I was recently asked a question about hyaluronidase by a colleague. He gives hyaluronidase injections around the eyes as a plastics/ENT doc. If a patient is bee sting allergic, he tells them he cannot do it. Is this necessary for all types of bee venom allergy? Should he get them tested for specific types of venom? Or maybe to the hyaluronidase itself? Thank you for your time.


Thank you for your inquiry.

Unfortunately, there is not enough information in the literature for me to give you a definitive answer, but I can share with you the information that does exist allowing us to come to a reasonably trustworthy opinion.

First, I assume that the physician employing the hyaluronidase is concerned because of a potential cross-reactivity between the product he is using and the hyaluronidase in bee venom.

There are a number of different issues that potentially bear upon such a potential cross-reactivity. First of all, I could find two different brands of hyaluronidase available. I am not sure which of the two he employs, but they are from different sources, and that could have an impact upon the incidence of allergic reactions to the product.

One, Hylenex, is a recombinant purified preparation of human hyaluronidase genetically engineered using Chinese hamster ovary cells. The other product, Vitrase, is a preparation of purified ovine testicular hyaluronidase. I could find no data comparing the incidence of allergic reactions to these drugs, but on the theoretical basis, the incidence should be lower to the recombinant product.

Of particular importance is the fact that in neither case is there a warning in the package inserts (at least that I could find) stating that patients with bee venom allergy are at an increased risk of an allergic reaction. Therefore, I am not sure how the physician you are referring to has established this procedure other than from conversations with other physicians or perhaps on a theoretical basis.

Secondly, the supposition that patients receiving hyaluronidase who had a bee venom allergy would be more susceptible to an allergic reaction would imply that hyaluronidase is an allergen in bee venom. In actuality, we do not know whether this is the case. As you know, the major bee venom allergen is phospholipase A.

Finally, there is no rationale for limiting the concern to bee venom if indeed the worry is with cross-reactivity, because hyaluronidase is also found in vespid venoms. There is limited and infrequent cross-reactivity between honeybee and vespid hyaluronidases. Of more importance, however, is that the clinical significance of hyaluronidase in terms of allergic reactions to venoms has not been clearly established.

Thus, taking all of these facts into consideration, it appears to be me that the risk of a reaction to hyaluronidase in a patient having a history of hymenoptera allergy is minimal, and it is unclear whether this risk exceeds that of an individual who has no history of hymenoptera allergy. In addition, such risk might depend upon the preparation of hyaluronidase that is employed.

However, if your physician is still concerned, then skin testing may be performed to the hyaluronidase. This is usually done by injecting 0.02 cc of a concentration of 150 units per ml.

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

1. Package insert for Vitrase.

2. Package insert for Hylenex.

3. Golden D. Insect allergy. In: Middleton’s Allergy: Principles and Practice, 7th edition; edited by Atkinson F, Bochner B, Busse W, Holgate S, Lemanske R, and Simons FER (Publisher Mosby, an affiliate of Elsevier, Inc.) 2009.

Phil Lieberman, M.D.

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