Q:

2/6/2013
We have read that both the wheal and flare should be measured after percutaneous testing, but some physicians feel the flare is unimportant, or in other words can be ignored as the wheal is what determines a positive response. What is the significance, if any, of a large flare after percutaneous skin testing without a significant wheal? (meaning that the wheal is not at least 2 mm greater than the negative control) Does the flare have any significance when determining a positive reaction?

A:

Thank you for your inquiry.

In my opinion, the flare is an important component of the allergy skin test and should be assessed. It has significance in the presence or absence of a significant wheal. An excellent reference for you to get a perspective on its importance in the grading system of the skin test is Patterson’s Allergic Disease (1).

We have dealt with a similar question on our website previously, and for your convenience, I have copied below that inquiry along with our response.

Finally, I have copied below links to two websites; one is to the CDC and the other is to Allergy and Asthma Foundation of America that touch upon this issue.

Thank you again for your inquiry and we hope this response is helpful to you.

Previously posted on our website:
Interpretation of the wheal and flare produced by a positive intradermal allergy skin test

Question:
In interpreting intradermal skin tests, if an allergen test has a wheal only slightly larger than the negative control, i.e. 3-4 mm. larger, does an accompanying flare, i.e. 20-25 mm. make this a positive test if the negative control has no flare?

Answer:
I am not sure that I understand the thrust of your question, but I assume that it is intended to assess whether or not interpretation of a positive erythema response (in the absence of a corresponding positive intradermal response) has clinical meaning . I have approached your inquiry with this thought in mind. Hopefully it reflects your intent.

I have attempted to answer this question by calling on quotes from two authoritative sources. One of these is the Practice Parameter entitled "Allergy Diagnostic Testing: An Updated Practice Parameter" published in the Annals of Allergy, 2008, Volume 121 (8). The lead author was Leonard Bernstein. The other is a chapter entitled "Percutaneous and intracutaneous diagnostic tests of IgE-mediated diseases" (immediate hypersensitivity) by Dr. Paul Turkeltaub, which appeared in Diagnostic Testing of Allergic Disease edited by Stephen Kemp and Richard Lockey. It is part of the Marcel-Dekker series, the lead editor of which was Michael Kaliner. It is Volume 15 in this series.

First, I might parenthetically mention that by many standards, the test you described would clearly be positive regardless of the lack of a correlation between the wheal and flare response. As you can see from the first quote taken from the Practice Parameters, in a survey of board certified allergists, 85% reported that they used a criterion of 3 mm above a negative control as the threshold for a positive intracutaneous test. The patient you describe meets that criteria, and also, of course, the large erythematous response is confirmatory. However, if I am "reading you correctly," you are inferring that the intradermal response would not be considered significant, and certainly this is an arguable point. For the sake of pursuing this issue, we will proceed with the assumption that you are interpreting the intradermal test as negative.

The next three quotes also are taken from the Practice Parameters and emphasize in a general way the importance of the measurement of erythema (as well as wheal) in the interpretation of the allergy skin test.

As you can see, the Practice Parameter, in spite of the fact that some investigators have "advocated the primary importance of the wheal diameter," states that both erythema and wheal should be measured and recorded, implying that both should be considered of course when interpreting the results of the test. It also states that erythema can be measured as reliably as wheal reactions and, arguably, as you can see from a later discussion below, perhaps more accurately and reliably.

In addition, these quotes point out that dose response assays of erythema in response to testing in sensitive volunteers are the standard for establishing BAU in the United States.

From these quotes taken from the Practice Parameter, we should turn next to the chapter by Dr. Turkeltaub who, as you know, has done an extensive amount of work in standardizing the allergy skin test. In this chapter, he has a section comparing "erythema versus wheal". It appears on Page 63 of the text. It states: "Because the erythema response is several times larger and has a steeper slope near the endpoint, it should be quantitated along with the wheal response… the precision of estimating erythema reactions versus wheal is similar. Because erythema dose response is steeper near the endpoint than wheal dose response, histamine doses differing tenfold were able to be detected by differences in the erythema response, but not by differences in the wheal response. Similarly, interpretation of positive and negative controls are enhanced when erythema is considered while assessing activity. Erythema size highly correlates with release of inflammatory mediators, such as histamine, and thermographic estimates of inflammation during the early cutaneous response, and with the release of leukotrienes during the late phase response."

I think that these quotes clearly establish the importance of using erythema to interpret the results of skin tests even when this response does not correlate with the wheal. When one thinks about the pathophysiology of this response, one could also envision that erythema (vasodilatation) occurs earlier in most instances than leakage of fluid from the vessel (edema/wheal), and we know of course that erythema can occur in the absence of wheal in both intradermal and percutaneous tests.

Again, I hope I have captured the intent of your question. If so, as you can see from above, I would think this test would be positive even if there was a smaller wheal response than the one you described.

Thank you again for your inquiry and we hope this response is helpful to you.

SOURCE Bernstein IL, Blessing-Moore J, Cox LS, Lang DM, Nicklas RA, et al. Allergy Diagnostic Testing: An Updated Practice Parameter: Ann Allergy 2008; 121(8):S1-S:

"Eighty-five percent of board-certified allergists recently surveyed reported that they used the criterion of 3 mm above the negative control as a threshold for a positive intracutaneous test result.174

Three quotes - SOURCE Bernstein IL, Blessing-Moore J, Cox LS, Lang DM, Nicklas RA, et al. Allergy Diagnostic Testing: An Updated Practice Parameter: Ann Allergy 2008; 121(8):S1-S:

"Although some investigators have advocated the primary importance of the wheal diameter,70 both erythema and wheal should be measured and recorded in millimeters for appropriate comparisons with positive (ie, histamine) and negative controls (ie, buffered diluent or 50% glycerinated extracts)."

"Both erythema and wheal diameters should be measured and recorded. Erythema can be measured as reliably as wheal reactions and is the sole criterion for bioequivalency tests in the United States.59,124"

"Dose response assays of erythema in response to intracutaneous testing in sensitive human volunteers are the basis of BAU in the United States.124"

National Health and Nutrition Examination Survey III
Training Manual for Allergy Component


Skin Testing to Diagnose Allergies

Reference:
1. Cho S, Blaiss M, and Lieberman P. Allergic Diseases of the Eye and Ear. In: Patterson’s Allergic Diseases, 7th Edition, Leslie C. Grammar and Paul A. Greenberger, editors (Lippincott Williams & Wilkins, Philadelphia, PA) 2009.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology