Food Hypersensitivity

Definition, Etiology, PathogenesisTop

Food adverse reactions are recurrent signs or symptoms that are caused by ingestion of particular foods or food components in amounts tolerated by healthy individuals.

Classification of food adverse reactions:

1) Immune-mediated reactions (hypersensitivity, also referred to as allergy):

a) IgE-mediated reactions (eg, acute urticaria, oral allergy syndrome, anaphylaxis): Incidence is highest in infancy but adult-onset disease is common. Designation of priority food allergens differs by country.

b) Non–IgE-mediated reactions (eg, celiac disease, food protein–induced enterocolitis, food protein–induced allergic proctocolitis).

c) Mixed reactions (IgE-mediated and non–IgE-mediated, eg, eosinophilic gastroenteritis and eosinophilic esophagitis, atopic dermatitis).

d) Cell-mediated reactions (eg, allergic contact dermatitis).

2) Non–immune-mediated reactions (primary intolerances):

a) Metabolic reactions (eg, lactose or fructose intolerance).

b) Pharmacologic reactions (eg, to tyramine [cheese, pickled herring], caffeine, theobromine [chocolate, tea, cola]), histamine [fish, sauerkraut], tryptamine [tomato, plum]).

c) Toxic reactions (eg, to toxins produced by the Scombridae fish).

d) Other, idiopathic, or unclassified (eg, to sulfites).

In Canada, in infants and children the foods that most commonly cause hypersensitivity reactions are cow’s milk, hen’s egg, peanut, and tree nuts. About 70% to 80% of patients lose their allergies to milk, soy, or egg by the age of 10 years. In adults the most frequent causes of food hypersensitivity are fish, shellfish, milk, peanut, and tree nuts.

Highly cross-reactive tree nuts are cashew with pistachio (~2 out of 3 of cashew allergic reactions are to pistachio), walnut with pecan (~2 out of 3 walnut allergic reactions are to pecan), and possibly almond with hazelnut, although almond allergy is less common than previously thought. As further discussed below, there are sparse data on the cross-reactivity between almond and hazelnut because almost all individuals sensitized to either almond (~98%) or hazelnut (~77%) tolerate the food despite having positive IgE. Common cross-reactivities: Table 1.

In oral allergy syndrome symptoms most commonly occur following ingestion of raw fruits or vegetables and are caused by cross-reactivity with pollens in pollen-allergic patients (most frequently birch, grass, ragweed, or mugwort pollen). The responsible allergens are degraded during extensive heating or processing, thereby leading most patients with oral allergy syndrome to be able to tolerate cooked forms of these fresh fruits or vegetables. However, systemic reactions due to cross-reactivity can occur and are thought to be due to heat-stable fruit or vegetable allergens of the lipid transfer protein family. These reactions are referred to as systemic pollen-food syndrome.

Clinical FeaturesTop

The clinical features depend on whether the allergy is immediate or delayed (Table 2).

1. In immediate hypersensitivity (IgE-mediated) the reaction typically develops within 30 to 60 minutes after ingestion:

1) Mucocutaneous: Urticaria, angioedema.

2) Respiratory: Upper (rhinitis) or lower (wheeze, bronchoconstriction).

3) Gastrointestinal (GI): Oral or pharyngeal pruritus (or both), abdominal pain.

4) Cardiovascular: Presyncope or syncope, hypotension, shock (anaphylactic).

Anaphylaxis is recognized in the case of (1) involvement of ≥2 organ systems after a likely allergen exposure or isolated hypotension after a known allergen exposure, or (2) a sudden onset of mucocutaneous and either respiratory or cardiovascular involvement.

2. In delayed hypersensitivity (typically non–IgE-mediated) the reaction occurs hours to days after exposure:

1) Food protein–induced enterocolitis syndrome (FPIES): Profuse repetitive vomiting 2 to 6 hours after ingestion, most commonly due to cow’s milk, soy, or grains.

2) Food protein–induced enteropathy (FPE): Chronic nonbloody diarrhea in the first year of life due to small bowel injury and malabsorption with possible failure to thrive. Implicated foods include cow’s milk, soy, wheat, and egg.

3) Allergic proctocolitis: Blood or mucus in stool (or both) in otherwise healthy newborns and infants.

4) Heiner syndrome (pulmonary hemosiderosis): A rare manifestation of allergy to cow’s milk leading to cough, rhinitis, recurrent fever, wheeze, hemoptysis, hematochezia, or failure to thrive, almost always with pulmonary infiltrates due to hemosiderosis.

5) Celiac disease and dermatitis herpetiformis (DH): A gluten-sensitive enteropathy leading to small intestinal inflammation, villous atrophy, and malabsorption with symptoms of abdominal pain, bloating, diarrhea, and possible weight loss. DH typically causes clustered pruritic papulovesicular eruptions over extensor surfaces, such as the elbows or lower back.

6) Eosinophilic esophagitis: Dysphagia to solid foods, liquids, or both associated with comorbid aeroallergen sensitization. The most common allergens are cow’s milk, soy, wheat, and egg.

DiagnosisTop

Establishing diagnosis can be difficult. The diagnosis of food hypersensitivity can be suspected on the basis of history (including a history of atopy in close relatives or causal relationship between a particular food and symptoms developing consistently after its repeated ingestion), results of skin tests, in vitro immunologic tests, as well as elimination diets and challenge tests.

Diagnostic Tests

1. Immediate hypersensitivity reactions:

1) Skin prick test: A mean wheal diameter ≥3 mm than the diameter of the saline control is positive. However, testing does not yield strictly binary results. The size of the skin test correlates with the probability of allergy and not with its severity, and the false-positive rate is high. For this reason, this test alone is not diagnostic and should not be used as a screening tool in the absence of a history of allergic reaction after food ingestion.

2) Serum-specific IgE (sIgE): This can help identify foods that provoke an IgE-mediated reaction, particularly those due to interfering medications (eg, ongoing antihistamine use) or in patients who cannot undergo skin testing for some reason (eg, no immediate access to an allergist; nonallergic skin disease prevents skin testing). Similarly to the skin prick test, this test identifies sensitization, that is, the presence of a specific IgE antibody whose level indicates the probability of a true underlying allergic disease. Asymptomatic sensitization is common. Diagnostic thresholds for both skin testing and sIgE vary by population studied, age, and food allergen. Among both symptomatic and asymptomatic patients with GI or food allergic concerns, there is no diagnostic value of serum-specific IgG testing to foods, which is frequently marketed directly to public without health-care provider counseling or request. Professional medical societies around the world have made statements denouncing such testing; in fact, these tests often cause unnecessary and potentially harmful food elimination.

2. Delayed hypersensitivity reactions:

1) Histologic examination of GI mucosal biopsy specimens: The presence of >15 eosinophils per high power field (HPF) on esophageal biopsies is consistent with eosinophilic esophagitis.

2) Elimination diet: If symptoms resolve after potentially harmful foods have been eliminated from the patient’s diet, it may be assumed that there is a causal relationship between the foods and the symptoms (a 6-week elimination period is required for non–IgE-mediated reactions; however, these findings have to be confirmed by a challenge test. Skin tests typically used for evaluation of IgE-mediated allergies, blood IgE testing, and patch tests are not reliable for guiding elimination diets in eosinophilic esophagitis.

3. Challenge tests for immediate and delayed hypersensitivity reactions: Graded allergen ingestion in a controlled (supervised) setting can be done, as it is the reference standard for diagnosis of immediate-type food allergy. However, as of now no universally accepted protocols exist and there is a risk eliciting severe life-threatening reactions (deaths have been reported). Hence, extensive training and emergency preparedness is required, along with informed consent to perform the challenge. Oral food challenge tests are often done for indeterminate or discordant results of skin or blood allergy testing or to differentiate asymptomatic sensitization from food allergy.

ManagementTop

1. Elimination diets (avoiding foods causing hypersensitivity reactions) are the primary way to prevent recurrent food allergic reactions. Care must be taken to avoid nutritional compromise. The treatment approach varies depending on the specific food the patient is allergic to and the type of food allergy. Tolerance to allergens may occur over time. Monitoring of symptoms and laboratory values may assist in identifying when to safely reintroduce certain foods. For some delayed hypersensitivity reactions, such as eosinophilic esophagitis, it may be necessary to use an elemental diet if empiric elimination of the most common allergens is not effective.

2. Anaphylaxis preparedness: Inform patients with allergic hypersensitivity reactions about early recognition of allergic symptoms and management in case of an anaphylactic reaction. Precisely who should or should not carry an epinephrine autoinjector is not standardized globally. In North America most patients with food allergy are given an epinephrine autoinjector, whereas in the United Kingdom and Australia prescription may be determined by the severity of previous allergic reactions or whether the patient has comorbid asthma. However, it should be kept in mind that the severity of previous reactions does not reliably predict the severity of future reactions and previously mild reactions can be subsequently fatal. Many professional societies advocate for health-care providers to develop a written anaphylaxis action plan in case of accidental consumption of a harmful allergen. Also see Anaphylaxis and Anaphylactic Shock.

3. Symptomatic treatment:

1) Management of anaphylaxis: see Anaphylaxis and Anaphylactic Shock.

2) Antihistamines (see Anaphylaxis and Anaphylactic Shock) may result in partial improvement in patients with oral allergy syndrome and IgE-mediated reactions but do not inhibit systemic reactions. They are only adjuncts, not first-line therapy, for anaphylaxis.

3) In patients with eosinophilic esophagitis:

a) Proton pump inhibitors (PPIs) improve symptoms and may reduce histologic changes of eosinophilia.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to inconsistency. Rank MA, Sharaf RN, Furuta GT, et al; AGA Institute; Joint Task Force on Allergy-Immunology Practice Parameters collaborators. Technical Review on the Management of Eosinophilic Esophagitis: A Report From the AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters. Gastroenterology. 2020 May;158(6):1789-1810.e15. doi: 10.1053/j.gastro.2020.02.039. PMID: 32359563. Given the safety profile and benefits, a trial of PPIs is recommended for inducing and maintaining remission.

b) Topical glucocorticoids are administered orally and swallowed by the patient (budesonide nebulization suspension 2 mg/d mixed with sucralose 5 mg, or fluticasone via a metered-dose inhaler 1000-2000 microg bid). This treatment is routinely continued for 8 weeks, and in patients with no response it may be repeated at the same or higher doses. There is a risk of thrush with both treatments.

c) Elimination diets: An elemental diet with total elimination of all food allergens or 4-food or 6-food elimination diet (removing soy, egg, milk, wheat, possibly peanut or tree nuts, and all seafood).

d) Esophageal dilation may be necessary for symptoms of dysphagia in patients who develop strictures.

e) Prevention.

4) Oral or parenteral glucocorticoids should be limited in their use to treat delayed hypersensitivity reactions as they have transient beneficial effects and significant adverse effects.

PreventionTop

Primary prevention of food allergy may be considered in infancy. It is critical to separate interventions during infancy to prevent food allergies from those associated with other benefits (eg, nutrition, maternal-infant bonding, brain development).

1. There are no specific diets or supplements for mothers that have been convincingly shown to influence the development of food allergy in their offspring.

2. Appropriate infant nutrition:

1) Currently available evidence, which is generally low quality, shows no association between breastfeeding and prevention of food allergies. The World Health Organization (WHO) guidelines recommend exclusive breastfeeding for all infants up to 6 months of life for its nutritional and other benefits, including the uncertain possibility of reduced incidence of infant wheeze, atopic dermatitis, and asthma.

2) If breastfeeding is not possible, consider formulas. Note that hydrolyzed formulas do not protect against cow’s milk allergy.

3) Elimination diets in breastfeeding mothers are not recommended.

Introduction of foods other than breast milk within 4 to 6 months of life while still breastfeeding is not associated with food allergiesEvidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Smith HA, Becker GE. Early additional food and fluids for healthy breastfed full-term infants. Cochrane Database Syst Rev. 2016 Aug 30;(8):CD006462. doi: 10.1002/14651858.CD006462.pub4. Review. PubMed PMID: 27574798. and may reduce the incidence of IgE-mediated allergy to certain foods such as milk, egg, or peanut.

TablesTop