Nut Allergies 

Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. ^{1 , 2 , 3} 

These immune responses may be immunoglobulin E (IgE)-mediated, non–IgE-mediated, or a result of multiple mechanisms.

• The term food intolerance refers to a non–immune-mediated reaction that may include metabolic, pharmacologic, or toxic mechanisms.
• Sensitization refers to having demonstrable IgE antibodies. Sensitization may occur in the absence of clinical symptoms.
• An immune-mediated food allergy requires both the presence of sensitization and clinical responsiveness when the food is ingested.

Epidemiology & Demographics

How common is nut allergies?

• Peanut allergy affects approximately 1.4% to 4.5% of children worldwide. ⁴
• Tree nut allergy is uncommon in the first year of life, likely because of limited tree nut consumption. At age 6 yr, tree nut allergy prevalence is similar to peanut allergy prevalence. More than a third of children with both peanut and egg allergy in infancy have tree nut allergy at age 6 yr. ⁵
• Approximately 20% of children with peanut allergy and 9% of children with tree nut allergy become tolerant to these foods with age. ⁶
• Children with peanut allergy are at greater risk for tree nut allergies, and previously patients with peanut allergy were advised to avoid all tree nuts because of the risk of coallergy and the risk for cross-contact with peanuts during processing. However, a study from the United Kingdom indicated that about 30% to 40% of peanut and tree nut allergic individuals are not sensitized to other tree nuts and tolerate them in their diets. ⁷
• A retrospective case series ⁸ found the majority of individuals with a peanut allergy or specific tree nut allergy passed oral food challenges to other tree nuts even when sensitized. Furthermore, development of tree nut allergy has been reported in sensitized but tolerant individuals after exclusion from the diet. ⁹ The British Society for Allergy and Clinical Immunology (BSACI) guidelines now recommend active inclusion of “nonallergic” nuts in diets of individuals with tree nut allergy, once tolerance has been ascertained. ¹⁰
• Cosensitization between peanuts and legumes is very high; however, clinical cross-reactions are rare, with only about 5% of those with a peanut allergy reacting to another legume. However, the legume lupine (lupin) appears to carry a greater risk of cross-reactivity with peanut, in particular Ara h 1, and it also cross-reacts with other legumes, so caution is warranted. ¹¹
• In recognition of the risk for cross-reactivity with peanut and the risk for having a primary allergy to lupine, the European Union and the United Kingdom have included lupine as a major allergen, with products containing lupine or its derivatives requiring full disclosure on E.U. and U.K. product labels. Lupine is not, however, considered a major allergen in the United States, Canada, or Australia. ¹²
• Tree nut allergies are usually lifelong and together with peanut allergy are the most common cause of food-induced anaphylaxis and related fatalities. ¹³ Unlike peanut allergy, population-based data regarding tree nut allergy are limited.
• Studies ¹⁴ have found that at 6 yr of age rates of tree nut allergy are almost as high as those of peanut allergy, with cashew the most common tree nut allergy.

Diagnosis

History & Physical Examination

• Common symptoms associated with nut allergy are summarized in the below table.

• Symptoms of Food-Induced Allergic ReactionsFrom Boyce JA et al: Guideline for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel, J Allergy Clin Immunol 126(6):S1–S58, 2010 (Table IV, p S19).Target OrganImmediate SymptomsDelayed SymptomsCutaneousErythema
  Pruritus
  Urticaria
  Morbilliform eruption
  AngioedemaErythema
  Flushing
  Pruritus
  Morbilliform eruption
  Angioedema
  Eczematous rashOcularPruritus
  Conjunctival erythema
  Tearing
  Periorbital edemaPruritus
  Conjunctival erythema
  Tearing
  Periorbital edemaUpper respiratoryNasal congestion
  Pruritus
  Rhinorrhea
  Sneezing
  Laryngeal edema
  Hoarseness
  Dry staccato coughLower respiratoryCough
  Chest tightness
  Dyspnea
  Wheezing
  Intercostal retractions
  Accessory muscle useCough, dyspnea, wheezingGastrointestinal (oral)Angioedema of the lips, tongue, or palate
  Oral pruritus
  Tongue swellingGastrointestinal (lower)Nausea
  Colicky abdominal pain
  Reflux
  Vomiting
  DiarrheaNausea
  Abdominal pain
  Reflux
  Vomiting
  Diarrhea
  Hematochezia
  Irritability and food refusal with weight loss (young children)CardiovascularTachycardia (occasionally bradycardia in anaphylaxis)
  Hypotension
  Dizziness
  Fainting
  Loss of consciousnessMiscellaneousUterine contractions
  Sense of “impending doom”

Laboratory Tests

Skin Testing

• Skin testing by the prick/puncture technique is an easy-to-perform, cost-effective method for identifying sensitization to a food and determining the probability that a food challenge is likely to be helpful. ¹²³
• Nut allergens eliciting wheal diameters of at least 3 mm or larger than the negative control are considered positive test results. Negative skin tests have a high negative predictive accuracy, thus usually excluding food allergy to common foods.
• The negative predictive accuracy for children younger than 3 or 4 yr of age tends to be lower than for older children. ¹²³
• Food extracts that elicit a positive result in the absence of a strong history of clinical reactivity typically have a positive predictive accuracy of less than 50% and cannot be considered diagnostic of symptomatic food allergy. Some studies suggest that larger skin tests (≥8-mm wheals for some foods) correlate better with symptomatic food allergy, but there is no clear correlation between skin test size and severity of reactions. ¹⁵
• If there is a history of a convincing allergic reaction to a food and the skin test is positive, the test may be viewed as diagnostic. Skin test outcomes can be variable depending on a few factors: Reagents and devices used for testing, experience of the testing personnel, and the interpretation of the test results. ¹⁶
• A strongly positive history incriminating a specific food in the face of a negative skin test must be evaluated further (e.g., food-specific serum IgE determination and/or physician-supervised oral food challenge [OFC]).
• Commercial skin test extracts vary considerably in allergen content. It is often very useful to use fresh fruits and vegetables for skin testing by the technique referred to as “prick to prick” especially when evaluating patients with pollen-food allergy syndrome. In this technique the fresh food is “pricked with the skin test device, and then the skin is pricked immediately.” ¹⁷

In Vitro Testing

• Numerous studies have shown that specific serum antibody levels correlate well with the outcome of OFCs, especially for peanut, egg, milk, and tree nuts, but there is less information on fish, shellfish, and a few other foods. ¹
• There is no consensus on whether skin tests or specific serum antibody levels are most sensitive. However, meta-analysis suggests that skin prick/puncture tests and immunoassays have similar sensitivities and specificities compared with double-blind, placebo-controlled food challenges. ¹⁸
• Additional diagnostic insight may be obtained by performing IgE antibody tests to specific proteins within foods (components). The benefit of component testing primarily results from the fact that different food proteins may contribute differentially to the allergenic potential of a food. For example, in peanut, the proteins Ara h 2 and Ara h 6 are stable to digestion, and IgE binding to these proteins is particularly correlated with reactions. ¹⁹ In contrast, Ara h 8 in peanut is a labile pollen-homologous protein, and IgE binding to this protein is often not related to clinical reactivity or only mild symptoms. ²⁰

Predictive Value of Food-Specific Immunoglobulin E

Allergen	∼95% Reaction Decision Point (kU A /L)	≤50% Reaction Rechallenge Value (kU A /L)
Egg	≥7.0	≤1.5
≤2 yr old	≥2.0
Milk	≥15.0	≤7.0
≤2 yr old	≥5.0
Peanut	≥14.0	≤5.0
Fish	≥20.0
Tree nuts	≥15.0	≤2.0

NOTE: Patients with food-specific IgE values less than the listed diagnostic values may experience an allergic reaction after challenge. Unless history strongly suggests tolerance, a physician-supervised food challenge should be performed to determine whether the child can ingest the food safely.

• Component TestsFrom Leung DYM et al: Pediatric allergy: principles and practice, ed 4, Philadelphia, 2021, Elsevier.FoodComponent Associated with Significant ReactionComponent Not Typically Associated with Significant ReactionPeanutAra h 2, Ara h 6, Ara h1, Ara h 3, Ara h 9Ara h 8EggOvomucoidOvalbuminWalnutJug r 1, Jug r 3CashewAna o 3BrazilBer e 1MilkCaseinα Lactalbumin, β lactoglobulinHazelnutCor a 14, Cor a 9, Cor a 8Cor a 1
• Atopy patch tests have not been found to be consistently useful for detection of clinically significant food allergy, and a number of additional tests, such as applied kinesiology, resistance testing, hair analysis, and others, are considered unproved and experimental and not recommended. ²

Food Challenges

• The best test for food allergy is observing whether a food is tolerated when ingested. This is why the history is so influential in diagnosis.
• When history and skin or serum testing is not sufficient for a diagnosis, a medically supervised gradual feeding, an OFC can be undertaken. The double-blind, placebo-controlled oral food challenge (DBPCFC) is the gold standard for precise diagnosis of allergic reactions to foods and has provided a standard by which to evaluate other tests. ²¹

Treatment

• •The most serious manifestation of nut allergy is anaphylaxis.
• •The diagnosis of anaphylaxis is a clinical emergency that is relatively common and requires immediate recognition.Clinical Criteria for Diagnosing Anaphylaxis
• Anaphylaxis is highly likely when any one of the following three criteria is fulfilled
  • 1.Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized urticaria, itching or flushing, swollen lips-tongue-uvula) and at least one of the following:2.Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, hypoxemia)3.Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
  ORTwo or more of the following that occur rapidly after exposure to a likely allergen (or other trigger) for that patient (minutes to several hours)
  • 1.Involvement of the skin/mucosal tissue (e.g., generalized urticaria, itch-flush, swollen lips-tongue-uvula)2.Respiratory compromise (e.g., dyspnea, wheeze or bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)3.Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)4.Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
  ORReduced blood pressure after exposure to a known allergen or other trigger for that patient (minutes to hours)
  • Infants and children: Low systolic blood pressure (age-specific) or greater than 30% decrease in systolic blood pressure
  • Adults: Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from that person’s baseline

Pharmacologic Therapy

Here are the lists medications used in anaphylaxis. 

Drugs and Other Agents Used in Anaphylaxis Therapy

Drug	Dose/Route of Administration	Comment
Epinephrine	Adult: 0.3-0.5 mL of 1:1000 (1 mg/mL) solution, IM lateral thigh Child: 0.01 mg/kg of 1:1000 (1 mg/mL) solution, to a maximum of 0.3 mL, IM lateral thigh	Initial drug of choice for all anaphylactic episodes; should be given immediately; may repeat every 5-15 minutes if needed
Antihistamines
H 1 antihistamine Diphenhydramine	Adult: 25-50 mg IM or IV Child: 1 mg/kg or 12.5-25 mg IM or IV	For relief of itching and urticaria
H 2 antihistamine Ranitidine	Adult: 50 mg IV or 1 mg/kg IV Child: 1 mg/kg IV
Drugs for Resistant Bronchospasm
Aerosolized β 2 -agonist Albuterol	Adult: 2.5 mg/3 mL or 5 mg/3 mL given by nebulizer and face mask Child: 2.5 mg/3 mL given by nebulizer and face mask	Useful for bronchospasm not responding to epinephrine
Corticosteroids
Hydrocortisone	Adult: 200 mg IV or IM Child: maximum 100 mg IV or IM	Exact dose not established
Methylprednisolone	Adult: 50-100 mg IV Child: 1 mg/kg, maximum 50 mg IV
Volume Expanders
Isotonic (0.9%) saline	Adult: 1000-2000 mL rapidly (i.e., 5-10 mL/kg in first 5-10 min) Child: 10-20 mL/kg in first 5-10 min	Rate titrated to BP response for IV volume expander After initial infusion, further administration requires tertiary care monitoring; larger amounts may be needed in β-blocked patients
Drugs in β-Blocked Patients
Glucagon	Initial dose of 1-5 mg IV, followed by infusion of 5-15 μg/min titrated to BP response	Glucagon probably drug of choice
Atropine sulfate	Adult: 0.3-0.5 mg IV; may repeat every 10 minutes to maximum 2 mg	Atropine probably useful only for bradycardia
Ipratropium	0.5 mg via nebulizer and face mask	As alternative or added to inhaled β-blockers for wheezing

BP, Blood pressure; IM, intramuscularly; IV, intravenously; PO, orally.

Treatment

Intramuscular injection of epinephrine at early signs of an anaphylactic reaction.

General Interventions

• 1.Obtain thorough history for drug allergy.
• 2.Avoid drugs that have immunologic or biochemical cross-reactivity with any agents to which patient is sensitive.
• 3.Administer drugs orally rather than parenterally, when possible.
• 4.Check all drugs for proper labeling.
• 5.Keep patients in the office 30 minutes after allergen immunotherapy injections.
• 6.Follow guideline for observation after specific drugs that are known to have an increased incidence of anaphylaxis (e.g., omalizumab, ecallantide).

Measures for Patients at Risk

• 1.Have patient wear and carry warning identification tags.
• 2.Teach self-injection of epinephrine, and advise patients to carry an epinephrine autoinjector.
• 3.Discontinue β-adrenergic blockers, angiotensin-converting enzyme inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors when possible.
• 4.Use preventive techniques when patients undergo a procedure or take an agent that places them at risk, including pretreatment, provocative dose challenge, and desensitization.

Immediate Action

• 1.Perform assessment
• 2.Check airway and secure if needed
• 3.Rapidly assess level of consciousness
• 4.Assess vital signs

Treatment

• 1.Epinephrine intramuscularly
• 2.Supine position, legs elevated
• 3.Oxygen
• 4.Tourniquet proximal to injection site (if following allergen immunotherapy)

Dependent on Evaluation

• 1.Peripheral intravenous fluids
• 2.Glucagon
• 3.H ₁ and H ₂ antihistamines
• 4.Vasopressors
• 5.Corticosteroids
• 6.Atropine
• 7.Electrocardiographic monitoring
• 8.Transfer to hospital

Hospital Management

• 1.Pressor therapy
• 2.Continued therapy with listed agents and management of complications

Equipment and Medications for Office Therapy of Anaphylaxis

Primary

• 1.Epinephrine solution (aqueous) 1:1000 (1-mL ampules and multidose vials)
• 2.Tourniquet
• 3.1-mL and 5-mL disposable syringes
• 4.Oxygen tank and mask/nasal prongs
• 5.Diphenhydramine injectable
• 6.Intravenous setup with large-bore catheter
• 7.Intravenous fluids: 2000 mL crystalloid
• 8.Aerosol β ₂ -bronchodilator and nebulizer
• 9.Glucagon
• 10.Defibrillator
• 11.Normal saline (10-mL vial for epinephrine dilution)

Prevention

• The development of specific food allergies such as peanut allergy can be prevented in some individuals through interventions in the first year of life; the protective effects of these interventions so far appear to be allergen specific. ²²
• Modifying the age at which allergenic foods such as egg and peanut are introduced into the infant diet is currently the only strategy that has been convincingly shown to prevent food allergy in randomized controlled trials. ²³
• One study showed that introduction of peanut into an infant’s diet from 4 to 11 mo of age led to an approximately 80% reduction in peanut allergy compared with peanut avoidance until 5 yr of age in a high-risk group of infants.
• Current U.S. guidelines specifically targeting peanut allergy prevention recommend introduction of peanut at 4 to 6 mo of age for infants with severe eczema, egg allergy, or both. ²⁴
• The dose of peanut recommended by current U.S. guidelines for children at high risk are for 6 to 7 g of peanut per week over three or more feedings. ²⁴

References

1.Sicherer S.H., Sampson H.A.: Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, prevention, and management . J Allergy Clin Immunol 2018; 141: pp. 41-58.

2.Boyce A., Assa’ad A., Burks A.W., et al.: Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report . J Allergy Clin Immunol 2010; 126: pp. 1105-1118.

3.Sampson H.A., Aceves S., Bock S.A., et al.: Food allergy: a practice parameter update-2014 . J Allergy Clin Immunol 2014; 134: pp. 1016-1025. e43 .

4.Sicherer S.H., Sampson H.A.: Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, prevention, and management . J Allergy Clin Immunol 2018; 141: pp. 41-58.

5.Skolnick H.S., Conover-Walker M.K., Koerner C.B., et al.: The natural history of peanut allergy . J Allergy Clin Immunol 2001; 107: pp. 367-374.

6.Fleischer D.M., Conover-Walker M.K., Matsui E.C., et al.: The natural history of tree nut allergy . J Allergy Clin Immunol 2005; 116: pp. 1087-1093.

7.Venter C., Groetch M., Netting M., Meyer R.: A patient-specific approach to develop an exclusion diet to manage food allergy in infants and children . Clin Exp Allergy 2018; 48: pp. 121-137.

8.Couch C., Franxman T., Greenhawt M.: Characteristics of tree nut challenges in tree nut allergic and tree nut sensitized individuals . Ann Allergy Asthma Immunol e3 2017; 118: pp. 591-596.

9.Elizur A., Bollyky J.B., Block W.M.: Elimination diet and the development of multiple tree-nut allergies . Pediatric Res 2017; 82: pp. 671-677.

10.Eigenmann P.A., Lack G., Mazon A., et al.: Managing nut allergy: a remaining clinical challenge . J Allergy Clin Immunol 2017; 5: pp. 296-300.

11.Venter C., Groetch M., Netting M., Meyer R.: A patient-specific approach to develop an exclusion diet to manage food allergy in infants and children . Clin Exp Allergy 2018; 48: pp. 121-137.

12.Gendel S.M.: Comparison of international food allergen labeling regulations . Regul Toxicol Pharmacol 2012; 63: pp. 279-285.

13.Ewan P.W.: Clinical study of peanut and nut allergy in 63 consecutive patients: new features and associations . BMJ 1996; 312: pp. 1074-1078.

14.Clark A.T., Ewan P.W.: The development and progression of allergy to multiple nuts at different ages . Pediatr Allergy Immunol 2005; 16: pp. 507-511.

15.Hill D.J., Heine R.G., Hosking C.S.: The diagnostic value of skin prick testing in children with food allergy . Pediatr Allergy Immunol 2004; 15: pp. 435-441.

16.Tversky J.R., Chelladurai Y., McGready J.: Performance and pain tolerability of current diagnostic allergy skin prick test devices . J Allergy Clin Immunol Pract 2015; 3: pp. 888-893.

17.Begin P., Des R.A., Nguyen M.: Freezing does not alter antigenic properties of fresh fruits for skin testing in patients with birch tree pollen-induced oral allergy syndrome . J Allergy Clin Immunol Pract 2011; 127: pp. 1624-1626.

18.Chafen J.J., Newberry S.J., Riedl M.A., et al.: Diagnosing and managing common food allergies: a systematic review . JAMA 2010; 303: pp. 1848-1856.

19.Klemans R.J., van Os-Medendorp H., Blankestijn M.: Diagnostic accuracy of specific IgE to components in diagnosing peanut allergy: a systematic review . Clins Exp Allergy 2015; 45: pp. 720-730.

20.Asarnoj A., Nilsson C., Lidholm J., et al.: Peanut component Ara h 8 sensitization and tolerance to peanut . J Allergy Clin Immunol 2012; 130: pp. 468-472.

21.Bird J.A., Groetch M., Allen K.J., et al.: Conducting an oral food challenge to peanut in an infant . J Allergy Clin Immunol Pract 2017; 5: pp. 301-311. e1 .

22.du Toit G., Sayre P.H., Roberts G., et al.: Allergen specificity of early peanut consumption and effect on development of allergic disease in the Learning Early about Peanut Allergy study cohort . J Allergy Clin Immunol 2018; 141 (4): pp. 1343-1353.

23.Du Toit G., Roberts G., Sayre P.H.: Randomized trial of peanut consumption in infants at risk for peanut allergy . N Engl J Med 2015; 372 (9): pp. 803-813.

24.Togias A., Cooper S.F., Acebal M.L., et al.: Addendum guidelines for the prevention of peanut allergy in the United States: report of The National Institute of Allergy and Infectious Diseases-sponsored expert panel . J Allergy Clin Immunol 2017; 139 (1): pp. 29-44.