This issue was sponsored by Laboratory Specialities http://www.labspec.co.za/

Contents A. Case study B. More information C. Editors' comments D. References E. CPD questions (South Africa, Australia)

Index

A. Case study
A 59-year-old man had experienced 6 episodes of adverse reactions over a period of 9 months. With the first incident, he experienced redness and itching of the skin alone. Each subsequent incident presented progressively worse symptoms, and the last 3 incidents were anaphylactic. The cause of the reactions was not clear.

After a thorough history was taken, it was determined that the patient experienced severe reactions within 25-45 minutes of a meal; 4 episodes occurred after breakfast on separate occasions, and 2 after dinner. No specific food could be identified as the cause. All the foods eaten were foods he had eaten before, without experiencing any adverse reactions.

The following blood tests were done:
Total IgE = 1818 kU/L
Paediatric Food Mix (fx5) = 0.76 kU/L (Class 1)
This is a screening test that measures the level of IgE to a combination of the 6 most common food allergens. A positive result indicates that the subject is sensitized to 1 or more of these foods, but does not indicate which. From there, one can test for specific allergens.
Phadiatop = 1.09 kU/L (Class 2)
This is a screening test containing a specific mixture of many inhalant allergens and designed to accurately identify those patients who are allergic to one or more inhalant allergens. From there, one can test for specific allergens.

DISCUSSION:
How does one interpret the blood tests?
Total IgE: This level is very high. The adverse reactions the patient had been experiencing were most likely IgE-mediated. (Note that parasitic infestation should normally also be considered as a cause for the elevation in total IgE, especially when the total IgE is very high.)
FX5: This indicates that it was very unlikely that the patient was reacting to 1 of the 6 foods in the FX5 mix. He could, however, be slightly sensitized to one or more of the allergens in the mix.
Phadiatop: This indicates that the patient was sensitized to 1 or more of the allergens in the Phadiatop mix. But it was circumstantially unlikely that it was the cause of a severe reaction.

THOUGHT PROCESS:
The blood results, in conjunction with the findings from the clinical history, showed that the patient had experienced severe IgE-mediated reactions. The fact that each reaction occurred within a specific period after a meal indicated that a food or foods were most probably causing the reactions. More specific details about the dietary intake at each of the incidents were needed.
A thorough diet history was taken to determine whether a pattern among the foods eaten at the different episodes could be identified. The patient was questioned about the specific foods he ate; whether he had eaten them before the first episode without experiencing an adverse reaction; and whether he had eaten them after the first episode without experiencing an adverse reaction. He could give the most details about the last 4 episodes, but could not remember everything from the first 2.

Possible patterns that could be identified:
Tomato: he ate tomato, either raw or cooked, before 5 (possibly 6) of the 6 episodes, and did not eat it on any other occasion after that. He did, however, tolerate tomato before the first episode.
Bread: he had some form of bread or bread roll before all 6 episodes, but did eat bread after them without experiencing adverse reactions. It was suspected that there was sesame in or on the bread that he had on the 6 occasions (and not on the other exposures to bread).

THOUGHT PROCESS:
Could a person have a reaction to a food that he/she has previously tolerated?
Yes, a person can become sensitized to an allergen over time.

In such a case, how does one determine whether tomato and/or sesame is in fact the responsible allergen(s)?
a. Do a skin prick or blood test to the foods.
b. Challenge the patient with the foods.

DISCUSSION:
a. Because the patient experienced severe reactions, skin prick testing was not advisable. There was a risk of the patient having a severe reaction to skin prick testing. Blood tests could be done safely.
b. If a patient does not appear at risk of having an anaphylactic reaction to the food(s), an oral challenge can be done. For this patient, oral challenges could be done, but only in a clinical setting with resuscitation equipment available.

Serum-specific IgE tests were done for tomato and sesame. The results were:
Tomato = 97 kU/L (Class 6)
Sesame = <0.35 kU/L (Class 0)

These results showed a strong likelihood that the patient was reacting to tomato, and it was very unlikely that he was reacting to sesame. This case shows the usefulness of blood tests where performing skin prick tests and oral challenges carries a high risk. The patient was therefore advised to avoid all tomato products.

TIP for Allergy Advisor users: When searching for a specific allergen in the main search function of the program, "Items, substances and allergens", the CAP-RAST code for that allergen is indicated on the same window as a quick reference. By clicking on the Diagnostic button, other possible diagnostic tests are highlighted, and where applicable, discussed in some detail.

B. More information:
The primary tools to diagnose food allergy are the clinical history, physical examination, food-symptom diaries, elimination diets, oral food challenges, and allergy tests. Appropriately designed challenge testing remains the gold standard, although it has many limitations.^1,2

The tests most often used to diagnose IgE-mediated allergy are the skin prick test (SPT; see April 2004's Educational Review for more details) and the serum IgE test (total and/or serum-specific IgE). However, patch tests have recently been used more often in the diagnosis of food allergy as well.¹

The SPT and serum IgE (s-IgE) tests indicate the presence of allergen-specific IgE, but they do not necessarily indicate that an allergic reaction would occur upon ingestion of the food to which sensitivity is tested for.^2,3 The presence of IgE antibodies to a specific food merely indicates a certain probability of a clinical reaction to that food; the risk levels are unique in each patient.¹ This is explained in more detail below.

This Educational Review will focus on the use, benefits and limitations of serum-IgE testing and atopy patch testing.

1. SERUM-IgE TESTING
A small sample of blood is taken from a vein in the arm and sent to a laboratory for testing. This is called radioallergosorbent testing (RAST). (RAST testing was the original assay 20 years ago, but has not been done, using this technology, for many years. The term "RAST" has remained as the term used. For the purpose of this Review, the term "serum-IgE testing" will be used.) Various companies that produce these tests, of which Pharmacia & Upjohn Diagnostics is the most well-known. Their specific IgE blood test is called CAP RAST/ImmunoCAP Specific IgE blood test.

Even though the test procedure is more standardized than skin prick testing, its reliability can vary from one laboratory to another and from one method to another.^{3 However, the advent of more reliable quantitative assays has reduced this variance.}

A. Total serum-IgE
The total IgE test measures the total amount of IgE-antibodies that the serum contains. It gives a rough indication of the level of allergic disease present in the patient. The normal IgE value range is age-dependent. An elevated total s-IgE level would support an IgE-mediated allergy diagnosis, but normal values do not exclude allergy. Non-IgE-mediated mechanisms could be involved.^1,3

Total IgE can also, however, be elevated in several non-allergic conditions, such as parasite infection.^1,3 Parasite infection can result in a significantly increased total IgE level. It may often be helpful to do an IgE level to ascaris to rule out parasitic infection, especially in young children living in rural areas.

Example of IgE testing report:

B. Serum-specific IgE
Over 400 different specific IgE allergen tests are commercially available. The results are a measure of the amount of serum-IgE produced in response to individual allergens. The original classification was expressed in classes from 0 (negative) to 6 (strongly positive). This has generally been replaced by the newer method of reporting values by the specific level of IgE in quantitative terms (kU/L).

Screening tests:
The 2 main screening tests available from Pharmacia are the Phadiatop assay, for the identification of patients allergic to inhalant allergens; and the Paediatric Food Mix (fx5), for the identification of patients allergic to one or more of the 6 most common food allergens. They can be used alone, where the history clearly indicates either an inhalant allergy or a food allergy; or they can be used together where the history does not indicate a specific type of allergen.

Recent research has indicated that the interpretation of s-IgE levels is more accurate when one considers the specific level of IgE to the allergen (rather than looking at the numerical class alone). In general, the higher the level, the more likely the patient is experiencing a clinical reaction to that allergen. Specific cut-off points have been established for each of the main allergens: the so-called "diagnostic decision points"4 (more details on this below).

It is generally considered that if the IgE level is >10-17 kU/L, there is a strong chance that the patient is reacting to the allergen. But lower levels of IgE have been known to result in allergic disease in some individuals.

Serum-IgE is only a snapshot of the level of IgE to a specific allergen in time. There are many factors that should be considered when interpreting the results. For example, if the IgE level is low, it may mean one of the following:

A IgE level of <0.35 kU/L (Class 0) indicates a negative result. It means that there is no IgE to this allergen in the serum. But a non-IgE-mediated reaction to this allergen is still possible.

In the initial assessment of the patient, it may be difficult to decide which allergens to test for. Because most patients with food allergy are sensitive to only a few foods, and a small number of foods (i.e., the 8 main allergens) are responsible for most reactions, it is usually inappropriate to test for an extensive number of foods. Selection of tests should be based on the clinical history and physical examination. Screening tests could be considered at this point. Also, it may be useful to opt for tests for which adequate data on the positive and negative accuracies have been established.⁵ Sampson⁴ has established lists of the recommended "diagnostic decision points" for the major childhood food allergens, namely egg, milk, peanut, soy, wheat, and fish (see table below).

Table: Food-specific IgE concentrations predictive of clinical reactivity

^a Proposed but not yet confirmed values.⁴

Considering the low PPV of most blood tests (i.e., a positive result would usually require an oral challenge to confirm the diagnosis), these decision points are very helpful. These points are used to eliminate the need for oral challenges by providing cut-off values(see table). If the specific IgE level exceeds the "diagnostic decision point value," it indicates that the patient is >95% likely to experience an adverse reaction to the food. For example, an oral egg challenge would not be necessary if the egg-specific IgE was 7 kU/L or greater, as it is >95% likely that the child will experience a positive reaction. If the egg-specific IgE was <7 kU/L but 0.35 kU/L (lower limit) or greater, some form of egg challenge would be necessary to determine whether the child was truly reactive to egg.^4,5

In young infants, especially those without atopic dermatitis (eczema), the "diagnostic decision points" are likely to be lower. Slightly different cut-off levels have been established for children <=2 years with cow milk and egg allergy (as indicated in Table).⁵

The reason for the PPV of the wheat and soy diagnostic decision points being <75% is that the allergens used in the test were suboptimal or had extensive cross-reactivity with other allergens.⁴

As with SPT's, a negative result on s-IgE testing is generally very reliable in ruling out an IgE-mediated reaction to a particular food, but a positive result generally has a low PPV (see April 2004's Educational Review).⁶ It is also possible to get false negative and false positive results. A person may be sensitized to an allergen without experiencing clinical symptoms. One may therefore produce some s-IgE and not necessarily be clinically sensitive to the allergen(s). A low level of s-IgE to an allergen may indicate that continued exposure to the allergen can eventually lead to clinical reactivity, and this could be interpreted in a prognostic manner.⁷

The clinical manifestations of allergic disease include a number of unknown variables, which limit accurate interpretation of results. It is essential to interpret s-IgE test results with the full clinical history in mind. For example, even if the s-IgE is <0.35 kU/L, the clinical history may still indicate the need for a challenge.^5,7

b. Comparing s-IgE tests to SPT's
Instances in which s-IgE tests are preferred to SPT's:

c. Limitations

2. ATOPY PATCH TESTING

The atopy patch test (APT) is classically used to identify cell-mediated responses to materials that trigger dermatitis on the skin surface after contact. Examples are chemicals, preservatives, detergents, perfumes and latex.1,6 Recent studies have shown promise for testing for food allergy as well. The test seems to be useful for determining delayed responses, for which the sensitivity of SPT is generally low; SPT's are better correlated with immediate symptoms. Other studies have shown the test to be of modest utility with a wide range of sensitivities and specificities in various settings.1 The test has been related to a relatively low positive predictive accuracy (40-63%).9 One benefit of APT is that the fresh product is used. The allergens are therefore in their natural state and would not be denatured, as may occur in commercial extracts used for skin prick testing.

Method
The test site is the surface of intact skin, usually on the back. The test material is applied to the skin in a metal cup (Finn chamber) under an occlusive dressing and is left in place. Controls are also applied to control for possible irritant reactions. The skin is not scratched or pricked. Application sites are checked after 15 minutes for immediate reactions. The occlusion time is 48 hours, and results are read 20 minutes after removal of the cups and again 24 hours later for the final evaluation. Final reactions (usually up to 72 hours) are classified as positive if there is a wheal-and-flare manifestation. If there is no response after this time, the test is considered to be negative.^{1,6,9,10,11,12}

The APT shows some promise as a diagnostic tool in food allergy, but the method needs to be further standardized.^1,2 The combination of patch testing and detection of IgE through SPT and s-IgE tests could enhance the accuracy of diagnosing food allergy and may eliminate the need for oral food challenges.^3,5,10

For more information on this subject and other allergy and intolerance related topics, visit:
http://www.allallergy.net
http://www.allergyadvisor.com
http://users.bigpond.net.au/allergydietitian

D. References
1. Metcalfe DD, Sampson HS, Simon RA. Food allergy: adverse reactions to foods and food additives 3rd edition. Blackwell Publishing, 2003.
2. Turjanmaa K. "Atopy patch tests" in the diagnosis of delayed food hypersensitivity. Allerg Immunol (Paris). 2002 Mar;34(3):95-7.
3. Bahna SL. Diagnosis of food allergy. Ann Allergy Asthma Immunol. 2003 Jun;90(6 Suppl 3):77-80.
4. Sampson HA. Improving in-vitro tests for the diagnosis of food hypersensitivity. Current opinion in allergy and clinical immunology 2002;2:257-61.
5. Bock SA. Diagnostic evaluation. Pediatrics 2003;111(6):1638-44.
6. Joneja JV. Dealing with Food Allergies. A practical guide to detecting culprit foods and eating a healthy, enjoyable diet. Bull Publishing Company, USA, 2003.
7. Williams PB. Usefulness of specific IgE antibody tests: a progress report. Ann Allergy Asthma Immunol 2003;91:518-24.
8. Sampson HA. Food allergy. Part 2: diagnosis and management. J Allergy Clin Immunol. 1999 Jun;103(6):981-9.
9. Sicherer SH. Beyond oral food challenges: improved modalities to diagnose food hypersensitivity disorders. Current opinion in allergy and clinical immunology 2003;3:185-8.
10. Nowak-Wegrzyn A. Future approaches to food allergy. Pediatrics 2003;111(6):1672-80.
11. Niggemann B. Evolving role of the atopy patch test in the diagnosis of food allergy. Current opinion in allergy and clinical immunology 2002;2:253-6.
12. Rance F. What is the optimal occlusion time for the atopy patch test in the diagnosis of food allergies in children with atopic dermatitis? Pediatr Allergy Immunol. 2004 Feb;15(1):93-6.

2. Which test is an example of a "screening test"?
(a.) Total IgE
(b.) Serum IgE for ascaris
(c.) Serum-IgE for peanut
(d.) Pediatric Food Mix (fx5)

3. Which of the following does not apply to a screening test?
(a.) It determines whether the patient is sensitized to one or more allergens, through only one test.
(b.) It tests for the presence of allergen-specific IgE in the serum sample to a range of common allergens.
(c.) A positive result may warrant further testing of one or more of the specific allergens in the screening test.
(d.) A negative result warrants the testing of the specific allergens in the screening test.

4. True or false: The rule of thumb when interpreting blood results is that, if the IgE level is >10-17 kU/L, the patient is allergic to the allergen.
(a.) True
(b.) False

5. Which of the following is not true regarding s-IgE testing?
(a.) A positive result on s-IgE testing is generally very reliable in confirming an IgE-mediated reaction to a particular food, but a negative result generally has a low NPV.
(b.) It is possible to get false negative and false positive results.
(c.) A person may test positive and not necessarily have a clinical reaction to the allergen.
(d.) A low level of s-IgE to an allergen may indicate that continued exposure to the allergen can eventually lead to clinical reactivity.

6. In which of the following cases would s-IgE testing be used instead of skin prick testing?
(a.) In patients with extensive skin lesions (e.g., eczema) or significant dermatographism
(b.) In patients who are unable to stop taking their antihistamine medication
(c.) In patients with a severe sensitivity to a specific food, especially by skin contact or inhalation
(d.) All of the above

7. Why would one monitor the allergen-specific IgE level over a period of time?
(a.) To see whether a patient has been avoiding the allergen
(b.) To see whether a patient has been exposed to hidden sources of the allergen
(c.) To predict whether the patient has "outgrown" an allergy
(d.) All of the above

8. Which of the following is true regarding atopy patch testing?
(a.) It is classically used to identify cell-mediated responses to materials that trigger dermatitis on the skin surface after contact.
(b.) It shows some promise as a diagnostic tool in food allergy.
(c.) It seems to be useful for determining delayed responses.
(d.) All of the above.

This issue was sponsored by Laboratory Specialities http://www.labspec.co.za/