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Food Allergy Learning Zone
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Diagnosing food allergy

Declaration of sponsorship Novartis Pharma AG
Read time: 45 mins
Last updated:4th Aug 2021
Published:4th Aug 2021

Learn about the pathophysiology of IgE-mediated food allergy and the tests used to support its diagnosis. Discover:

  • Mechanisms of oral tolerance and sensitisation in our infographic
  • The diagnostic pathway of food allergy in our interview with Dr Alexandra Santos
  • A summary of diagnostic tests in our underlying mechanisms of sensitisation diagram

Pathophysiology of food allergy

Both oral tolerance and sensitisation can be promoted by five key components of the immune system: the epithelium, innate immune cells, T cells, B cells, and effector cells1.

A greater understanding of these underlying mechanisms is essential for the diagnosis and treatment of immunoglobulin E (IgE)-mediated food allergy as well as the development of novel therapeutics and diagnostic techniques.

Explore IgE sensitisation with Dr Santos and discover the complex pathophysiology of IgE-mediated food allergy.

What is oral tolerance?

Oral tolerance is the process of immune unresponsiveness to orally ingested antigens. It is initiated when antigenic material is sampled from the intestinal lumen by CX3CR1 macrophages, which is then processed by non-activated dendritic cells (Figure 1)1,2.

These non-activated dendritic cells then present the food peptide, displayed on the major histocompatibility complex (MHC), to the T cell receptors (TCR) on naïve T cells1,2.

This causes naïve T cell differentiation into T regulatory cells (Tregs), which then travel via α4β7 to the lamina propria. These Tregs support the maintenance of tolerance via CTLA-4 expression and the release of transforming growth factor-beta (TGF-β) and interleukin (IL)-101,2.

Pathogenic type 2 helper T (TH2) cells play a central role in the pathophysiology of allergic disease3

CTLA04 then suppresses antigen-specific TH2 cells, while TGF-β and IL-10 inhibit effector cells: eosinophils, basophils, and mast cells. In the presence of IL-10 and TGF-β, B cells produce IgA and IgG4 that are necessary for maintaining tolerance while suppressing IgE production1,2.

An intact epithelial barrier also plays an essential role in the maintenance of tolerance and the loss of integrity of this barrier can lead to sensitisation to food allergens and the development of food allergy1,2.

T2 Food Allergy_Fig1.png

Figure 1. Overview of the tolerogenic (left) and allergic (right) response to food antigen in the gut (Adapted1). CTLA-4, cytotoxic T lymphocyte-associated antigen-4; CX3CR1, C-X3-C Motif Chemokine Receptor 1; DC, dendritic cells; IgA, immunoglobulin A; IgE, immunoglobulin E; IL, interleukin; ILC2, type 2 innate lymphoid cells; MHC, major histocompatibility complex; TCR, T cell receptors; TGF-β, transforming growth factor-beta; TH2, type 2 helper T cells; TH9, type 2 helper T cells; Tregs, T regulatory cells; TSLP, thymic stromal lymphopoietin.

What is sensitisation?

Allergic sensitisation is the first step of the allergic immune response following exposure to an allergen. It is defined by the presence of detectable food-specific IgE (in blood or by skin prick test), which can lead to the development of clinical food allergy1,2.

Sensitisation occurs when a food allergen triggers the secretion of pro-inflammatory cytokines, such as IL-33, IL-25, and thymic stromal lymphopoietin (TSLP). This promotes the expansion of type innate lymphoid cells (ILCs) and activates dendritic cells that usually defend against pathogens1,2.

Activated dendritic cells then take up and process the antigen into short peptides in addition to upregulating the expression of the surface protein OX40L. The interaction of MHC and OX40L on dendritic cells with TCR and OX40 on naïve T cells then triggers the differentiation of naïve T cells to TH2 cells, which are central to the pathophysiology of food allergy1,2.

What are the effector cells of allergic reactions?

Following differentiation, TH2 cells and ILCs secrete pro-inflammatory cytokines, such as IL-5 and IL-13, which promotes the recruitment of eosinophils and basophils. TH2 cells also secrete IL-4, which prompts food allergen-specific B cells to class switch, leading to amplified production of food antigen-specific IgE antibodies and a state of sensitisation and allergy1,2.

TH9 cells are also involved in the development of the allergic response through the secretion of IL-9, which promotes the recruitment of mast cells1,2

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Diagnostic pathway for food allergy

The precise diagnosis of food allergy is essential for guiding safe and suitably restrictive dietary management, while minimising the impact on a patients’ quality of life6,7. The foundation of accurate diagnosis is the clinical history, which is reviewed in the context of the clinical manifestations and the epidemiology of food allergy7,8.

Get to know the optimal diagnostic pathway with Dr Sharon Chinthrajah, from collecting a comprehensive clinical history to specific testing.

What is the key information to collect from a clinical history?

A comprehensive clinical history is essential for establishing the pre-test probability of food allergy and guiding further investigations7. A detailed clinical history, using structured questions, is recommended by various international guidelines for the diagnosis of food allergy9,10. As part of a clinical history, there are numerous important pieces of information to collect (Table 1), including dietary history, timing and chronicity, reproducibility, known risk (co)factors, and coexisting conditions10,11.

Table 1. Key information to collect from a clinical history (Adapted11). NSAID, non-steroid anti-inflammatory drug.

Key information Examples
Offending food
Cow’s milk, egg, wheat, soy, peanut, tree nut, fish, shellfish
(accounting for 90% of reactions)
Timing of exposure to onset of symptoms Minutes to hours (usually within the first two hours); however,
late reactions can occur with normal foods and within three to six hours after ingestion of red meat, such as beef, pork and lamb in “Alpha Gal” allergy
Route of exposure Oral ingestions tend to have more severe reactions; mild skin
reactions occur with cutaneous exposure
Type of food Oral pruritus with raw forms of fruits or vegetables, but
tolerance of cooked forms, would suggest oral allergy syndrome
Nature of symptoms Cutaneous, gastrointestinal, and respiratory symptoms
predominate
Duration of symptoms Less than one hour to several hours; however, late reactions and biphasic reactions can occur
Treatment of symptoms Responsive to antihistamines and/or epinephrine
Dietary history Foods eaten before and after an allergic episode without
reaction are typically not the culprit of an IgE-mediated food allergy (exception is Exercise Induced Anaphylaxis); note avoidance patterns
Supplemental factors Alcohol consumption, NSAID use, exercise, concurrent Illness

Food allergy can also lead to poor growth in children, necessitating the intervention of a dietician. A physical examination should therefore assess the growth and development of children, in addition to their nutritional status, especially in children with multiple food allergies7.

What conditions induce a similar clinical manifestation to IgE-mediated food allergy?

It is also important to consider alternative diseases, triggers, and syndromes with similar clinical manifestations to IgE-mediated food allergy, such as11,12:

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Diagnostic tests for IgE-mediated food allergy

Following the collection and interpretation of a clinical history, when IgE-mediated food allergy is suspected, further evidence of sensitisation can then be obtained through appropriately selected diagnostic tests9,10.

Join Dr Santos and examine the skin prick test (SPT) and serum IgE (sIgE) diagnostic tests and learn the importance of assessing these widely used tools in combination with a clinical history and the wider clinical context.

What diagnostics are commonly used for diagnosing food allergy?

Two commonly utilised standardised tests to determine the causative food are the skin prick test (SPT) and the measurement of total and allergen-specific sIgE levels in whole extracts (Figure 2)7.

T2 Food Allergy_Fig2.png

Figure 2. The diagnostic tests used to diagnose IgE-mediated food allergy utilise specific aspects of the underlying mechanisms of sensitisation (Adapted13). IgE, immunoglobulin E; IgG, immunoglobulin G.

The skin prick test entails pricking the skin with various candidate food allergens to measure the response of cutaneous mast cells to allergen. A wheal and flare response within 15 minutes suggests the presence of cutaneous mast cells with allergen specific bound IgE13,14.

By contrast, the measurement of total IgE or sIgE utilises fluorescent enzyme immune assays to detect the presence of either total or serum IgE to allergen extracts or individual allergen components. Ratios with allergen sIgE can be calculated using total IgE and allergen-specific IgG413,14.

The basophil activation test (BAT) is an emerging test that measures the response of circulating basophils to allergen that has shown high sensitivity and specificity, but is not yet fully commercialised15.

In isolation, SPT and sIgE should not be considered diagnostic as they indicate IgE sensitisation but not necessarily the development of a clinically significant food allergy9–11

Careful patient selection, with diagnostic testing guided by clinical histories, is advised as these tests are associated with a high rate of false positive or false negative diagnoses that can lead to unwarranted dietary restrictions or delayed diagnostic workups9–11.

Diagnoses should then be confirmed with oral food challenges or elimination diets assessing the clinical symptoms associated with the ingestion of the suspected food allergen11.

What are the predictive values of SPTs and sIgE?

The threshold values for SPTs and sIgE have been determined for several allergens (Table 2) that define the 95% Positive Predictive Value (PPV) likelihood of patients having a reaction during a food challenge11.

Table 2. >95% positive predictive value for SPT weal diameter and sIgE level for a positive oral food challenge. SPT, skin prick test; sIgE, specific IgE (Adapted7).

Food SPT (mm) slgE (kU/L)
Egg White ≥7 ≥7
Cow’s Milk ≥8 ≥15
Peanut ≥8 ≥14
Sesame ≥8 ≥7
Fish Undetermined ≥20
Wheat Undetermined ≥100

Compared with the oral food challenge, SPTs have a low specificity and Positive Predictive Value for an initial diagnosis of food allergy7. Moreover, SPTs have a high sensitivity and high negative predictive values (NPV>90%), which can be a valuable tool for excluding food allergy7.

However, it is possible to have negative SPTs in patients with IgE-mediated food allergy. In cases of negative SPTs where clinical histories suggest food allergy, further evaluation and OFC should be carried out7.

In a systematic review (N=2,831) investigating the accuracy of tests used to diagnose food allergy, both sIgE and SPT showed reasonable sensitivity (70–100%) and moderate specificity (40–70%) using the double-blind, placebo-controlled food challenge as a reference standard16. However, the sensitivity and specificity of both diagnostic tests varied due to differences between studies and the specific food being studied16.

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References

  1. Anvari S, Miller J, Yeh CY, Davis CM. IgE-Mediated Food Allergy. Clin Rev Allergy Immunol. 2019;57(2):244–260.
  2. Fu L, Cherayil BJ, Shi H, Wang Y, Zhu Y. Food allergy: From molecular mechanisms to control strategies. 2019. Springer Singapore doi:10.1007/978-981-13-6928-5.
  3. Bertschi NL, Bazzini C, Schlapbach C. The Concept of Pathogenic TH2 Cells: Collegium Internationale Allergologicum Update 2021. Int Arch Allergy Immunol. 2021;182(5):365–380.
  4. Hoh RA, Joshi SA, Lee JY, Martin BA, Varma S, Kwok S, et al. Origins and clonal convergence of gastrointestinal IgE+ B cells in human peanut allergy. Sci Immunol. 2020;5(45). doi:10.1126/sciimmunol.aay4209.
  5. Hemmings O, Niazi U, Kwok M, James LK, Lack G, Santos AF. Peanut diversity and specific activity are the dominant IgE characteristics for effector cell activation in children. J Allergy Clin Immunol. 2021. doi:10.1016/j.jaci.2021.02.029.
  6. Bird JA, Crain M, Varshney P. Food Allergen Panel Testing Often Results in Misdiagnosis of Food Allergy. 2015. doi:10.1016/j.jpeds.2014.07.062.
  7. Gomes-Belo J, Hannachi F, Swan K, Santos AF. Advances in Food Allergy Diagnosis. Curr Pediatr Rev. 2018;14(3):139–149.
  8. Sicherer SH, Sampson HA. Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management. J Allergy Clin Immunol. 2018;141(1):41–58.
  9. Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the diagnosis and management of food allergy in the United States: Report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 SUPPL.):S1.
  10. Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C, et al. EAACI Food Allergy and Anaphylaxis Guidelines: Diagnosis and management of food allergy. Allergy Eur J Allergy Clin Immunol. 2014;69(8):1008–1025.
  11. Chinthrajah RS, Tupa D, Prince BT, Block WM, Rosa JS, Singh AM, et al. Diagnosis of Food Allergy. Pediatr Clin North Am. 2015;62(6):1393–1408.
  12. National Institute for Health and Clinical Excellence (NICE). Differential diagnosis | Diagnosis | Food allergy. 2018. https://cks.nice.org.uk/topics/food-allergy/diagnosis/differential-diagnosis/. Accessed 1 June 2021.
  13. Santos AF, Brough HA. Making the Most of In Vitro Tests to Diagnose Food Allergy. J Allergy Clin Immunol Pract. 2017;5:237–248.
  14. Salazar A, Velázquez-Soto H, Ayala-Balboa J, Jiménez-Martínez MC. Allergen-Based Diagnostic: Novel and Old Methodologies with New Approaches. In: Allergen. 2017. InTech doi:10.5772/intechopen.69276.
  15. Lopes JP, Sicherer S. Food allergy: epidemiology, pathogenesis, diagnosis, prevention, and treatment. Curr Opin Immunol. 2020;66:57–64.
  16. Soares-Weiser K, Takwoingi Y, Panesar SS, Muraro A, Werfel T, Hoffmann-Sommergruber K, et al. The diagnosis of food allergy: A systematic review and meta-analysis. Allergy Eur J Allergy Clin Immunol. 2014;69(1):76–86.
  17. Sindher S, Long AJ, Purington N, Chollet M, Slatkin S, Andorf S, et al. Analysis of a large standardized food challenge data set to determine predictors of positive outcome across multiple allergens. Front Immunol. 2018;9(NOV):2689.
  18. Yu W, Freeland DMH, Nadeau KC. Food allergy: Immune mechanisms, diagnosis and immunotherapy. Nat Rev Immunol. 2016;16(12):751–765.
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