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Assessment of Allergic Disease

Atopy refers to a genetic tendency to produce IgE responses to allergens, while allergy, seen in about one third of atopic patients, refers to the IgE mediated pathology arising from this atopic response to innocuous environmental agents. The commonest forms of allergic disease encountered in clinical practice include asthma, allergic rhinoconjunctivitis, atopic eczema, urticaria, and systemic anaphylaxis. The prevalence of allergy is rising, occurring in up to 40% of the population and its personal and economic impact is significant. While there is growing recognition of non-IgE-mediated contributions to allergic disease, this review will exclusively address the approach to the patient with suspected "Type I" IgE-mediated allergy.

Allergy pathogenesis

Allergy begins when low-molecular weight antigens pass transmucosally and are processed and presented to T cells. Various genetic and environmental factors provide a cytokine and cellular environment that favours the subsequent promotion of IgE production by B cells. Important cytokines involved in this process are the so-called "TH2" cytokines IL4, IL5, IL10 and IL13. Allergen-specific IgE binds to the surface of tissue mast cells via the high-affinity Fce receptor, and subsequent cross-linking of these mast-cell-bound IgE antibodies by further allergen exposure promotes mast cell degranulation (mainly histamine) and leukotriene and cytokine synthesis. These factors cause the vasodilatation, bronchospasm and swelling which manifest clinically as allergic phenomena.

Diagnosing Allergic Disease

The diagnosis of allergy relies on the presence of appropriate clinical symptoms and signs associated with evidence of IgE antibodies directed towards relevant allergens. The assessment of patients with suspected allergy involves three steps:

1. Confirming the presence of atopy

10% of patients with a strong clinical history for allergic disease may demonstrate evidence of allergen-specific IgE (either by skin testing or blood testing) in the absence of total IgE elevation. Less commonly, allergic patients may demonstrate elevation of total serum IgE in the absence of evidence of allergen-specific IgE. Because of this discordance, optimum sensitivity for diagnosing atopy is provided by measuring both total serum IgE and allergen-specific IgE. In interpreting the results of serum total IgE, it must be remembered that many factors modulate IgE levels (Table 1).

The specificity of total IgE for allergic disease is compromised by its appearance in other clinical settings (Table 2).

2. Demonstrating allergen-specific IgE

The gold standard for establishing the presence of allergen-specific IgE antibodies is the skin-prick test (SPT), where an intracutaneous prick applied through a drop of allergen results in a characteristic "wheal-and-flare" response in sensitive individuals. This procedure requires trained staff and the availability of facilities for resuscitation, as there is a small but real risk of precipitating anaphylaxis. In addition to being highly sensitive for identifying allergen sensitisation, skin prick testing is cheap and provides immediate results which are readily demonstrable to the patient, having some salutatory value in highlighting the nature of their pathology. The use of certain medications invalidates SPT results (Table 3) by interfering with the mast cell and histamine response. However, other medications which are commonly used in allergic patients have no effect on SPT results (Table 3).

In certain situations, skin prick testing is not a practical option (Table 4). In these cases, allergen-specific IgE can be measured in the blood with a sensitivity approaching, but inferior to, that of SPT (false negative rate is about 5-10%).

3. Demonstrating an allergic end-organ response

The presence of allergy is ultimately revealed by clinical manifestations such as wheeze, rhinorrhoea, and rash. Physiological responses can be measured objectively, for example peak expiratory flow rates in asthma or nasal smear eosinophilia in rhinitis. Mast cell degranulation can be proven by the measurement of serum tryptase levels in cases of systemic anaphylaxis.

Tryptase

Tryptase is a tetrameric serine protease present only in mast cells. When there has been extreme mast cell degranulation, as occurs in systemic anaphylaxis, tryptase levels rise within 1 hour and remain elevated for 4-6 hours. Histamine, another mast cell product, peaks at 5 minutes and declines rapidly within fifteen minutes. In patients with life-threatening systemic reactions to diverse allergens (such as foods, insect venoms, latex, and drugs), the finding of elevated serum tryptase levels (>1ng/mL) between 1 and 6 hours after the event is highly sensitive and specific for confirming mast-cell degranulation as the cause of the event.

Allergic Disease associated with Aeroallergens

Aeroallergens cause the majority of cases of allergic rhinoconjunctivitis and are an important factor in asthma. A seasonal history of illness, with symptoms worse in spring time, strongly suggests that outdoor aeroallergens (predominantly pollens) may be implicated in disease, while perennial symptoms may be a clue to indoor aeroallergens, particularly house dust mite, animal danders, and cockroach allergens. Features of housing design such as sealing and insulation to reduce energy loss, and extensive carpeting have been linked with the increase in dust-mite-related allergy seen over the last few decades. The importance of cockroach hypersensitivity is increasing in households with low socioeconomic status in inner-city regions. Alternaria sensitivity is an important contributor to asthma in rural areas.

Although the history is useful for offering clues to likely groups of implicated allergens, it often provides poor discrimination regarding the specific causative agent. Patients presenting with allergic rhinitis or allergic asthma should have a screen for sensitivity to all the common aeroallergens (Table 5) which includes allergen mixes for pollens, animal/epithelial danders, house dust mite, and moulds.

Screening against individual aeroallergens can be requested where the history suggests these may be clinically relevant. Broad screens against specific allergens which are not historically linked with symptoms should not be performed, as many of the positive results will be false positives, reflecting the common entity labelled "asymptomatic
hypersensitivity."

Allergic Disease associated with Ingested Allergens

Most adverse food reactions are not due to IgE-related mechanisms, but instead represent food intolerance (e.g. lactase deficiency, irritative reactions to curry), pharmacological reactions (e.g. caffeine in chocolate, vasoactive amines in red wines), or toxic reactions (e.g. salmonellosis, scombroid toxin (mainly histamine) in poorly stored tuna).
IgE-mediated adverse reactions to foods usually manifest as urticaria-angiooedema, gastrointestinal symptoms (diarrhoea, vomiting, abdominal discomfort), or (uncommonly) anaphylaxis immediately after the ingestion of foods. Rarer presentations of food allergy include respiratory symptoms, the oral allergy syndrome, and contact urticaria with various foods. Cell-mediated immune mechanisms are also being recognised in many cases of food allergy. Some food allergic reactions depend upon an interplay between allergen ingestion and exercise or other environmental factors. The commonest foods involved in allergic reactions are peanuts, tree nuts, seeds, egg, milk, seafood, spices, soy bean, wheat, celery and fruits.

Patients presenting with unexplained urticaria-angiooedema, anaphylaxis or gastrointestinal symptoms should have a screen for sensitivity to ingested allergens which have been identified as relevant by clinical history. Screening for commonly implicated foods can be performed by requesting a food allergen mix (Table 6) which includes allergens from cereals, nuts, seafood and staple foods.

Screening against individual ingested allergens can be requested where the history suggests that these may be clinically relevant. Again, broad screens against specific allergens which are not historically linked with symptoms pose a real danger of producing false positives which may result in inappropriate dietary restrictions. Once IgE antibodies to potentially relevant allergens have been detected, their contribution to clinical symptoms should in most cases be proven with an elimination diet followed by provocation challenge with the offending agent. The reproduction of symptoms using a double-blind placebo-controlled food challenge (DBPCFC) represents the diagnostic gold-standard for food allergy.

Allergy to ingested allergens is unlikely to play a major role in asthma, although about 10% of asthma patients have non-allergic adverse reactions to dietary constituents such as sulphites and food additives. Testing for allergen-specific IgE is not indicated in these cases. Allergic rhinitis in infants and young children may be caused by cow’s milk protein, but food allergy is unlikely to cause rhinitis in adults. Coeliac disease and dermatitis herpetiformis are associated with aberrant cellular and humoral responses to gliadin, but these are not IgE-mediated.

Conditions where both aeroallergens and food allergens may be relevant

Aeroallergens are a significant contributor to atopic eczema in many adults and children, and foods are also important in many children with eczema. The role of food allergy in adult atopic eczema is controversial. Patients presenting with allergic eczema should have a screen for sensitivity to inhalant and ingested allergens which have been identified as relevant by clinical history.

Other Clinical Situations Where Allergen-Specific IgE Measurement Can Prove Helpful

Latex Allergy

Latex allergy is a problem of growing significance, with universal precautions resulting in prevalence rates of up to 10% among health-care workers. Clinical manifestations include irritant reactions (the commonest reaction), type IV delayed-type contact hypersensitivity reactions, and type I IgE-mediated reactions. IgE-mediated problems often occur in an occupational setting and include rhinoconjunctivitis, asthma, contact urticaria, and rarely systemic anaphylaxis. Latex allergy should be considered in cases of perioperative anaphylaxis or hypotension. It should also be remembered that latex reactions can occur outside the health-care setting, as latex is a ubiquitous substance found, for example, in balloons, condoms, shoe soles, and elevator handrails. Up to 75% of latex-allergic patients also experience allergies to cross-reacting foods such as banana, avocado and kiwi-fruit, ranging from local oral tingling to rhinitis and asthma and, rarely, anaphylaxis. The gold standard for assessing sensitivity is skin-prick testing. Latex-specific IgE antibodies can be detected in blood samples with a sensitivity and specificity of up to 90%.

Insect Venom Anaphylaxis

In patients who have life-threatening reactions to insect stings, usually from bees or wasps but sometimes from ants, history may aid in identifying the offending insect. For example, the honey bee is the only culprit that leaves its stinger behind. However, often there is doubt about the specific agent, and as many of these patients will be candidates for specific immunotherapy (desensitisation), it is important to precisely define which insect is involved. Diagnostic SPT can be performed one month after an anaphylactic reaction (to avoid the potential for false negatives), or venom-specific IgE can be measured in the blood. While there is a false negative rate of about 10% for the blood test compared with the gold-standard of SPT at one month, blood testing avoids the risk of anaphylaxis associated with SPT. In cases where the identity of the insect is unclear, a screen looking for allergen-specific IgE to bee and wasp venom (the two allergens for which specific immunotherapy is currently available) is diagnostically helpful. Where allergy to the "jumper ant" (myrmecia pilosula) is suspected, specific IgE antibodies to this agent can be requested, but this test is only performed by a private laboratory, so patient charging issues will first need to be clarified.

Drug Reactions

SPT is the optimal method for establishing the presence of specific IgE antibodies in cases of suspected drug reactions, but where this is not possible or where the risk of anaphylaxis is deemed to be unacceptable, blood tests for allergen-specific IgE can be performed for penicillin G & V. Other previously available tests for IgE antibodies to a range of other antibiotics and anaesthetics are no longer routinely available.

General Recommendations for Allergy Testing

Like many laboratory tests, positive results are only relevant in the appropriate clinical setting. Broad screening for multiple allergens which have not been linked with symptoms on history will result in many false-positive results of no clinical value. For example, screening an atopic patient for peanut allergy when there is no history of peanut reactions may produce a positive result. It is inappropriate to recommend allergen avoidance on the basis of testing alone, as most of the positive results in patients without a corresponding history are falsely positive.

A sensible work-up for possible allergic disease has been provided in Table 8.

References

1. Metcalfe DD Sampson HA Simon RA. Food Allergy: Adverse reactions to foods and food additives. 2nd Edition. Blackwell Science Cambridge, Massachusetts 1997. pp. 137-166

2. Wutrhrich B. Classification, symptoms and epidemiology of food allergy. Current Allergy and Clinical Immunology 1996;9:13-18

3. Sampson HA. Food Allergy. Journal of the American Medical Association 1997;278:1888-1894

4. Bradley J, McCluskey J. Clinical Immunology. Oxford University Press Oxford 1997. pp.73-143

Written by:        Dr Glenn Reeves, Immunology HAPS
Written:             May 1998
Reviewed:         August 2001

Other Relevant Information

Food Allergy

Latex

Tryptase

Other Relevant Websites

Allergy, Asthma & Immunology Online

Allergy Society of South Africa

American Academy of Allergy, Asthma and Immunology

Food Allergy Network