June 2017

Allergy Testing: Have we Been Wrong for Forty Years?

Author: Thomas C. Beller, MD

In 1919, a case of allergy was reported that was transferred from one patient to another by blood transfusion. The recipient of the transfusion had an asthma attack after exposure to horses, something the donor was allergic to. It became apparent that a substance in blood was responsible for allergic reactions. This substance was eventually discovered to be an immunoglobulin, or antibody. It was named Immunoglobulin Type E (IgE) because of the erythema (redness) caused by the histamine released upon activation of this antibody.

For more than 40 years, we have tested patients for IgE, either by measuring levels in the blood or by looking for these reactive responses related to histamine release in the skin. We have identified patients as having or not having allergies to various substances based on the presence or absence of IgE.

Some patients who have allergy testing become confused and frustrated because they can’t make sense of the results. Some patients who develop sneezing, runny nose and itchy eyes during pollen season are being told they do not have allergies. “How can that be doctor? When the pollen is here, I can see it. It makes me sneeze and makes my eyes itch. Isn’t that allergy? Am I crazy?”

Allergists can find IgE to be confusing as well. Patients who receive allergy shots will continue to show responsive IgE skin tests long after their allergy symptoms have improved. Allergy shots contain the allergens to which a person reacts, and repeated injections allow the patient to lose sensitivity to the allergens over time. In theory, as symptoms improve, IgE responses in the skin should diminish and IgE levels in the blood should go down. They don’t! At least not right away. If IgE responses are remaining active while symptoms are dwindling, how exactly are the shots helping to reduce allergy symptoms? Is IgE really what allergy is all about?

To understand this question, we must understand exactly what an allergy is. The immune system fights allergens, probably because of a case of mistaken identity. The hygiene hypothesis suggests that as we have fewer infections in modern society, we tend to mistakenly identify allergens as infectious organisms. Immunoglobulins are only one weapon used by the immune system to attack infections. In the same way that the military uses many weapons ranging from guns and bullets to nuclear weapons, the immune system uses not only immunoglobulins but also white blood cells, pattern recognition molecules (called Toll-like Receptors or TLRs) and small attack proteins (the complement system) to name a few. The long-standing belief that the allergic response only utilizes immunoglobulins seems to have been a hasty assumption. To decide whether the immune system is, or is not “fighting” allergens based purely on IgE responses is similar to deciding an army is, or is not at war based purely on the use of nuclear weapons.

There are known hypersensitivity responses that do not involve IgE. For example, if a person touches poison ivy, he or she may develop a rash 6-12 hours after exposure. This type of hypersensitivity is called delayed-type hypersensitivity since the response is delayed significantly when compared to an IgE response, which occurs rapidly and is known as immediate-type hypersensitivity. One mechanism of delayed hypersensitivity is the cellular infiltration of tissue with white blood cells. Delayed-type hypersensitivity has not been considered as a possible contributing factor for environmental allergies until recently. It can now be shown that patients who have negative allergy tests for IgE will often exhibit swelling 6-12 hours after allergens are injected more deeply and in higher concentrations than what is used for IgE testing. A comparison of these two tests can be seen in figure 1.

The importance of delayed hypersensitivity in causing typical allergy symptoms is not firmly established, as no formal studies have been done using placebo control groups. However, there are anecdotal cases suggesting they could be important and that they can improve with allergen immunotherapy. Delayed-type allergy could also link hypersensitivities to environmental allergens to other disorders never thought to be related to allergy. One convincing report has already linked delayed pollen allergy to an inflammatory condition called Kawasaki’s vasculitis, which commonly affects children in Japan, S. Korea and other countries.

Clearly, IgE-histamine pathways play a role in the development of some allergy symptoms, which is why antihistamines can be helpful. However, the lack of response many patients experience with antihistamines coupled with new insight about delayed-type hypersensitivities suggests IgE may only be a small piece of the allergy puzzle. It will be exciting to see new pathways of allergy unravel as research continues to study mechanisms beyond IgE. If these findings hold up to the scrutiny of further research and you are one of those patients who felt confused by an allergy test, we’ll know one piece of good news: You’re not crazy! 

Thomas C. Beller is an allergist-immunologist treating adult and pediatric patients at Allergy & Asthma Center, located at 60 Main Street, Unit D, Hilton Head Island. For more information, visit hiltonheadallergy.com or call (843) 689-6442 for an appointment.

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