uncommon. Furthermore, results of PST and RAST correlate poorly with clinical
response to elimination of the food and thus must be interpreted with caution. Resolution of symptoms
typically occurs within 3 to 8 weeks following the elimination of the responsible food allergen
(frequently multiple foods, most commonly: cow’s milk, soy, wheat, egg). Since patients with AEE and
AEG can be sensitive to trace amounts of the offending foods in the diet and testing may fail to identify
all relevant food allergens, an elemental diet based on an amino acid formula may be needed to
achieve improvement.

                                                                    Barium swollow may show esophageal
         Allergic Eosinophilic                                      narrowing. Endoscopy may reveal
              Esophagitis
                                                                    “trachealization” of esophagus (with ringed
                                                                    appearance), and longitudinal ulcerations
                                                                    (furrows). Biopsy reveals intense
                                                                    eosinophilic infiltration in lamina propria.




               Celiac Disease                                              Dermatitis Herpetiformis
                        Gliadins
                                                                      • Symmetric vesiculation,
                           APC: HLA-DQ2/8                               crusts and erosions are
                                                                        distributed over the
                        CD4+T lymphocyte                                extensor areas of the
                    Th1                   IFN-γ
                                                                        elbows, knees, buttocks,
                                                                        shoulders and scalp, with
        Mucosal remodeling
                                                                        a tendency to grouping of
        Villous blunting
                                                                        individual lesions.
        Malabsorption                      B lymphocyte               • Extremely pruritic,
                                                                        burning
                           Anti-gliadin IgA, IgG
                           Anti-tTG2 IgA-deamination of gliadin-
                                                                      • Associated with celiac
                           increased interaction with HLA –DQ 2/8       disease
                           molecules on APC




Celiac disease (CD) is a dietary protein enteropathy characterized by an extensive loss of absorptive
villi and hyperplasia of the crypts that leads to malabsorption, chronic diarrhea, steatorrhea, abdominal
distention, flatulence, weight loss or failure to thrive. Oral ulcers and a linear papular, intensely pruritic
rash of dermatitis herpetiformis may occur, occasionally in the absence of gastrointestinal symptoms.
Patients with CD are permanently sensitive to gliadin, the alcohol soluble portion of gluten found in
wheat, rye, and barley.Symptoms of CD resolve completely with exclusion of gluten from diet but recur
when gluten is reintroduced. Celiac disease is associated with HLA-DQ2 and HLA-DQ8, and affects as
much as 1% of some Caucasian populations. CD is diagnosed by intestinal biopsy showing classic
villus atrophy; serologic ELISA tests detecting IgA antibodies to tissue transglutaminase have a
sensitivity of 92%-98% and are a useful screening tool. Biopsy and serologic tests may be falsely
negative when taken during gluten elimination, thus testing for CD is only conclusive when the patient
ingests gluten on regular basis for at least several weeks.
                                                                                       Pulmonary hemosiderosis has been
                                                                                        reported in children with cow’s milk-
                                                                                        induced anemia and respiratory symptoms
                       Heiner’s Syndrome                                                of chronic cough, hemoptysis, recurrent
                                                                                        lung infiltrates, wheezing, and persistent
       • Infantile pulmonary hemosiderosis                                              rhinitis. Recently, a single case of
       • Anemia, cough, hemoptysis, recurrent                                           buckwheat-induced hemosiderosis and
         pulmonary infiltrates, wheezing, melena
                                                                                        melena was described. Respiratory
       • Associated with cow’s milk and buckwheat                                       symptoms and anemia resolved upon
         (reports from Japan)
       • OFC proven                                                                     elimination of the offending food and
                                                                                        relapsed following oral challenge. Iron-
       • Iron-laden macrophages in bronchial or
         gastric washings or at lung biopsy                                             laden macrophages were recovered from
       • No IgE but serum IgG precipitins to milk                                       bronchial or gastric washings or at lung
       • Lung bx: IgG, IgA and complement, no IgE                                       biopsy. Prick skin tests and serum food
                                                                                        specific IgE levels were negative but high
                                                                                        titers of serum milk and buckwheat
                                                                                        precipitins were reported.
Increased lymphoproliferative responses of PBMCs upon stimulation with buckwheat flour were
observed in one patient with buckwheat-induced pulmonary hemosiderosis. Biopsy specimens of the
lung revealed deposits of IgG, IgA and complement components, without evidence of IgE. Pulmonary
symptoms tend to be persistent, with relapses described in 6 and 8-year olds but the natural history of
food protein-induced pulmonary hemosiderosis is unknown. Considering the seriousness of pulmonary
hemorrhage, diagnostic oral food challenges must be done with extreme caution under close physician
supervision in the hospital setting and only when potential benefits out-weigh the risks, such as
identification of an offending food in a patient with ongoing symptoms or determination of tolerance
after a long period of food avoidance without accidental reactions.
                                                             Food proteins may be related botanically or
                                                             by a high degree of homologous proteins.
        Cross-Reactivity Patterns                            There is a higher prevalence of positive test
                                                             than of clinical reactivity.
                                                                                        If allergic to  Risk of reaction to at   Risk
                  Risk of reaction to
                  at least one related                                                                  least one other
                  food                                                                  Tree nut        Tree nuts                37%
                      55%                                                               Fish            Fish                     50%
                                                                                        Shellfish       Shellfish                75%
        Peach                        Apple Plum Pear    Cherry     Apricot    Almond    Grain           Grain                    20%
                                                                                        Cow’s milk      Beef                     10%
                                                                                        Cow’s milk      Goat’s milk              92%
                      92%
                                                                                        Cow’s milk      Mare’s milk              4%
                                                                                        Pollen          Fruits/ vegetables       55%
        Cantaloupe                   Avocado Banana     Kiwi     Watermelon Peach       Peach           Rosaceae*                55%
                                                                                        Melon           Melons, peach            92%
                                                                                        *Apple, plum, pear, cherry

                                                                                       Structural protein homology is also a basis
                                                                                       for latex-plant food cross-reactivity.
     Latex-Food Cross-Reactivity

                     35% risk of reaction
                     to at least one food   Kiwi       Banana        Peach




                        11% risk of          Avocado    Chestnut        Fig
 Natural rubber         reaction to latex
 latex


                                              Bell pepper Tomato     White potato
                                                                    Careful medical history is the first step to
        Food Allergy Diagnosis                                      establishing food allergy diagnosis.
    • History                                                       However, history needs to be validated by
        Food ingested
        Timing of symptoms, acute reaction versus chronic disease
                                                                    laboratory tests and oral food challenges,
        Co-ingestion of ASA, alcohol
        Association with exercise
                                                                    especially in chronic disorders such as
                                                                    atopic dermatitis or AEG, in which
    • Physical examination
        Urticaria pigmentosa (mastocytosis)
                                                                    symptoms wax and wane. In such remitting
        Atopic dermatitis
                                                                    and relapsing disorders, accurate
    • Laboratory tests: are they necessary?                         identification of the offending food is
        IgE-mediated allergy
          • In vivo                                                 particularly difficult and sometimes
          • In vitro
        Non-IgE-mediated allergy                                    impossible. A food intake diary may be
    • Oral food challenges “GOLD STANDARD”                          helpful in tracing back the reactions and
                                                                    foods that might have caused them.
Dietary elimination of the suspected foods may be helpful, although, in general it should be followed
be reintroduction of the food because in some patients symptoms improve with dietary restriction but
do not recur upon reintroduction of the suspected food.

                                                                     Well-standardized diagnostic tests are
                                                                     available for IgE-mediated food allergy
        Diagnosis: Lab Evaluation                                    disorders. Intradermal skin testing should
                                                                     not be used for diagnosis of food allergy
     • IgE-mediated                                                  because of the risk of systemic reaction and
         – PST ( fresh food for PFAS)
         – Serum food-specific IgE                                   high rate of false positive results. Prick skin
     • Non-IgE-mediated                                              testing with commercial food allergen
         – Biopsy                                                    extract has a high negative predictive value
         – Atopy patch test ???
     • Non-allergic:
                                                                     >95%, whereas a positive skin test has only
         – Breath hydrogen test                                      a 30-50% positive predictive value. In
         – Sweat test                                                infants and young children, large prick skin
         – Biopsy
                                                                     test wheal (mean size 8-10 mm) is
                                                                     associated with high > 95% likelihood of
                                                                     clinical reactivity to cow’s milk, egg and
                                                                     peanut. In patients with pollen-food allergy
                                                                     syndrome caused by raw fruits and
                                                                     vegetables, testing with raw fruit is typically
more sensitive than testing with the commercial extract of fruit because the responsible allergens are
very unstable and disintegrate during the allergen extraction process. Prick-prick method involves
puncturing the fruit through the peel and then puncturing the skin. Prick skin testing will become more
sophisticated and accurate with the availability of recombinant food allergens Recombinant allergens
of high purity offer superior safety and specificity in allergy testing, although diagnostic sensitivity is
generally lower than of allergen extracts. Recombinant allergens may be of special value in
diagnosing allergy to plant foods in subjects with allergy to pollens.
                                                                     It must be emphasized that the guidelines
                                                                     for interpretation of skin test and serum
                                                                     food-IgE levels evolve with more available
        Diagnostic Decision Points                                   evidence. Some studies suggest that there
                                                                     may be regional differences and that
    Food                                          SPT wheal (mm)+
                       Serum       food-IgE                          different standards may be needed for
                   (kIU/L)*
                                                                     interpretation depending on the country.
               ∼95% Fail ∼50% Fail           ∼95% Fail ∼50% Fail     A child older than 2 years with milk-IgE
    Cow’s milk 15           2                8                       antibody level > 15 kIU/L is highly (>95%)
               5 (<1 yr)                     7                       likely to react during an oral milk challenge
                                             8
    Egg white 7             2                          3 (EW IgE <2) and milk challenge should be deferred
               2 (<2 yr)                                             unless there is a compelling evidence that
    Peanut     14           2 (Hx+), 5 (Hx-)           3
    Fish       20
                                                                     the child tolerated a significant amount of
                                                                     milk without a reaction. Food-specific IgE
                                                                     antibody levels below the decision points
                                                                     indicate decreasing likelihood of reaction
                                                                     that need to be determined with OFC.
                                                                          Oral food challenges (OFC) remain the
                                                                          most accurate method for diagnosing food
        Interpretation of Allergy Tests                                   allergy. OFC can be utilized for diagnosing
                                                                          IgE-mediated as well as for non-IgE
       Serum IgE                       Prick skin test                    mediated food allergy. OFC can be done to
                                                                          confirm whether the suspected food is
                                                                          indeed causing problems or to determine if
                                            Peanut
                                                                          a person with known food allergy might
                                                                          have lost reactivity to food (“outgrew” food
                                                                          allergy). OFC are particularly useful
                                                                          because IgE antibodies persist after clinical
                                                                          reactivity has cleared. With increasing IgE
                                                                          antibody concentration there is an increase
          Sampson and Ho, JACI, 1997
                                           Roberts and Lack, JACI, 2004
                                                                          in risk of clinical reactions but the curve is
          Sampson, JACI, 2001
                                                                          distinct for each food and may vary with age
                                                                          and atopic disorder. In general, severity of
                                                                          the reaction does not correlate well with IgE
                                                                          level.
                                                                          During an oral food challenge for an IgE-
                                                                          mediated food allergy, a pre-measured
        Diagnosis: Elimination Diet                                       amount of food (typically 8-10 gram of dry
           and Food Challenges                                            food or 80-100 ml of liquid food) mixed with
                                                                          a masking food that is well tolerated by the
    • Elimination diet (1-6 weeks)                                        patient is administered in small increments
       – Elimination of suspected foods                                   every 10-15 minutes over 90 minutes. OFCs
       – “Rx foods”: e.g 5 foods only diet                                can be open (both patient and person
       – Elemental formula                                                administering the challenge know what food
                                                                          is administered) or blinded, placebo
    • Physician-supervised oral food challenge                            controlled. In a placebo-controlled
       – Open                                                             challenge, two 90 minute sessions (one with
       – Single-blind                                                     real food, one with placebo food) may be
       – Double-blind, placebo-controlled (DBPCFC)                        separated by a 90 minute break and
                                                                          completed on a single day or each session
                                                                          may be done on separate days.



The double-blind, placebo controlled food challenge is considered a gold standard for diagnosis of
food allergy and is a preferred type of a challenge in research setting or in patients in whom anxiety
may interfere with interpretation of symptoms. Placebo-controlled OFCs in which the patient tolerated
both sessions without a reaction are always followed by an open challenge, during which a regular
portion of food is ingested by a patient over a 30 minute period. OFCs are stopped at the first sign of
an objective reaction such as hives, rhinorrhea, sneezing, coughing, or vomiting. Patients are
observed for at least 2 hours following a completion of an open challenge. In patients with FPIES, the
amount of food for challenge is calculated as 0.15 to 0.3 g protein / kg body weight (not to exceed 3 g
of protein or 10 g of whole food) and administered gradually in 3 feedings over 45 minutes. If the
patient remains symptom-free for 4 hours, a second dose is given, generally a serving amount
followed by 2-3 hours observation. OFCs are always conducted under physician supervision in a
controlled environment with emergency medications (epinephrine, diphenhydramine,
methylprednisolone, and volume expanders) immediately available to treat an allergic reaction.

Patients with asthma, a history of severe reactions, or at higher risk for having a positive challenge
and all patients with FPIES must have an intravenous line in place before starting a challenge for an
immediate vascular access in case of hypotension. Double-blind placebo controlled food challenges
can be completed during one day or sessions may be conducted on separate days. Patients with AEE
or AEG, whose food-induced symptoms are delayed, may require prolonged challenges over several
days.
                                                             Caution is warranted in case of history of
                                                             convincing severe reactions to a suspected
      Diagnosis: IgE-Mediated FA                             food even in the setting of negative tests. In
                                                             such cases, physician-supervised OFC may
     • IgE                                                   be advisable. Reports from children with AD
          – Negative: reintroduce food*                      found that following a period of dietary food
          – Positive: start elimination diet                 avoidance, the pattern of symptoms
     • Elimination diet                                      induced by food ingestion may change from
                                                             eczematous type rash to more acute,
          – No resolution: reintroduce food*
                                                             immediate skin and systemic reactions.
          – Resolution
              • Open/SB OFC to screen
              • DBPCFC for equivocal OFC

  * Unless convincing history warrants a supervised OFC




                                                             Prick skin test and measurement of serum
                                                             food-IgE antibody concentration are not
          Diagnosis: Non-IgE-Mediated FA                     helpful in food allergic disorders with non-
                                                             IgE, cell-mediated mechanism, such as
      •   Elimination diet                                   FPIES and have limited usefulness in
      •   APT? – not standardized
                                                             disorders with mixed mechanism, such as
                                                             AEE and AEG. Recently patch testing for
      •   Endoscopy and biopsy
                                                             the diagnosis of food allergy in children with
      •   OFC                                                AD and AEE has been investigated in a
          – Protocol customized based on type of symptoms:
            FPIES may cause shock within 2-4 hours,
                                                             number of studies. Patch testing is typically
            AEE/AEG require prolonged feeding to induce      used for diagnosis of delayed contact
            symptoms                                         hypersensitivity reactions in which T cells
          – Blinded challenges preferred                     play prominent role and involves prolonged
                                                             contact of the allergenic extract with intact
                                                             skin under occlusion for 48 hours. The
                                                             results are evaluated 20 minutes and 72
                                                             hours after removing the patch.



A positive reaction to patch tests consists of erythema and induration. In children with challenge-
proven milk allergy, prick skin tests were positive in 67% of the cases with acute-onset reactions
(under 2 hours) to milk challenge, whereas patch tests tended to be negative. Patch tests were
positive in 89% of children with delayed-onset reactions (25-44 hours), although prick skin tests were
frequently negative. In another study of children with atopic dermatitis, the combination of a positive
patch test with evidence of specific IgE or with positive prick skin test had highest positive predictive
value. These results indicate that combination of patch testing and detection of IgE could enhance the
accuracy of diagnosis of food allergy and eliminate the need for oral food challenges. However, before
incorporating atopy patch testing into clinical practice, standardization of the reagents, timing of the
results reading, and scoring system for the interpretation of the results are necessary.

For gastrointestinal food allergy disorders such as AEE and AEG, ultimate diagnosis is established by
biopsying of the mucosa and finding increased numbers of eosinophils. Non-invasive diagnostic tests
are highly desirable but currently available laboratory techniques offer rather limited insight into these
conditions. Peripheral blood eosinophil numbers can be followed in approximately in 50% of subjects
with AEE/AEG. Testing stool samples for occult blood may be useful in a subset of patients in whom
gastrointestinal inflammation results in microscopic bleeding. Patients with AEG and protein-losing
gastroenteropathy can be followed with serial evaluations of serum albumin, total protein, and
immunoglobulins (low IgG with preserved IgM and IgA). Measurements of stool alpha1-antitrypsin may
be used to approximate gastrointestinal protein loss.
                                                                     Management of food allergy currently
                                                                     focuses on dietary avoidance of the
    Treatment: Dietary Elimination                                   offending foods, prompt recognition and
                                                                     treatment of food allergic reactions, and
    • Guidelines for avoidance                                       nutritional support. Educating patients how
    • Awareness of cross-contamination from                          to read food labels is very important
      shared equipment                                               because common foods may be labeled
                                                                     using non-intuitive terms. Patients
    • Dietitian evaluation
                                                                     commonly make mistakes and are unable to
                                                                     identify the food allergens in store-bought
                                                                     foods correctly; in a recent study only 7% of
                                                                     parents of children with milk allergy were
                                                                     able to correctly identify products that
                                                                     contained milk and 22% of parents of
                                                                     children with soy allergy were able to
                                                                     correctly identify products that contain soy.

Children with food allergy, particularly those with multiple food allergy are at risk for nutritional
deficiencies as a result of restricted diets. Nutritional support may be limited to calcium
supplementation in children avoiding dairy or may be extensive in children on severely restricted diets.
Children allergic to multiple major food allergens are at risk for protein and calorie deficiency, and may
require a hypoallergenic formula to meet their needs. Hypoallergenic formulas available in the US are
either based on extensively hydrolyzed casein derived from cow’s milk (Pregestimil, Nutramigen,
Mead Johnson; Alimentum, Ross) or on a mixture of single aminoacids (Neocate, SHS; Elecare,
Ross). Hypoallergenic formulas are well tolerated by children with IgE-mediated and with cell-
mediated food allergy.

Another impediment faced by food allergic patients is undisclosed contamination with trace amounts of
food resulting from sharing of equipment. Current industry cleaning standards, although very stringent,
are not sufficient to prevent contamination with trace amounts of food allergens that may trigger
severe reactions in highly sensitive food allergic individuals. Families of patients with food allergies
need information on how to cook safely foods at home and how to handle school, travel, and social
situations such as parties and dining. An excellent resource is the Food Allergy and Anaphylaxis
Network (www.foodallergy.org) that provides practical advice on dietary avoidance, “survival
strategies” for school, restaurants, camps, manufacturers’ updates and special support programs for
teens. American Partnership for Eosinophilic Disorders website (www.apfed.org) contains useful
information for patients with eosinophilic gastroenteropathies.
             Food Allergen Labeling and
              Consumer Protection Act                                   Treatment: Emergency Management
                                                                         • Clear emergency plan in writing
    • Effective January 1, 2006
                                                                         • Emergency identification bracelet
    • Content of milk, eggs, fish, crustacean shellfish, peanuts,
      tree nuts, wheat, and soy must be declared in plain                • Prompt recognition of symptoms
      language                                                           • Intramuscular epinephrine
    • listed even if they are present in colors, flavors, or spice          – Self-injectable device
      blends.                                                               – EpiPen Jr / Twinject Jr 0.15 mg, under 66 lbs
                                                                            – Epi Pen / Twinject 0.3 mg, over 66 lbs
    • Such ingredients must be
    • Specific nut or seafood that is used (e.g., almond, walnut,        • Oral antihistamines (secondary therapy)
      cashew; or tuna, salmon, shrimp, or lobster) must be                  – Benadryl syrup, 1-1.5 mg/kg/dose
      declared
                                                                         • Follow up in the ED or call 911
    IMPORTANT:
    FALPCA does not cover other food allergens: seeds, garlic,
                                                                         • 4-hour observation period
      spices, etc.


In spite of strict avoidance, accidental ingestions and exposures occur and every food allergic patient
must always be prepared to recognize symptoms and treat food allergic reaction. In children with
peanut allergy, 50% reported reactions to peanuts despite avoidance over 2 year period. Individuals
with history of immediate allergic reactions, anaphylaxis, those with asthma, and those with allergy to
foods typically associated with severe reactions (i.e., peanut, tree nuts, fish, shellfish) should be
prescribed an epinephrine auto-injector (EAI). A clear emergency treatment plan indicating symptoms
that require treatment with oral antihistamine and/ or epinephrine must be provided to the patient by
an allergist or primary physician. Templates of anaphylaxis emergency treatment plans may be
downloaded from the www.foodallergy.org or from www.foodallergyinititive.com websites.
Administration of the EAI should be demonstrated to the patient and the technique reviewed
periodically. A single demonstration is not sufficient for most patients. Patients frequently forget to
carry their EAI with them and to check the expiration date. These issues should be reviewed regularly
during follow up visits. Patients must be instructed to seek evaluation in the emergency room following
the use of an EAI. Given the approximately 20% risk of recurrence of allergic symptoms following
initial improvement with or without treatment (so called biphasic anaphylaxis), a minimum 4 hour
observation period is recommended. Medic Alert bracelets indicating food allergy and specifying
treatment needed in case of a sudden reaction are helpful for older children and adults.
                                                             Periodic evaluations are recommended,
                                                             especially for children who mostly outgrow
            Treatment: Follow-Up                             food allergy.

    • Periodic re-evaluations: children every
      6-12 months
    • Decision to perform an OFC
          • No recent reactions (past 6-12 months)
          • No severe anaphylaxis in the past 24 months
          • PST/ serum food-IgE negative or significantly
            decreased from previous evaluation
          • Nutritional or social importance of the food




              Natural History                               Food allergy to cow’s milk and egg is
                                                            outgrown by most children. 85% of milk
  • Milk, egg, wheat and soy allergy majority               allergic children and 66% of egg-allergic
    resolve by school-age                                   children become food tolerant by age 5
  • Peanut, tree nuts and seafood                           years, although recent study by Skripak et
     – 20% of young children outgrow peanut, 9%             al suggested that the age of outgrowing milk
       tree nuts; 7-9% recurrence of PN allergy             allergy for children with multiple food
       (increased risk if not ingested regularly)           allergies may be older. In contrast, only
  • Non-IgE-mediated GI allergy                             approximately 20% of all children with
     – Infant forms resolve 1-3 years                       peanut allergy become peanut tolerant.
     – Toddler/adult forms more persistent
However, children with peanut-IgE antibody level <5 kIU/L have at least 50% chance of tolerating
peanut. Periodic evaluation should be offered to children with peanut allergy and OFC to peanut
should be considered in patients who have not had reactions in the past 1-2 years and who have
peanut IgE level <5.0 kIU/L. Unlike milk and egg allergy, peanut allergy can recur in children who
outgrew peanut allergy. It appears that risk of recurrence is approximately 10% in children who refuse
to eat peanut on regular basis compared with no recurrences in children eating peanut regularly. We
recommend that the possibility of peanut allergy recurrence is discussed prior to offering OFC to
peanut and that patients ingest peanut frequently following a negative OFC. EAI should be carried
until patient had proven tolerance to multiple ingestions of regular servings of peanut and peanut-
containing foods. It appears that tree nuts, seeds, fish and shellfish are generally not outgrown, similar
to peanut.

Little information exists regarding the course of food allergy in adults. In one study, 10 adults with
DBPCFC-confirmed allergy to 13 foods were followed for 1 to 2 years. Upon re-challenge, 38% of 13
foods were well tolerated, including milk in 2 patients and wheat, egg, and tomato in 1 patient each.
The 2 patients with nut allergy, 2 patients with milk allergy, and 1 patient each with potato, garlic, and
rice remained reactive.

Food allergy can be viewed as a marker of an atopic predisposition. In many children food allergy
coexist with other atopic conditions such as AD, asthma and allergic rhinitis. Sensitization to egg white
in children with atopic dermatitis is associated with 70% risk of respiratory allergic disease (asthma or
allergic rhinitis) at the age 5 years. Therefore, subjects with past and current food allergy should be
considered at high risk for asthma and environmental allergy.

         Food Allergy Prevention:                                    Food Allergy Prevention:
            AAP Report 2008                                             AAP Report 2008
    1. No evidence for protective effect of dietary maternal   5. There is no convincing evidence for the use
       restrictions during pregnancy and lactation
                                                                 of soy formula for allergy prevention
    2. For infants at high risk of atopy, exclusive breast-
       feeding for at least 4 months decreases cumulative      6. There is no evidence that delayed intro solid
       incidence of AD in the first 2 years                      beyond 4-6 months has a protective effect
    3. Exclusive BF for at least 3 months protects against
                                                               7. For infants older than 4-6 months, there is no
       wheezing in early life but not beyond 6 years
    4. For high risk infants feeding with extensively
                                                                 sufficient data to support a protective effect of
       hydrolized formula protects from development of AD        dietary intervention
       in early childhood.
                                                               • Pediatrics 2008; 121;183-191




New report from AAP was released recently and revised previously published guidelines. The report
emphasizes inconclusive research on the value of extensive maternal dietary restrictions during
pregnancy and lactation for prevention of atopic diseases and delayed introduction of solid foods past
4-6 months of age.

The documented benefits of nutritional intervention that may prevent or delay the onset of atopic
disease are largely limited to infants at high risk of developing allergy (ie, infants with at least 1 first-
degree relative [parent or sibling] with allergic disease). Current evidence does not support a major
role for maternal dietary restrictions during pregnancy or lactation. There is evidence that
breastfeeding for at least 4 months, compared with feeding formula made with intact cow milk protein,
prevents or delays the occurrence of atopic dermatitis, cow milk allergy, and wheezing in early
childhood. In studies of infants at high risk of atopy and who are not exclusively breastfed for 4 to 6
months, there is modest evidence that the onset of atopic disease may be delayed or prevented by the
use of hydrolyzed formulas compared with formula made with intact cow milk protein, particularly for
atopic dermatitis. Comparative studies of the various hydrolyzed formulas also indicate that not all
formulas have the same protective benefit. There is also little evidence that delaying the timing of the
introduction of complementary foods beyond 4 to 6 months of age prevents the occurrence of atopic
disease. At present, there are insufficient data to document a protective effect of any dietary
intervention beyond 4 to 6 months of age for the development of atopic disease.
                                                   Novel approaches to the treatment of IgE-
                                                   mediated food allergy such as anti-IgE antibodies,
    Food Allergy: Future Therapy                   food allergy vaccines, herbal preparations and
                                                   probiotics will hopefully provide definitive therapy
                                                   for food allergic patients and prevent development
    • Recombinant anti-IgE                         of food allergy in at risk infants. However, these
    • Oral desensitization/sublingual IT           immunomodulatory therapies will have to be
    • Chinese herbs                                carefully evaluated for potential side effects, over-
                                                   stimulation of Th1 immune responses, priming of
    • Recombinant hypoallergenic peanut            autoimmune reactions, and long-term effects of
      expressed in E.coli                          suppression of circulating IgE antibodies.
    • DNA therapy                                  Nevertheless, these new approaches bring real
                                                   hope to the patients for whom no specific therapy
    • Probiotics
                                                   is currently available.




                                                   The history and physical examination are crucial
                 Summary                           for accurate food allergy diagnosis. The diagnosis
                                                   includes laboratory tests as well as elimination
   • Positive test results must be interpreted     diet and oral food challenges. Current
     in the context of clinical history            management relies on avoidance and nutritional
   • Testing should be judicious                   support and treatment of acute reactions. Periodic
   • Elimination diet and OFC                      re-evaluations with laboratory tests and oral food
   • Patient education re avoidance and            challenges are required to monitor for tolerance
     anaphylaxis management                        development.
   • Nutritional consultation
   • Periodic re-evaluations with skin/blood
     tests and OFC



BONUS: Peanut allergy (PNA) clinical pearls:
Prevalence of PNA is estimated at 1%; it has doubled in young children in USA, Canada and UK in the
past decade.
Sibling of a child with PNA has 7% chances of having PNA, thus siblings should be tested before
introducing peanut.
PNA may resolve (about 20% of young children).
PNA may recur following a passed OFC: about 8% recurrence rate.
PNA is associated with TNA in 25-50% of patients.
Legumes are typically well tolerated by >90% of patients with PNA despite 50% rate of positive IgE
(PST, serum); lupine, lentil and chickpea may present higher risk (up to 40% clinical reactions in
persons with PNA)
Typical reactions occur to about 1 kernel of peanut but reactions may occur to trace amounts (0.1-10
mg).
FOOD ALLERGY
Anna Nowak-Wegrzyn, MD, Mount Sinai School of Medicine, New York, NY

No disclosures

Learning Objectives:
Upon completion of this activity, participants should be able to:
1. Explain prevalence of food allergy
2. Understand pathophysiology of food allergy
3. Be familiar with manifestations of food allergy
4. Be familiar with interpretation of diagnostic laboratory testing and utilization of oral food challenges
5. Understand the principles of managing food allergy
6. Be familiar with most promising future approaches to food allergy therapy

The content of this handout is based on the following review articles:
(1) Sicherer SH, Sampson HA. 9. Food allergy. J Allergy Clin Immunol 2006; 117(2 Suppl Mini-
Primer):S470-S475.
(2) Food Allergy: A Practice Parameter. Ann Allergy Asthma Immunol 96[3, Supplement 2]. 2006.
(3) Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004; 113(5):805-819.
(4) Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin
Immunol 2005; 115(1):3-12.
(5) Sicherer SH, Teuber S. Current approach to the diagnosis and management of adverse reactions
to foods. J Allergy Clin Immunol 2004; 114(5):1146-1150.
(6) Nowak-Wegrzyn A, Sampson HA. Food allergy therapy. Immunol Allergy Clin North Am 2004;
24(4):705-25, viii.
(7) Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of
atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of
introduction of complementary foods, and hydrolyzed formulas Pediatrics 2008; 121(1):183-191.
(8). Sicherer SH, Sampson HA. Peanut allergy: emerging concepts and approaches for an apparent
epidemic. J Allergy Clin Immunol 2007; 120(3):491-503.
(9). Sicherer S.H. Food allergy. Syllabus. Board Review Course 2007.

The following topics will be reviewed:
   • Definition / differential diagnosis
   • Prevalence
   • Pathophysiology
   • Specific food allergy disorders
   • Diagnosis and management
   • Natural history
   • Prevention of food allergy
   • Novel therapies for food allergy

                                                                              IgE-mediated food allergy reactions typically
            Food Allergy=                                                     start within minutes to 1 hour (rarely past 2
    Immune System-Mediated Adverse                                            hours) and may affect skin (urticaria,
            Food Reaction                                                     angioedema, morbilliform eruptions,
                                                                              flushing, pruritus), respiratory tract
IgE-Mediated                Mixed               Non-IgE-Mediated
                                                                              (sneezing, rhinorrhea, congestion, cough,
   Anaphylaxis; FDEIA
                                                                              wheezing, difficulty breathing), and
                                                                              gastrointestinal tract (pollen-food allergy
                                                Dermatitis herpetiformis
   Urticaria / Angioedema   Atopic dermatitis                                 syndrome, nausea, vomiting, diarrhea,
                                                                              crampy abdominal pain). Generalized
   Immediate GI symptoms    AEE/AEG             Celiac disease; Enteropathy   reactions, involving cardiovascular system
   PFAS
                                                FPIES                         (tachycardia, hypotension) are called
                                                Allergic proctocolitis
                                                                              anaphylactic shock. Mixed and cell-
                                                                              mediated mechanisms typically have
   Bronchospasm             Asthma              Heiner’s syndrome             delayed onset of symptoms (> 2 hours) and
                                                                              a chronic relapsing course.
                                                                 Food allergy must be distinguished from a
                Non-Immune Mediated                              variety of adverse reactions to foods that do
               Adverse Food Reactions                            not have an immune basis but may
                                                                 resemble food allergy in clinical
                                                                 manifestations.
      Toxic / Pharmacologic        Non-Toxic/ Intolerance
                                                                 Toxic reactions are host-independent and
                                                                 can be elicited in anyone who ingests a
                                  Lactase deficiency
       Food poisoning
                                  Galactosemia
                                                                 sufficient quantity of the tainted food. Non-
       Scombroid fish
                                  Pancreatic insufficiency       toxic reactions are dependent upon host
       poisoning
       Histamine
                                  Gallbladder / liver disease    factors and are referred to as intolerances.
       Tyramine
                                  Panic, anxiety                 Examples include lactose intolerance due to
                                  Depression, anorexia, bulimia
       Caffeine                   Hiatal hernia
                                                                 disaccharidase deficiency, metabolic
       Alcohol                    Gustatory rhinitis             disorders, pancreas or liver disease,
                                  Auriculotemporal syndrome      psychiatric disorders, anatomic defect,
                                  Blepharochalasis               neuronally-mediated disease (gustatory
                                                                 rhinitis-rhinorrhea from spicy foods), or
                                                                 auriculotemporal syndrome.*
*Frey’s syndrome: transient uni or bilateral facial flushing or sweating following ingestion of spicy or
flavored foods, infants and children with history of forceps delivery and damage to auriculotemporal
nerve.
                                                                 In spite of the tremendous diversity of the
                                                                 human diet, relatively few foods account for
                      Food Allergens                             the majority of food allergies. In the USA,
       Children              Adults                              milk, egg, peanut, wheat and soybean are
                                                                 the most common culprits in children;
       6-8% affected         2-4 % affected
                                                                 whereas peanut, tree nuts, fish and shellfish
            Milk
            Egg
                              Peanut                             are the most common culprits in adults.
                              Tree nuts
            Peanut
                              Fish
                                                                 Raw fruits and vegetables are responsible
            Soybean
            Wheat
                              Shellfish                          for pollen-food allergy syndrome that affects
            Tree nuts
                              Fruits/vegetables in PFAS (50-75%)
                                                                 approximately 50% of adults with rhinitis
            Fish                                                 caused by birch pollen.
               Shellfish




Modern diets that routinely include exotic foods as well as a variety of fresh fruits and vegetables have
resulted in an increase in allergic reactions to fruits such as kiwi and papaya, and seeds, such as
sesame, poppy, mustard, and rape (canola).
                                                                Food allergy affects about 6% of infants and
                                                                young children and approximately 3.5-4% of
       Prevalence of Food Allergy-                              adults. The most common food allergens in
           General Population                                   the pediatric population include cow’s milk,
                                                                egg, peanut, tree nuts, soy, wheat, fish and
                           Young children            Adults     shellfish, whereas peanut, tree nuts, fish
     Cow’s milk            2.5%                      0.3%       and shellfish prevail in adults. Recent
     Egg white             1.3%                      0.2%       studies reported doubling of peanut allergy
     Peanut*               0.8%                      0.6%       in young children. A 5-year follow up study
     Tree nuts             0.2%                      0.5%       of peanut and tree nut allergy utilizing a
     Fish                  0.1%                      0.4%
                                                                random digit dial telephone survey found
     Shellfish             0.1%                      2.0%
                                                                that in comparison with the 0.4%
     Overall               6%                        3.7%
                                                                prevalence of peanut allergy in American
     Prevalence doubled in the past decade in USA, Canada, UK
                                                                children 5 years of age or younger in 1997,
                                                                there was an increase to 0.8% in 2002.

Similarly, results reported from Isle of Wight in the UK indicated a doubling of clinical peanut allergy
and a tripling of IgE peanut sensitization in young children over a period of 10 years.
                                                                                   Food allergy remains the leading single
                                                                                   cause of anaphylaxis outside the hospital
            Prevalence of Food Allergy-                                            and an increasing trend has been noted in
                Specific Disorders                                                 recent years. More than 50% of adults with
                                                                                   birch pollen allergic rhinits report symptoms
                                                                                   of PFAS. Children with moderate to severe
                                                                                   persistent atopic dermatitis have a higher
     Anaphylaxis                         35-55%                                    prevalence of IgE-mediated food allergy,
     PFAS, adults                        25-75%
                                                                                   estimated at about 35%.
                                                                                   In addition, there is a significant increase in
     Atopic dermatitis, children         37% (moderate-severe, persistent)
                                                                                   reports of eosinophilic gastroenteropathies
     Atopic dermatitis, adults           Rare
                                                                                   such as allergic eosinophilic esophagitis
     Urticaria, acute                    20%                                       and allergic eosinophilic gastroenteritis,
     Urticaria, chronic                  Rare (4% children; 1.4% adults)           which in a subset of patients are due to
     Asthma, childhood, general          5-6%                                      dietary food protein hypersensitivity. Finally,
     Chronic rhinitis                    Rare                                      it has been recently appreciated that up to
                                                                                   50% of gastroesophageal reflux in infants
                                                                                   younger than 1 year may be caused by
                                                                                   hypersensitivity to dietary food proteins,
                                                                                   mainly cow’s milk and soybean.

                                                                                   Cooking can reduce the allergenicity of
                          Food Allergens                                           fruits and vegetables responsible for the
                                         • Class II
 • Class I                                                                         pollen-food allergy syndrome, and with
 • Water-soluble glycoproteins           • Plant-derived
                                         • Highly homologous with
                                                                                   cooked versus raw or undercooked egg and
 • 10-70 kDa
                                           pollen                                  fish, by destroying heat-labile
 • Resistant to heat, acid and
   proteases                             • Highly heat labile, cooking             conformational allergenic epitopes. In
                                           reduces allergenicity
 • Sensitization: G.I.                                                             contrast, high temperatures (e.g. roasting)
                                         • Sensitization: Respiratory to
      Protein             Nomenclature     cross-reactive pollen                   can increase allergenicity of certain
      Cow’s milk                                                                   allergens such as peanut through the
       Caseins
                                         Protein                    Nomenclature   induction of covalent binding that leads to
       Whey
       β-lactoglobulin    Bos d 5        Birch Bet v 1 homologous
                                                                                   new antigens or improved stability.
      Chicken egg white
       Ovalbumin          Gal d 1
                                         (PRP-10)                                  Traditional or class I food allergens induce
                                          Apple                     Mal d 1
       Ovomucoid          Gal d 2         Carrot                    Dau c 1        allergic sensitization via the gastrointestinal
      Peanut
       Vicilin            Ara h 1
                                          Celery
                                         Birch bet v 2 homologous
                                                                    Api g 1        tract and are responsible for systemic
       Conglutin          Ara h 2        (profilin)                                reactions (traditional or class I food allergy).
       Glycinin
      Wheat
                          Ara h 3         Latex
                                          Celery
                                                                    Hev b 8        Type I food allergens are typically heat- and
                                                                    Api g 4
       ω-5 gliadin        Tri a 19                                                 low pH- stable, water-soluble glycoproteins
                                                                                   ranging in size from 10 to 70 kD.


Type II food allergens are heat-labile and susceptible to digestion. Type II food allergens are highly
homologous with proteins in pollens and sensitization occurs in the respiratory tract as a consequence
of sensitization to the cross-reactive pollen allergens (pollen-food allergy syndrome or class II food
allergy).

A single food contains many proteins; areas of protein that bind IgE or interact with T cells are called
the epitope. Epitopes may be comprised of amino acid residues that are brought together by protein
folding are called “conformational”, whereas epitopes comprised of sequential amino acids and not
dependent on protein folding, are called “linear” epitopes.
                                                                       Immaturity of the immune system and
                  Gut Mucosal Barrier                                  gastrointestinal tract predisposes young
                                                                       infants to food allergy. Compared with older
     • Immaturity of gut barrier in infants and young children children and adults, infants and young
          – ↑ intestinal permeability                                  children have an immature glycocalyx,
          – ↑ gastric pH                                               decreased gastric acidity, as well as
          – ↓ activity of the proteolytic enzymes                      decreased intestinal and pancreatic enzyme
          – ↓ secretion of IgA                                         activity. The intestinal permeability is
          – ↑ T cell reactivity toward food Ags
                                                                       increased, resulting in higher concentrations
     • 2% of ingested food Ags are absorbed in an “intact              of intact food proteins in the circulation and
        form” → food-IgG in tolerant individuals                       likely leading to stimulation of the immune
                                                                       system and development of IgE-
     • Factors inreasing intestinal permeability associated            sensitization. The mucosal immune
        with FA                                                        response is immature; surface secretory IgA
          – ASA
                                                                       concentration is lower but T lymphocyte
          – Alcohol
          – Exercise
                                                                       reactivity to food proteins is increased. Early
          – Infection (virus)                                          introduction of food allergens have been
                                                                       shown to stimulate IgE antibody production
                                                                       and induce allergic conditions in
                                                                       predisposed infants.
Impaired mucosal gut barrier and the resulting increased intestinal permeability has been proposed as
one of the important factors contributing to the development of food allergy in infants and young
children. During the first two years of life, gradual maturation of the intestinal barrier corresponds to
decreased prevalence of food allergy and may be associated with the process of “outgrowing” food
allergy.
                                                                       Even in the mature gut, about 2% of
                  Oral Tolerance                                       ingested food allergens are absorbed and
                                                                       transported throughout the body in an
     • GALT largest secondary lymphoid organ, 5x1010                   immunologically intact form. However in
       cells in an adult
                                                                       most individuals these food proteins do not
     • Soluble antigens →specific non-responsiveness                   cause clinical symptoms because of oral
         – Low Ag dose: ↑ TGF-β, IL-10 and IL-4 in the Peyer’s patches tolerance-the physiological mucosal
         – High Ag dose: anergy or deletion of reactive T-cells and    immune response to soluble antigens such
           induction of allergen-specific CD8 suppressor T cells       as in foods, resulting in a state of
     • Endogenoues gut bacterial flora: animals in                     unresponsiveness. Oral tolerance is
       germ-free environment from birth fail to acquire                hypothesized to result from T cell anergy or
       normal tolerance                                                induction of regulatory T cells. Intestinal
                                                                       epithelial cells act as non-professional
     • Ingested Ag penetrates the gut barrier →immune                  antigen presenting cells and induce
       responses in the absence of food allergy                        tolerance. In addition, intestinal dendritic
         – PCA: rapid Ag uptake
                                                                       cells express interleukin-10 (IL-10) and
         – IgE receptor facilitates Ag uptake in sensitized mice
                                                                       interleukin-4 (IL-4) which favor the
                                                                       generation of tolerance in vivo.

The regulatory T cells that are potent sources of tumor growth factor- β (TGF-β) are generated in
mucosal lymphoid tissue in response to low-dose antigen. The gut flora is also believed to play a
significant role in the induction of normal mucosal immunity because animals raised in a germ-free
environment fail to develop normal tolerance. Childhood food allergy therefore can be viewed as a
failure to develop oral tolerance in the setting of immature gastrointestinal and immune systems.

When immune tolerance fails, sensitization to ingested food allergens occurs. In genetically
predisposed, atopic individuals, sensitization leads to the generation of allergic IgE antibodies that
facilitate immediate reactions such as food-induced anaphylaxis, urticaria, angioedema,
bronchospasm or gastrointestinal symptoms of emesis and diarrhea. In others, allergic sensitization
affects mainly T lymphocytes without generation of IgE antibody. Such non-IgE, cell-mediated food
allergic disorders are represented by allergic proctocolitis and food protein-induced enterocolitis
syndrome. Atopic dermatitis and allergic eosinophilic gastroenteritis are examples of disorders with
mixed mechanism, in which both IgE antibody and cell immunity may play a role.
     Antigen Sampling in the GI Tract                                                             Antigen-presenting cells, especially
                                                                                                  intestinal epithelial cells and regulatory T
                          Soluble Ag
                          uptake                                                                  cells play a central role in oral tolerance.
                                                                                                  Five regulatory T cells have been identified
                                                                                                  in conjunction with mucosal immunity:Th3
                                                                                                  cells, a population of CD4+ cells that secret
                                 Particulate Ag and                                               TGF-beta; TR1 cells, CD4+ cells that secret
                Lamina propria
                                 receptor mediated




                                                            Lamina propria
                                 uptake                                                           IL-10; CD4+ cells that secrete IL-1; CD4+,
                                                                              Intraepithelial
                                                                              lymphocytes
                                                                                                  CD25+ regulatory T cells; CD8+suppressor
                                                                                                  T cells, and gd T cells.
                                                                                                  Intestinal epithelial cells process luminal
                                                        M cell                                    antigen and present it to T cells on an MHC
                                                                             CD8 T cells          class II complex, but lack a “second signal”,
                                        PP                                   activation
            Th3 T cells                               sIgA B cells                                suggesting their potential to play a role in
            CD4 T cells                                                           Meyer L, 2000   tolerance induction.



Properties of antigens, dose and frequency of exposure also influence tolerance induction. Dendritic
cells residing in the lamina propria and non-inflammatory environment of Peyer’s patches express IL-
10 and IL-4, which favor the generation of tolerance. High dose tolerance involves deletion of effector
T cells, while low dose tolerance is mediated by activation of regulatory T cells with suppressor
function.
                                                                                                  Anaphylaxis represents the most severe
          Food-Induced Anaphylaxis                                                                form of IgE-mediated food allergy and is
                                                                                                  clinically defined as a food-allergic reaction
    • Rapid onset, multi-system, potentially fatal                                                involving two or more organ systems. In
                                                                                                  extremely sensitive individuals reactions
    • Course: may be biphasic in about 20%                                                        can be triggered by minute amounts of food
    • Tryptase level not elevated                                                                 proteins. Symptoms start within seconds to
    • Any food, highest risk: peanut and tree nuts                                                2 hours following allergen ingestion and
                                                                                                  include feelings of “impending doom”, throat
    • Risk factors for fatality:                                                                  tightness, coughing or wheezing, abdominal
       – Delayed epinephrine;                                                                     pain, vomiting, diarrhea, and loss of
       – Young adult/ teenager;                                                                   consciousness. Cutaneous symptoms of
                                                                                                  flushing, urticaria, and angioedema are
       – Underlying asthma;                                                                       present in the majority of the anaphylactic
       – Absence of cutaneous symptoms                                                            reactions; however, the most rapidly
    • FDEIA:                                                                                      progressive anaphylaxis may involve no
                                                                                                  cutaneous manifestations.
          – Specific food (wheat, celery, fish), or any food;
          – Severity increased with co-administration of alcohol and
            NSAIDs/ASA




                                                                                                  Acute urticaria and angioedema are the
        Food-Induced Urticaria and                                                                most common manifestations of acute
                                                                                                  allergic reactions to ingested foods in
               Angioedema
                                                                                                  children and adults. Onset of symptoms
   • ACUTE:                                                                                       may be rapid, within minutes of ingesting
        – <6 weeks duration                                                                       the responsible food. Skin involvement may
        – Onset within minutes to 1-2 hours following
          food ingestion
                                                                                                  be isolated or associated with other organ
        – The most common sign in immediate FA                                                    systems in food anaphylaxis. Acute IgE-
   • CHRONIC: >6 weeks duration                                                                   mediated urticaria can by induced by skin
        – Very unlikely to be associated with FA:                                                 contact with cow’s milk, raw egg white, raw
          children 4%, adults 1.4% confirmed with                                                 meats, fish, vegetables and fruits.
          DBPCFC
Skin contact reactions are typically local in nature but contact with oral mucous membranes (e.g.
kissing) or conjunctiva (e.g. eye rubbing) may lead to generalized reactions.
Chronic urticaria (symptoms lasting longer than 6 weeks) is rarely caused by food allergy.
                                                              Food allergy is frequently seen in children
                                                              with atopic dermatitis (AD) but infrequently
        Atopic Dermatitis and Food                            in adults. AD is a chronic inflammatory
                        Allergy                               disease of the skin characterized by marked
                                                              pruritus and a remitting and relapsing
     • 90% of children with food allergy have AD              course. The vesiculopapular rash of AD has
     • 30-40% of children with AD have skin                   a typical distribution, with generalized
       symptoms provoked by food hypersensitivity             involvement in infants and young children,
       (Eigenman et al, 1998)                                 and with localization to flexural areas in
     • Food allergy-related AD usually starts <1 year         older children. AD starts under age 5 years
       of age                                                 in over 95% of patients. In a study of
     • 90% of food allergy caused by egg, milk, soy,
                                                              patients with moderate to severe AD
       wheat, peanut, and fish                                referred to a pediatric dermatologist in a
                                                              tertiary medical center who underwent
     • Children have IgE antibody to foods                    1,613 double-blind placebo-controlled food
     • Food-allergen specific T cells have been               challenges, 37% of children were allergic to
                                                              at least one food.
In the presence of extensive chronic eczematous skin lesions, acute skin symptoms are not easily
appreciated and identification of the responsible food allergen is notoriously difficult, if not impossible.
However, following a 2-week strict dietary elimination period, reintroduction of the causative food
results in clear-cut immediate cutaneous reactions. In some adults with birch pollen sensitivity,
ingestion of birch pollen-related foods (e.g., apple, carrot, celery) causes immediate and /or late
eczematous reactions. Strict elimination of the causative food allergen results in significant
improvement in dermatitis.

                                                                           PFAS is a form of contact allergy to raw
     Pollen-Food Allergy Syndrome                                          fruits and vegetables that is confined to the
                                                                           oropharyngeal mucous membranes and
            (PFAS aka OAS)                                                 affects subjects allergic to pollens such as
   • Contact IgE-mediated reaction in the oro-pharyngeal                   birch (apple, cherry, peach, carrot), grass
     mucosa, onset <5 minutes                                              (tomato, kiwi), ragweed (melon, banana,
   • Rare cases my progress to systemic reactions (<1% risk of             tomato), or mugwort (carrot, celery). PFAS
     anaphylaxis)
                                                                           affects approximately 50% of birch pollen-
   • Caused by raw fruits or vegetables, cooked foods are well-            allergic adults and represents the most
     tolerated
                                                                           common food allergy in adults. It is due to
   • Cross-reactive allergens in pollen and plant foods (primary
     respiratory sensitization to pollen then reaction to food             the cross-reactivity between the allergenic
     ingestion)                                                            proteins in the pollens and plant foods.
   • Typical associations:                                                 Local IgE-mediated mast cell activation
   BIRCH         Apple, peach, apricot, hazelnut, potato, carrot, celery   provokes the rapid onset of pruritus, tingling
   RAGWEED Banana, cucumber, cantaloupe, watermelon, zucchini, cucumber    and angioedema of the lips, tongue, palate,
   MUGWORT Celery, onion, mustard, cabbage                                 and throat; and occasionally a sensation of
                                                                           pruritus in the ears, tightness in the throat or
                                                                           both. These symptoms resolve promptly
                                                                           when the food is swallowed or removed.
Patients typically tolerate cooked or baked forms of fruits and vegetables in which unstable allergens
are destroyed by high temperature. Symptoms of PFAS are typically mild but in a small subset of
patients allergy to fruits and vegetables may progress to systemic reactions. Risk factors for systemic
reaction are not well delineated but may involve sensitization to heat-stable and protease-resistant
lipid transfer proteins and storage proteins such as globulins (7S and 11 S) and albumins (2S); lack of
pollen allergy; peach hypersensitivity; positive allergy tests with commercial extracts (64% rate of
systemic reaction versus 6% (p<0.001); history of systemic reaction to one of the related foods; and
reactions to cooked foods.
                                                                                Food protein-induced enterocolitis
            Pediatric GI Syndromes                                              syndrome (FPIES) is most frequently seen
                                                                                in young infants who present with irritability,
                      FPIES                Enteropathy       Proctocolitis
                                                                                protracted vomiting and diarrhea. Twenty
 Onset                1 day-1 year         Up to 2 years     Newborn
                                                                                percent of cases may result in shock,
 Most common          Cow’s milk, soy      Cow’s milk, soy   Cow’s milk, soy    presumably due to intense intestinal
 Less common          Rice, oat, barley,   Wheat, egg
                      chicken, turkey,                                          inflammation leading to third-spacing and
                         fish                                                   intravascular volume depletion. Vomiting
 Multiple FA          >50% both cow’s      Rare              >50% both cow’s
                         milk and soy                           milk and soy    generally occurs 1 – 3 hours after feeding
                                                                                but continued exposure may result in bloody
 Feeding at onset     Formula              Formula           60% breast-fed
 Symptoms                                                                       diarrhea, anemia, abdominal distention, and
  Emesis              Prominent            Intermittent      No                 failure to thrive. FPIES is most frequently
  Diarrhea            Severe               Moderate          No
  Bloody stools       Severe               Rare              Yes                due to cow’s milk and soy, but other foods
  Edema               Acute, severe        Moderate          No                 such as grains (rice, oat), meats (turkey,
  Shock               15%                  No                No
  Failure to thrive   Moderate             Moderate          No or minimal      chicken) and vegetables (pea) have also
                                                                                been reported. Breast-feeding appears to
                                                                                have a protective effect.
The pathophysiology of FPIES may involve depressed TGF-alpha expression in intestinal mucosa and
increased secretion of TNF-alpha by circulating milk-specific T cells that result in increased intestinal
permeability.
Enteropathy syndrome occurs in infants and toddlers and resembles celiac disease in regard to
malabsorption and villus atrophy but is induced by cow’s milk or soy proteins and typically resolves by
age 2 years.
Allergic proctocolitis typically starts in the first few months of life, with blood-streaked stools in
otherwise healthy-looking infants and is considered a major cause of colitis under age 1 year, with
more than 50% of infants in published reports being exclusively breast-fed. Food protein-induced
proctocolitis typically presents in the first four months of life, usually at 1 to 4 weeks of age with
intermittent blood-streaked normal to moderately loose stools. Pathologic findings are limited to the
colon and include focal acute inflammation with epithelial erosions and eosinophilic infiltration of the
lamina propria, the epithelium and lamina muscularis. After 9-12 months of age, the infants typically
tolerate an unrestricted diet.

                                                                                Allergic eosinophilic esophagitis (AEE) and
             Allergic Eosinophilic                                              gastroenteritis (AEG) are characterized by
   Esophagitis (AEE) & Gastroenteritis (AEG)                                    infiltration of the gastrointestinal tract with
                                                                                eosinophils, basal zone hyperplasia,
   • Mixed IgE- and non-IgE-mediated disorders; 50% atopic
   • Clinical symptoms correlate with the extent of eosinophilic infiltration
                                                                                papillary elongation, and absence of
     of the bowel wall                                                          vasculitis. The eosinophilic infiltrates may
   • Symptoms: vomiting, anorexia, difficulty swallowing, pain, irritability,   involve the mucosal, vascular, and/or
     diarrhea, poor weight gain/weight loss, protein-losing enteropathy
   • Eosinophilic infiltrates resolve with elimination of the offending food    serosal layers of the esophagus, stomach
     (within 3-8 weeks) and recur with food reintroduction
   • Food-induced IgE-mediated reactions in a minority of patients;
                                                                                or small intestine. The underlying
     results of allergy tests correlate poorly with response to dietary         pathophysiology of these disorders is poorly
     restrictions; most common foods: cow’s milk, soybean, hen’s egg,
     wheat, fish                                                                understood, but both T lymphocyte and
   • Diagnosis: endoscopy and biopsy! Skin tests / IgE tests negative           food-specific IgE antibody are implicated.
   • IL-5 and Eotaxin-3 important for eos accumulation
   • Management: dietary avoidance, elemental (AA-based) diet,
                                                                                Data from animal models suggest important
     systemic steroids, topical steroids (inhaled-swallowed fluticasone);       role of IL-5 and Eotaxin-3 in the
     anti-IL-5 monoclonal AB
                                                                                pathophysiology of these disorders.
Clinical symptoms correlate with the extent of eosinophilic infiltration of the bowel wall. AEE is seen
most frequently in infants, children and adolescents and presents with symptoms of gastroesophageal
reflux, such as nausea, dysphagia, emesis and epigastric pain that fail to resolve with standard anti-
reflux therapy. Patients typically have a negative pH probe; on esophageal biopsy more than 10-20
eosinophils per 40X high-power field are seen. AEG can occur at any age, including young in infants
and failure to thrive is common. In young infants, AEG may cause gastric outlet obstruction with pyloric
stenosis. Patients also present with abdominal pain, emesis, diarrhea, blood loss in the stool, anemia,
and protein-losing gastroenteropathy.

Up to 50% of patients with these eosinophilic disorders are atopic and have detectable (by prick skin
test or RAST) IgE sensitization to food allergens. However, food-induced IgE-mediated immediate
reactions are uncommon. Furthermore, results of PST and RAST correlate poorly with clinical
response to elimination of the food and thus must be interpreted with caution. Resolution of symptoms
typically occurs within 3 to 8 weeks following the elimination of the responsible food allergen
(frequently multiple foods, most commonly: cow’s milk, soy, wheat, egg). Since patients with AEE and
AEG can be sensitive to trace amounts of the offending foods in the diet and testing may fail to identify
all relevant food allergens, an elemental diet based on an amino acid formula may be needed to
achieve improvement.

                                                                    Barium swollow may show esophageal
         Allergic Eosinophilic                                      narrowing. Endoscopy may reveal
              Esophagitis
                                                                    “trachealization” of esophagus (with ringed
                                                                    appearance), and longitudinal ulcerations
                                                                    (furrows). Biopsy reveals intense
                                                                    eosinophilic infiltration in lamina propria.




               Celiac Disease                                              Dermatitis Herpetiformis
                        Gliadins
                                                                      • Symmetric vesiculation,
                           APC: HLA-DQ2/8                               crusts and erosions are
                                                                        distributed over the
                        CD4+T lymphocyte                                extensor areas of the
                    Th1                   IFN-γ
                                                                        elbows, knees, buttocks,
                                                                        shoulders and scalp, with
        Mucosal remodeling
                                                                        a tendency to grouping of
        Villous blunting
                                                                        individual lesions.
        Malabsorption                      B lymphocyte               • Extremely pruritic,
                                                                        burning
                           Anti-gliadin IgA, IgG
                           Anti-tTG2 IgA-deamination of gliadin-
                                                                      • Associated with celiac
                           increased interaction with HLA –DQ 2/8       disease
                           molecules on APC




Celiac disease (CD) is a dietary protein enteropathy characterized by an extensive loss of absorptive
villi and hyperplasia of the crypts that leads to malabsorption, chronic diarrhea, steatorrhea, abdominal
distention, flatulence, weight loss or failure to thrive. Oral ulcers and a linear papular, intensely pruritic
rash of dermatitis herpetiformis may occur, occasionally in the absence of gastrointestinal symptoms.
Patients with CD are permanently sensitive to gliadin, the alcohol soluble portion of gluten found in
wheat, rye, and barley.Symptoms of CD resolve completely with exclusion of gluten from diet but recur
when gluten is reintroduced. Celiac disease is associated with HLA-DQ2 and HLA-DQ8, and affects as
much as 1% of some Caucasian populations. CD is diagnosed by intestinal biopsy showing classic
villus atrophy; serologic ELISA tests detecting IgA antibodies to tissue transglutaminase have a
sensitivity of 92%-98% and are a useful screening tool. Biopsy and serologic tests may be falsely
negative when taken during gluten elimination, thus testing for CD is only conclusive when the patient
ingests gluten on regular basis for at least several weeks.
                                                                                        Pulmonary hemosiderosis has been
                                                                                         reported in children with cow’s milk-
                                                                                         induced anemia and respiratory symptoms
                       Heiner’s Syndrome                                                 of chronic cough, hemoptysis, recurrent
                                                                                         lung infiltrates, wheezing, and persistent
       • Infantile pulmonary hemosiderosis                                               rhinitis. Recently, a single case of
       • Anemia, cough, hemoptysis, recurrent                                            buckwheat-induced hemosiderosis and
         pulmonary infiltrates, wheezing, melena
                                                                                         melena was described. Respiratory
       • Associated with cow’s milk and buckwheat                                        symptoms and anemia resolved upon
         (reports from Japan)
       • OFC proven                                                                      elimination of the offending food and
                                                                                         relapsed following oral challenge. Iron-
       • Iron-laden macrophages in bronchial or
         gastric washings or at lung biopsy                                              laden macrophages were recovered from
       • No IgE but serum IgG precipitins to milk                                        bronchial or gastric washings or at lung
       • Lung bx: IgG, IgA and complement, no IgE                                        biopsy. Prick skin tests and serum food
                                                                                         specific IgE levels were negative but high
                                                                                         titers of serum milk and buckwheat
                                                                                         precipitins were reported.
Increased lymphoproliferative responses of PBMCs upon stimulation with buckwheat flour were
observed in one patient with buckwheat-induced pulmonary hemosiderosis. Biopsy specimens of the
lung revealed deposits of IgG, IgA and complement components, without evidence of IgE. Pulmonary
symptoms tend to be persistent, with relapses described in 6 and 8-year olds but the natural history of
food protein-induced pulmonary hemosiderosis is unknown. Considering the seriousness of pulmonary
hemorrhage, diagnostic oral food challenges must be done with extreme caution under close physician
supervision in the hospital setting and only when potential benefits out-weigh the risks, such as
identification of an offending food in a patient with ongoing symptoms or determination of tolerance
after a long period of food avoidance without accidental reactions.
                                                             Food proteins may be related botanically or
                                                             by a high degree of homologous proteins.
        Cross-Reactivity Patterns                            There is a higher prevalence of positive test
                                                             than of clinical reactivity.
                                                                                         If allergic to  Risk of reaction to at   Risk
                  Risk of reaction to
                  at least one related                                                                   least one other
                  food                                                                   Tree nut        Tree nuts                37%
                      55%                                                                Fish            Fish                     50%
                                                                                         Shellfish       Shellfish                75%
        Peach                        Apple Plum Pear    Cherry      Apricot    Almond    Grain           Grain                    20%
                                                                                         Cow’s milk      Beef                     10%
                                                                                         Cow’s milk      Goat’s milk              92%
                      92%
                                                                                         Cow’s milk      Mare’s milk              4%
                                                                                         Pollen          Fruits/ vegetables       55%
        Cantaloupe                   Avocado Banana     Kiwi     Watermelon Peach        Peach           Rosaceae*                55%
                                                                                         Melon           Melons, peach            92%
                                                                                         *Apple, plum, pear, cherry

                                                                                        Structural protein homology is also a basis
                                                                                        for latex-plant food cross-reactivity.
     Latex-Food Cross-Reactivity

                     35% risk of reaction
                     to at least one food   Kiwi       Banana         Peach




                        11% risk of          Avocado     Chestnut        Fig
 Natural rubber         reaction to latex
 latex


                                              Bell pepper Tomato      White potato
                                                                    Careful medical history is the first step to
        Food Allergy Diagnosis                                      establishing food allergy diagnosis.
    • History                                                       However, history needs to be validated by
        Food ingested
        Timing of symptoms, acute reaction versus chronic disease
                                                                    laboratory tests and oral food challenges,
        Co-ingestion of ASA, alcohol
        Association with exercise
                                                                    especially in chronic disorders such as
                                                                    atopic dermatitis or AEG, in which
    • Physical examination
        Urticaria pigmentosa (mastocytosis)
                                                                    symptoms wax and wane. In such remitting
        Atopic dermatitis
                                                                    and relapsing disorders, accurate
    • Laboratory tests: are they necessary?                         identification of the offending food is
        IgE-mediated allergy
          • In vivo                                                 particularly difficult and sometimes
          • In vitro
        Non-IgE-mediated allergy                                    impossible. A food intake diary may be
    • Oral food challenges “GOLD STANDARD”                          helpful in tracing back the reactions and
                                                                    foods that might have caused them.
Dietary elimination of the suspected foods may be helpful, although, in general it should be followed
be reintroduction of the food because in some patients symptoms improve with dietary restriction but
do not recur upon reintroduction of the suspected food.

                                                                     Well-standardized diagnostic tests are
                                                                     available for IgE-mediated food allergy
        Diagnosis: Lab Evaluation                                    disorders. Intradermal skin testing should
                                                                     not be used for diagnosis of food allergy
     • IgE-mediated                                                  because of the risk of systemic reaction and
         – PST ( fresh food for PFAS)
         – Serum food-specific IgE                                   high rate of false positive results. Prick skin
     • Non-IgE-mediated                                              testing with commercial food allergen
         – Biopsy                                                    extract has a high negative predictive value
         – Atopy patch test ???
     • Non-allergic:
                                                                     >95%, whereas a positive skin test has only
         – Breath hydrogen test                                      a 30-50% positive predictive value. In
         – Sweat test                                                infants and young children, large prick skin
         – Biopsy
                                                                     test wheal (mean size 8-10 mm) is
                                                                     associated with high > 95% likelihood of
                                                                     clinical reactivity to cow’s milk, egg and
                                                                     peanut. In patients with pollen-food allergy
                                                                     syndrome caused by raw fruits and
                                                                     vegetables, testing with raw fruit is typically
more sensitive than testing with the commercial extract of fruit because the responsible allergens are
very unstable and disintegrate during the allergen extraction process. Prick-prick method involves
puncturing the fruit through the peel and then puncturing the skin. Prick skin testing will become more
sophisticated and accurate with the availability of recombinant food allergens Recombinant allergens
of high purity offer superior safety and specificity in allergy testing, although diagnostic sensitivity is
generally lower than of allergen extracts. Recombinant allergens may be of special value in
diagnosing allergy to plant foods in subjects with allergy to pollens.
                                                                     It must be emphasized that the guidelines
                                                                     for interpretation of skin test and serum
                                                                     food-IgE levels evolve with more available
        Diagnostic Decision Points                                   evidence. Some studies suggest that there
                                                                     may be regional differences and that
    Food                                          SPT wheal (mm)+
                       Serum       food-IgE                          different standards may be needed for
                   (kIU/L)*
                                                                     interpretation depending on the country.
               ∼95% Fail ∼50% Fail           ∼95% Fail ∼50% Fail     A child older than 2 years with milk-IgE
    Cow’s milk 15           2                8                       antibody level > 15 kIU/L is highly (>95%)
               5 (<1 yr)                     7                       likely to react during an oral milk challenge
                                             8
    Egg white 7             2                          3 (EW IgE <2) and milk challenge should be deferred
               2 (<2 yr)                                             unless there is a compelling evidence that
    Peanut     14           2 (Hx+), 5 (Hx-)           3
    Fish       20
                                                                     the child tolerated a significant amount of
                                                                     milk without a reaction. Food-specific IgE
                                                                     antibody levels below the decision points
                                                                     indicate decreasing likelihood of reaction
                                                                     that need to be determined with OFC.
                                                                          Oral food challenges (OFC) remain the
                                                                          most accurate method for diagnosing food
        Interpretation of Allergy Tests                                   allergy. OFC can be utilized for diagnosing
                                                                          IgE-mediated as well as for non-IgE
       Serum IgE                       Prick skin test                    mediated food allergy. OFC can be done to
                                                                          confirm whether the suspected food is
                                                                          indeed causing problems or to determine if
                                            Peanut
                                                                          a person with known food allergy might
                                                                          have lost reactivity to food (“outgrew” food
                                                                          allergy). OFC are particularly useful
                                                                          because IgE antibodies persist after clinical
                                                                          reactivity has cleared. With increasing IgE
                                                                          antibody concentration there is an increase
          Sampson and Ho, JACI, 1997
                                           Roberts and Lack, JACI, 2004
                                                                          in risk of clinical reactions but the curve is
          Sampson, JACI, 2001
                                                                          distinct for each food and may vary with age
                                                                          and atopic disorder. In general, severity of
                                                                          the reaction does not correlate well with IgE
                                                                          level.
                                                                          During an oral food challenge for an IgE-
                                                                          mediated food allergy, a pre-measured
        Diagnosis: Elimination Diet                                       amount of food (typically 8-10 gram of dry
           and Food Challenges                                            food or 80-100 ml of liquid food) mixed with
                                                                          a masking food that is well tolerated by the
    • Elimination diet (1-6 weeks)                                        patient is administered in small increments
       – Elimination of suspected foods                                   every 10-15 minutes over 90 minutes. OFCs
       – “Rx foods”: e.g 5 foods only diet                                can be open (both patient and person
       – Elemental formula                                                administering the challenge know what food
                                                                          is administered) or blinded, placebo
    • Physician-supervised oral food challenge                            controlled. In a placebo-controlled
       – Open                                                             challenge, two 90 minute sessions (one with
       – Single-blind                                                     real food, one with placebo food) may be
       – Double-blind, placebo-controlled (DBPCFC)                        separated by a 90 minute break and
                                                                          completed on a single day or each session
                                                                          may be done on separate days.



The double-blind, placebo controlled food challenge is considered a gold standard for diagnosis of
food allergy and is a preferred type of a challenge in research setting or in patients in whom anxiety
may interfere with interpretation of symptoms. Placebo-controlled OFCs in which the patient tolerated
both sessions without a reaction are always followed by an open challenge, during which a regular
portion of food is ingested by a patient over a 30 minute period. OFCs are stopped at the first sign of
an objective reaction such as hives, rhinorrhea, sneezing, coughing, or vomiting. Patients are
observed for at least 2 hours following a completion of an open challenge. In patients with FPIES, the
amount of food for challenge is calculated as 0.15 to 0.3 g protein / kg body weight (not to exceed 3 g
of protein or 10 g of whole food) and administered gradually in 3 feedings over 45 minutes. If the
patient remains symptom-free for 4 hours, a second dose is given, generally a serving amount
followed by 2-3 hours observation. OFCs are always conducted under physician supervision in a
controlled environment with emergency medications (epinephrine, diphenhydramine,
methylprednisolone, and volume expanders) immediately available to treat an allergic reaction.

Patients with asthma, a history of severe reactions, or at higher risk for having a positive challenge
and all patients with FPIES must have an intravenous line in place before starting a challenge for an
immediate vascular access in case of hypotension. Double-blind placebo controlled food challenges
can be completed during one day or sessions may be conducted on separate days. Patients with AEE
or AEG, whose food-induced symptoms are delayed, may require prolonged challenges over several
days.
                                                             Caution is warranted in case of history of
                                                             convincing severe reactions to a suspected
      Diagnosis: IgE-Mediated FA                             food even in the setting of negative tests. In
                                                             such cases, physician-supervised OFC may
     • IgE                                                   be advisable. Reports from children with AD
          – Negative: reintroduce food*                      found that following a period of dietary food
          – Positive: start elimination diet                 avoidance, the pattern of symptoms
     • Elimination diet                                      induced by food ingestion may change from
                                                             eczematous type rash to more acute,
          – No resolution: reintroduce food*
                                                             immediate skin and systemic reactions.
          – Resolution
              • Open/SB OFC to screen
              • DBPCFC for equivocal OFC

  * Unless convincing history warrants a supervised OFC




                                                             Prick skin test and measurement of serum
                                                             food-IgE antibody concentration are not
          Diagnosis: Non-IgE-Mediated FA                     helpful in food allergic disorders with non-
                                                             IgE, cell-mediated mechanism, such as
      •   Elimination diet                                   FPIES and have limited usefulness in
      •   APT? – not standardized
                                                             disorders with mixed mechanism, such as
                                                             AEE and AEG. Recently patch testing for
      •   Endoscopy and biopsy
                                                             the diagnosis of food allergy in children with
      •   OFC                                                AD and AEE has been investigated in a
          – Protocol customized based on type of symptoms:
            FPIES may cause shock within 2-4 hours,
                                                             number of studies. Patch testing is typically
            AEE/AEG require prolonged feeding to induce      used for diagnosis of delayed contact
            symptoms                                         hypersensitivity reactions in which T cells
          – Blinded challenges preferred                     play prominent role and involves prolonged
                                                             contact of the allergenic extract with intact
                                                             skin under occlusion for 48 hours. The
                                                             results are evaluated 20 minutes and 72
                                                             hours after removing the patch.



A positive reaction to patch tests consists of erythema and induration. In children with challenge-
proven milk allergy, prick skin tests were positive in 67% of the cases with acute-onset reactions
(under 2 hours) to milk challenge, whereas patch tests tended to be negative. Patch tests were
positive in 89% of children with delayed-onset reactions (25-44 hours), although prick skin tests were
frequently negative. In another study of children with atopic dermatitis, the combination of a positive
patch test with evidence of specific IgE or with positive prick skin test had highest positive predictive
value. These results indicate that combination of patch testing and detection of IgE could enhance the
accuracy of diagnosis of food allergy and eliminate the need for oral food challenges. However, before
incorporating atopy patch testing into clinical practice, standardization of the reagents, timing of the
results reading, and scoring system for the interpretation of the results are necessary.

For gastrointestinal food allergy disorders such as AEE and AEG, ultimate diagnosis is established by
biopsying of the mucosa and finding increased numbers of eosinophils. Non-invasive diagnostic tests
are highly desirable but currently available laboratory techniques offer rather limited insight into these
conditions. Peripheral blood eosinophil numbers can be followed in approximately in 50% of subjects
with AEE/AEG. Testing stool samples for occult blood may be useful in a subset of patients in whom
gastrointestinal inflammation results in microscopic bleeding. Patients with AEG and protein-losing
gastroenteropathy can be followed with serial evaluations of serum albumin, total protein, and
immunoglobulins (low IgG with preserved IgM and IgA). Measurements of stool alpha1-antitrypsin may
be used to approximate gastrointestinal protein loss.
                                                                     Management of food allergy currently
                                                                     focuses on dietary avoidance of the
    Treatment: Dietary Elimination                                   offending foods, prompt recognition and
                                                                     treatment of food allergic reactions, and
    • Guidelines for avoidance                                       nutritional support. Educating patients how
    • Awareness of cross-contamination from                          to read food labels is very important
      shared equipment                                               because common foods may be labeled
                                                                     using non-intuitive terms. Patients
    • Dietitian evaluation
                                                                     commonly make mistakes and are unable to
                                                                     identify the food allergens in store-bought
                                                                     foods correctly; in a recent study only 7% of
                                                                     parents of children with milk allergy were
                                                                     able to correctly identify products that
                                                                     contained milk and 22% of parents of
                                                                     children with soy allergy were able to
                                                                     correctly identify products that contain soy.

Children with food allergy, particularly those with multiple food allergy are at risk for nutritional
deficiencies as a result of restricted diets. Nutritional support may be limited to calcium
supplementation in children avoiding dairy or may be extensive in children on severely restricted diets.
Children allergic to multiple major food allergens are at risk for protein and calorie deficiency, and may
require a hypoallergenic formula to meet their needs. Hypoallergenic formulas available in the US are
either based on extensively hydrolyzed casein derived from cow’s milk (Pregestimil, Nutramigen,
Mead Johnson; Alimentum, Ross) or on a mixture of single aminoacids (Neocate, SHS; Elecare,
Ross). Hypoallergenic formulas are well tolerated by children with IgE-mediated and with cell-
mediated food allergy.

Another impediment faced by food allergic patients is undisclosed contamination with trace amounts of
food resulting from sharing of equipment. Current industry cleaning standards, although very stringent,
are not sufficient to prevent contamination with trace amounts of food allergens that may trigger
severe reactions in highly sensitive food allergic individuals. Families of patients with food allergies
need information on how to cook safely foods at home and how to handle school, travel, and social
situations such as parties and dining. An excellent resource is the Food Allergy and Anaphylaxis
Network (www.foodallergy.org) that provides practical advice on dietary avoidance, “survival
strategies” for school, restaurants, camps, manufacturers’ updates and special support programs for
teens. American Partnership for Eosinophilic Disorders website (www.apfed.org) contains useful
information for patients with eosinophilic gastroenteropathies.
             Food Allergen Labeling and
              Consumer Protection Act                                   Treatment: Emergency Management
                                                                         • Clear emergency plan in writing
    • Effective January 1, 2006
                                                                         • Emergency identification bracelet
    • Content of milk, eggs, fish, crustacean shellfish, peanuts,
      tree nuts, wheat, and soy must be declared in plain                • Prompt recognition of symptoms
      language                                                           • Intramuscular epinephrine
    • listed even if they are present in colors, flavors, or spice          – Self-injectable device
      blends.                                                               – EpiPen Jr / Twinject Jr 0.15 mg, under 66 lbs
                                                                            – Epi Pen / Twinject 0.3 mg, over 66 lbs
    • Such ingredients must be
    • Specific nut or seafood that is used (e.g., almond, walnut,        • Oral antihistamines (secondary therapy)
      cashew; or tuna, salmon, shrimp, or lobster) must be                  – Benadryl syrup, 1-1.5 mg/kg/dose
      declared
                                                                         • Follow up in the ED or call 911
    IMPORTANT:
    FALPCA does not cover other food allergens: seeds, garlic,
                                                                         • 4-hour observation period
      spices, etc.


In spite of strict avoidance, accidental ingestions and exposures occur and every food allergic patient
must always be prepared to recognize symptoms and treat food allergic reaction. In children with
peanut allergy, 50% reported reactions to peanuts despite avoidance over 2 year period. Individuals
with history of immediate allergic reactions, anaphylaxis, those with asthma, and those with allergy to
foods typically associated with severe reactions (i.e., peanut, tree nuts, fish, shellfish) should be
prescribed an epinephrine auto-injector (EAI). A clear emergency treatment plan indicating symptoms
that require treatment with oral antihistamine and/ or epinephrine must be provided to the patient by
an allergist or primary physician. Templates of anaphylaxis emergency treatment plans may be
downloaded from the www.foodallergy.org or from www.foodallergyinititive.com websites.
Administration of the EAI should be demonstrated to the patient and the technique reviewed
periodically. A single demonstration is not sufficient for most patients. Patients frequently forget to
carry their EAI with them and to check the expiration date. These issues should be reviewed regularly
during follow up visits. Patients must be instructed to seek evaluation in the emergency room following
the use of an EAI. Given the approximately 20% risk of recurrence of allergic symptoms following
initial improvement with or without treatment (so called biphasic anaphylaxis), a minimum 4 hour
observation period is recommended. Medic Alert bracelets indicating food allergy and specifying
treatment needed in case of a sudden reaction are helpful for older children and adults.
                                                             Periodic evaluations are recommended,
                                                             especially for children who mostly outgrow
            Treatment: Follow-Up                             food allergy.

    • Periodic re-evaluations: children every
      6-12 months
    • Decision to perform an OFC
          • No recent reactions (past 6-12 months)
          • No severe anaphylaxis in the past 24 months
          • PST/ serum food-IgE negative or significantly
            decreased from previous evaluation
          • Nutritional or social importance of the food




              Natural History                               Food allergy to cow’s milk and egg is
                                                            outgrown by most children. 85% of milk
  • Milk, egg, wheat and soy allergy majority               allergic children and 66% of egg-allergic
    resolve by school-age                                   children become food tolerant by age 5
  • Peanut, tree nuts and seafood                           years, although recent study by Skripak et
     – 20% of young children outgrow peanut, 9%             al suggested that the age of outgrowing milk
       tree nuts; 7-9% recurrence of PN allergy             allergy for children with multiple food
       (increased risk if not ingested regularly)           allergies may be older. In contrast, only
  • Non-IgE-mediated GI allergy                             approximately 20% of all children with
     – Infant forms resolve 1-3 years                       peanut allergy become peanut tolerant.
     – Toddler/adult forms more persistent
However, children with peanut-IgE antibody level <5 kIU/L have at least 50% chance of tolerating
peanut. Periodic evaluation should be offered to children with peanut allergy and OFC to peanut
should be considered in patients who have not had reactions in the past 1-2 years and who have
peanut IgE level <5.0 kIU/L. Unlike milk and egg allergy, peanut allergy can recur in children who
outgrew peanut allergy. It appears that risk of recurrence is approximately 10% in children who refuse
to eat peanut on regular basis compared with no recurrences in children eating peanut regularly. We
recommend that the possibility of peanut allergy recurrence is discussed prior to offering OFC to
peanut and that patients ingest peanut frequently following a negative OFC. EAI should be carried
until patient had proven tolerance to multiple ingestions of regular servings of peanut and peanut-
containing foods. It appears that tree nuts, seeds, fish and shellfish are generally not outgrown, similar
to peanut.

Little information exists regarding the course of food allergy in adults. In one study, 10 adults with
DBPCFC-confirmed allergy to 13 foods were followed for 1 to 2 years. Upon re-challenge, 38% of 13
foods were well tolerated, including milk in 2 patients and wheat, egg, and tomato in 1 patient each.
The 2 patients with nut allergy, 2 patients with milk allergy, and 1 patient each with potato, garlic, and
rice remained reactive.

Food allergy can be viewed as a marker of an atopic predisposition. In many children food allergy
coexist with other atopic conditions such as AD, asthma and allergic rhinitis. Sensitization to egg white
in children with atopic dermatitis is associated with 70% risk of respiratory allergic disease (asthma or
allergic rhinitis) at the age 5 years. Therefore, subjects with past and current food allergy should be
considered at high risk for asthma and environmental allergy.

         Food Allergy Prevention:                                    Food Allergy Prevention:
            AAP Report 2008                                             AAP Report 2008
    1. No evidence for protective effect of dietary maternal   5. There is no convincing evidence for the use
       restrictions during pregnancy and lactation
                                                                 of soy formula for allergy prevention
    2. For infants at high risk of atopy, exclusive breast-
       feeding for at least 4 months decreases cumulative      6. There is no evidence that delayed intro solid
       incidence of AD in the first 2 years                      beyond 4-6 months has a protective effect
    3. Exclusive BF for at least 3 months protects against
                                                               7. For infants older than 4-6 months, there is no
       wheezing in early life but not beyond 6 years
    4. For high risk infants feeding with extensively
                                                                 sufficient data to support a protective effect of
       hydrolized formula protects from development of AD        dietary intervention
       in early childhood.
                                                               • Pediatrics 2008; 121;183-191




New report from AAP was released recently and revised previously published guidelines. The report
emphasizes inconclusive research on the value of extensive maternal dietary restrictions during
pregnancy and lactation for prevention of atopic diseases and delayed introduction of solid foods past
4-6 months of age.

The documented benefits of nutritional intervention that may prevent or delay the onset of atopic
disease are largely limited to infants at high risk of developing allergy (ie, infants with at least 1 first-
degree relative [parent or sibling] with allergic disease). Current evidence does not support a major
role for maternal dietary restrictions during pregnancy or lactation. There is evidence that
breastfeeding for at least 4 months, compared with feeding formula made with intact cow milk protein,
prevents or delays the occurrence of atopic dermatitis, cow milk allergy, and wheezing in early
childhood. In studies of infants at high risk of atopy and who are not exclusively breastfed for 4 to 6
months, there is modest evidence that the onset of atopic disease may be delayed or prevented by the
use of hydrolyzed formulas compared with formula made with intact cow milk protein, particularly for
atopic dermatitis. Comparative studies of the various hydrolyzed formulas also indicate that not all
formulas have the same protective benefit. There is also little evidence that delaying the timing of the
introduction of complementary foods beyond 4 to 6 months of age prevents the occurrence of atopic
disease. At present, there are insufficient data to document a protective effect of any dietary
intervention beyond 4 to 6 months of age for the development of atopic disease.
                                                   Novel approaches to the treatment of IgE-
                                                   mediated food allergy such as anti-IgE antibodies,
    Food Allergy: Future Therapy                   food allergy vaccines, herbal preparations and
                                                   probiotics will hopefully provide definitive therapy
                                                   for food allergic patients and prevent development
    • Recombinant anti-IgE                         of food allergy in at risk infants. However, these
    • Oral desensitization/sublingual IT           immunomodulatory therapies will have to be
    • Chinese herbs                                carefully evaluated for potential side effects, over-
                                                   stimulation of Th1 immune responses, priming of
    • Recombinant hypoallergenic peanut            autoimmune reactions, and long-term effects of
      expressed in E.coli                          suppression of circulating IgE antibodies.
    • DNA therapy                                  Nevertheless, these new approaches bring real
                                                   hope to the patients for whom no specific therapy
    • Probiotics
                                                   is currently available.




                                                   The history and physical examination are crucial
                 Summary                           for accurate food allergy diagnosis. The diagnosis
                                                   includes laboratory tests as well as elimination
   • Positive test results must be interpreted     diet and oral food challenges. Current
     in the context of clinical history            management relies on avoidance and nutritional
   • Testing should be judicious                   support and treatment of acute reactions. Periodic
   • Elimination diet and OFC                      re-evaluations with laboratory tests and oral food
   • Patient education re avoidance and            challenges are required to monitor for tolerance
     anaphylaxis management                        development.
   • Nutritional consultation
   • Periodic re-evaluations with skin/blood
     tests and OFC



BONUS: Peanut allergy (PNA) clinical pearls:
Prevalence of PNA is estimated at 1%; it has doubled in young children in USA, Canada and UK in the
past decade.
Sibling of a child with PNA has 7% chances of having PNA, thus siblings should be tested before
introducing peanut.
PNA may resolve (about 20% of young children).
PNA may recur following a passed OFC: about 8% recurrence rate.
PNA is associated with TNA in 25-50% of patients.
Legumes are typically well tolerated by >90% of patients with PNA despite 50% rate of positive IgE
(PST, serum); lupine, lentil and chickpea may present higher risk (up to 40% clinical reactions in
persons with PNA)
Typical reactions occur to about 1 kernel of peanut but reactions may occur to trace amounts (0.1-10
mg).

				
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