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Investigation of immediate-onset IgE-mediated food allergy

Johannes Kock, MB ChB, MMed (Chem Path)

Chemical Pathologist, PathCare Reference Laboratory, PathCare Park, N1City, Goodwood, Cape Town

Correspondence to: J Kock (jkock@pathcare.co.za)

It is important to differentiate between food allergy and other causes of adverse reactions to food because patients with severe immediate-onset IgE-mediated food allergy are at risk of developing anaphylaxis that may cause death (Fig. 1).

Up to 35% of the population in Western countries self-report ‘food allergies’, but the true prevalence is probably between 3% and 6% in children and 1% and 4% in adults.1 Approximately 90% of documented cases of food allergy in the USA are caused by a relatively small number of foods that comprise cow’s milk, egg, soy, wheat, peanut, tree nuts, fish and shellfish. Food-induced anaphylaxis is caused mainly by peanut, followed by tree nuts, fish, cow’s milk and egg.

Laboratory investigations

Current food allergy guidelines emphasise that a true diagnosis of immediate-onset IgE-mediated food allergy requires a positive history of clinical allergy to a specific food as well as a positive allergy test that matches that history.2

Any investigation into food allergy has to commence with a detailed allergy-focused history and examination, followed by a selection of appropriate tests to confirm or exclude allergy. It is important to distinguish between sensitisation (the presence of allergen-specific IgE antibodies) and allergy (the presence of sensitisation plus clinical signs and symptoms of allergic reactivity). Skin-prick tests (SPTs) and blood allergen-specific IgE tests measure sensitisation, while oral food challenge tests measure clinical reactivity.

Skin-prick test

A SPT is an indirect qualitative measurement of IgE sensitisation. A positive SPT is triggered by specific allergen-induced cross-linking of IgE antibodies on sensitised mast cells and the subsequent release of histamine that causes an itch, a flair and a wheal response at the prick site. Although this immune-mediated mechanism is by far the most potent trigger of mast cell degranulation, there are other non-immune mediated triggers that have similar effects. SPTs are sensitive (few false negative results), but they lack specificity (many false positive results). A SPT only has a 50% positive predictive value (PPV) for the diagnosis of food allergy in the absence of a clear history. Interpreting SPTs without a proper evaluation of the supporting history often leads to the over-diagnosis of food allergy.

Certain constraints need to be considered before ordering a SPT. Medications that inhibit the typical histamine reaction should be stopped (Fig. 2). SPTs cannot be performed in patients with dermatographism, or when there is extensive atopic dermatitis or eczema. SPTs should not be selected as first-line tests if there is a history of severe reactions to specific foods, because of the risk of allergen-induced anaphylaxis during the test. None of the former constraints applies to allergen-specific IgE (sIgE) blood tests.

Allergen-specific IgE

The acronym RAST (radioallergosorbent test) is still erroneously used to refer to new-generation sIgE tests, which provide a better measurement of allergen-specific IgE antibodies than RASTs. A positive blood test indicates that specific antibodies are/have been made to a specific food antigen. It confirms sensitisation of the individual, but not necessarily allergy, because <50% of sensitised individuals develop signs and symptoms of allergy during their lifetime. A positive diagnosis of IgE-mediated food allergy requires evidence of both sensitisation and clinical reactivity; a positive sIgE alone cannot confirm allergy in the absence of a clear history of allergy to that food.

sIgE is reported in quantitative units. This allows manipulation of cut-off points to improve the diagnostic specificity of sIgE; the higher the chosen diagnostic cut-off level, the more likely the diagnosis of allergy becomes. Diagnostic cut-off points with a 95% PPV for allergy have been determined for a number of the most important food allergens. They are recommended for use when properly validated (Fig. 3).1 Unfortunately, such cut-off points are not available for other allergens. It should also be borne in mind that >50% of patients will have sIgE values that are <95% PPV cut-off points; their diagnoses will rely on the supportive history and oral food challenge data.

Although sIgE is generally, but not invariably, less sensitive than SPT, current guidelines indicate that negative tests can be used to rule out allergy in most patients. In instances where sIgE and SPT results are both negative and where the history of allergy is highly suggestive, oral food challenge (OFC) tests have to be done to exclude allergy with more certainty.

Oral food challenge test

The double-blind placebo-controlled food challenge (DBPCFC) is still the gold standard for the diagnosis of food allergy; all allergy guidelines emphasise its importance and encourage its use.2 A DBPCFC is recommended to confirm a diagnosis of food allergy in all instances where there are no reliable 95% PPV diagnostic cut-off points and where the history of allergy is equivocal. A DBPCFC is also indicated if there is a clear mismatch between history and laboratory data. It is costly and time consuming and very few centres in South Africa are equipped to do DBPCFCs routinely.

Single-blind placebo-controlled food challenges (SBPCFCs) and open food challenges are more readily available, but unlike DBPCFCs they do not eliminate clinician and patient bias. Despite this limitation, negative challenges with such tests are considered diagnostic for ruling out food allergy, but the predictive value of positive tests (when allergic symptoms are elicited) is less certain and relies on supportive history and other laboratory test data.

Because of the risk of anaphylaxis in patients with a history of severe allergic reactions, especially in patients with asthma, OFC tests must be conducted in facilities with on-site medical supervision that are properly equipped to deal with medical emergencies. The same applies to SPTs with food allergens.

Evaluation of tolerance

Prolonging avoidance diets unnecessarily is harmful and has a negative impact on patients’ nutritional health and psychosocial wellbeing.

The majority of allergic children develop tolerance to cow’s milk, egg, soy and wheat between the ages of 3 and 16 years. Approximately 20% of peanut-allergic children will develop tolerance, while <10% outgrow allergy to tree nuts. The likelihood of outgrowing allergy to fish and shellfish is slim and adults who develop any type of food allergy are less likely to develop tolerance than children.

A high initial level of sIgE against food is usually associated with a lower rate of resolution of clinical allergy over time, while declining sIgE levels in children (but not always in adults) is an indication that tolerance is developing. Following quantitative sIgE values over time helps to determine when it is safe to do an OFC test to decide whether an avoidance diet can be stopped. Annual sIgE testing is accepted practice for milk, egg, soy, and wheat, while the test interval can be increased up to three years for peanut, tree nuts, fish and shellfish.

SPTs remain positive long after patients have developed tolerance; they are better suited for initial diagnosis rather than follow-up. Inadvertent sensitisation to specific allergens is also a theoretical possibility during a SPT.

Limitations of traditional diagnostic tests

There are currently no diagnostic tests that can accurately predict anaphylaxis or the severity of future reactions in patients who are allergic to certain foods.

Traditional allergy tests are based on crude natural food extracts that consist of complex mixtures of allergenic and non-allergenic proteins and other molecules.5 Those based on such extracts are useful screening tests for allergy, but do not discriminate between primary sensitisation to major or minor allergens that have either more or less potential to elicit allergenic reactivity. They also do not discriminate between sensitisation to single or multiple allergens in extract mixtures, and can’t establish whether positive reactions are due to cross-reactivity or co-sensitisation to allergenic proteins that are not species specific and that might be very similar to proteins in other foods or pollen to which the patient has been exposed.

Food extracts are very difficult to standardise owing to the complexity of the components in the extracts and the variability of natural products and their endogenous degradation processes. This explains the lack of diagnostic sensitivity and specificity of SPTs and sIgEs that are based on primary food extract mixtures.

Component-resolved diagnostics (CRD) and recombinant allergens

Component-resolved diagnostics (CRDs) and molecular allergology attempt to circumvent the above-mentioned problems. CRDs focus on the use of mono-component sIgE tests that are based on single native allergenic proteins (purified from complex natural food extracts), or on single recombinant antigens (obtained from biogenetically engineered protein fragments that are virtually identical to major IgE-binding epitopes identified on various allergenic food proteins).

Standardisation of recombinant sIgE (rsIgE), either as a single artificial component test or as tests based on mixtures of artificial recombinant allergens, is significantly better than tests based on purified native extracts (nsIgE) and is clearly superior to tests based on crude food extracts. The development of standardised recombinant allergen rsIgE tests has provided clinicians with quantitative tools that can delve more deeply into the precise aetiology of allergy.

Recombinant allergen-based tests have some limitations, however. Individuals are exposed to allergens from natural sources and not to recombinant proteins. They are capable of developing antibodies to a range of different fragments of natural allergens that will not necessarily be present in recombinant allergen-based tests. The use of CRDs and recombinant allergens is currently not recommended to replace, but rather to complement and refine, the results obtained from traditional diagnostic tests.

CRD and peanut allergy

Peanut allergy is the most common cause of food-induced anaphylaxis, but not all peanut-allergic patients have the same risk for anaphylaxis and not all require a strict avoidance diet. Each of the 13 peanut allergens currently identified has its own specific risk- and cross-reactivity profile and each peanut-allergic patient may be sensitised to any one or more of those allergens. This variation explains why some peanut-allergic patients have a higher risk for anaphylaxis and are unlikely to become tolerant, and why some of them will tolerate tree nuts while others will not. A positive peanut recombinant Ara h 2 rsIgE has for example become an established risk factor to differentiate patients with true peanut allergy from those who are sensitised but clinically tolerant to peanuts.6

CRDs have helped to elucidate the varied nature and risk profiles of other important foods, such as tree nuts, fish, milk, egg, soy, wheat, where recombinant allergens play an increasingly important diagnostic role.5

Microarrays and comprehensive allergen profiles

A comprehensive allergen profile is required to fully understand an individual’s specific risk and cross-reactivity profile. The development of biochip protein-microarrays in combination with multiplexing technology has enabled the simultaneous analysis of large numbers of different allergens on minute samples in a cost-efficient manner. The ImmunoCap ISAC microarray is available in South Africa and provides semi-quantitative measurement of 112 mono-components from more than 50 allergen sources. Nanotechnology benefits paediatric diagnosis, because it requires very little blood to do a comprehensive allergen profile. It is mainly indicated for patients with multiple food and inhalant allergies. Its main drawbacks are onerous validation procedures and the risk of overdiagnosis; it requires specialist knowledge to prevent misinterpretation of the complex results of these tests.7

Ongoing research is required to improve the ability of laboratory tests to assess the presence and severity of food allergy and to predict prognosis and resolution of disease.

Summary (Fig. 4)

• Commence investigation of food allergy with a detailed allergy-focused medical history and examination.

• Select the appropriate allergens and co-allergens for sIgE or SPTs to confirm or exclude IgE-mediated allergy.

• Confirm equivocal findings with an OFC test.

• Monitor development of tolerance with sIgE (in children) and confirm with an OFC test.

• Allergy tests should only be undertaken by healthcare professionals who are competent to perform and interpret them.

• SPTs and OFC tests should only be undertaken where there are facilities to deal with an anaphylactic reaction.

• CRDs employing recombinant allergens and comprehensive allergen profiles using microarray nanotechnology offer complementary diagnostic tools for the allergy specialist.

Fig. 1. Adverse reactions to food.

Fig. 2. Medications that inhibit the typical antihistamine reaction.

Fig. 3. Reference values.

Fig. 4. Investigation of immediate-onset IgE-mediated food allergy.

Further reading

Green RJ, Motala C, Potter PC, eds. ALLSA Handbook of Practical Allergy. 3rd ed. Allergy Society of South Africa, Cape Town, SA, 2010.

References

1. Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113(5):805-819.

2. NIAID-sponsored Expert Panel. Guidelines for the diagnosis and management of food allergy in the United States. J Allergy Clin Immunol 2010;126(6):S1-S58.

3. NICE Clinical Guideline 116: Diagnosis and assessment of food allergy in children and young people in primary care and community settings, 2011 Nov. http://www.nice.org.uk/cg116 (accessed 23 April 2012).

4. World Allergy Organisation. Diagnosis and rationale for action against cows milk allergy (DRACMA). WAO Journal 2010;April:58-161.

5. Caubet J, Sampson HA. Beyond skin testing: state of the art and new horizons in food allergy diagnostic testing. Immunol Allergy Clin N Am 2012;32:97-109.

6. Nicolaou N, Murray C, Belgrave D, et al. Quantification of specific IgE to whole peanut extract and peanut components in prediction of peanut allergy. J Allergy Clin Immunol 2011;27(3):684-685.

7. D’Urbano LE, Pellegrino K, Artesani MC, et al. Performance of a component based allergen-microarray in the diagnosis of cow’s milk and hen’s egg allergy. Clin Exp Allergy 2010;40(10):1561-1570.