Although hyaluronidase has been extensively used in anesthesia and pain medicine, there are very few reported cases of hypersensitivity reaction. Kempeneers et al. [4] were the first to report on the etiology of hyaluronidase reaction in five cases. Allergic reactions to hyaluronidase are rare (incidence is 1/2,000) [2], and most of these occur in peribulbar anesthesia during ophthalmic surgery [8]. To our knowledge, however, this is the first report of allergic reaction to hyaluronidase during pain management.

The clinical manifestation of allergic reaction to hyaluronidase after peribulbar anesthesia appears to be similar in most cases [5]. Symptoms are usually mild without optic nerve compromise; however, a number of cases with reversible visual deterioration have occurred.

In general, allergic reactions to hyaluronidase result in localized responses in the injection area without generalized symptoms. However, more generalized reactions can occur according to the route of administration [8]. Szépfalusi et al. [1] reported that five of sixteen pediatric cancer patients showed immediate generalized allergic reactions after hyaluronidase-chemotherapeutic agent mixture was intravenously injected. In this report, only our first patient presented with an immediate, generalized symptom after injection. As the aforementioned cases suggest, the reaction can also occur as a result of an incidental intravenous injection during caudal block. Since capillary permeability is massively increased by hyaluronidase [6], extra caution should be taken. However, further evaluation is needed to determine whether or not intravenous injection causes generalized allergic reactions.

Two patients had a history of uneventful hyaluronidase injection. Due to previous exposure, sensitization has taken place and allergic reaction to additional hyaluronidase injection was identified. On the other hand, there was a case of allergic response that appeared at the first administration of hyaluronidase [4]; thus, more than two types of allergic mechanisms may be involved. Although the exact types of hypersensitivity are unclear, many researchers have suggested that Type I and Type IV hypersensitivity are associated [2,4,7]. In this report, an immediate onset of symptom could represent a Type I (IgE-mediated) anaphylactic reaction. Further, reaction delayed for 24 hours could be a Type IV (T-cell- mediated) anaphylactic reaction.

The complete blood analysis, including white blood cell count, erythrocyte sedimentation rate, and C-reactive protein, could be useful to make a differential diagnosis of infection. Because all our patients had normal blood test results and they were afebrile and were systemically well, we easily ruled out infection. Skin allergy tests, such as intradermal and skin prick test, are the most specific and common methods for determining the drug responsible for Type I (IgE-mediated) anaphylactic reactions [4,5]. Furthermore, confirmation of delayed cell-mediated allergic reaction can be performed by lymphocytic transformation test [4]. In this report, intradermal skin test was performed with hyaluronidase (15 IU/ml) and a positive result was recorded for a persistent wheal of greater than 0.8 cm [9].

The addition of hyaluronidase to local anesthetics has been a controversial issue [2]. Some authors have insisted that there is insufficient evidence for using hyaluronidase with local anesthetics for chronic back pain management [10], while another study failed to show the advantage of hyaluronidase injection for local anesthesia [11]. When only these considerations are taken into account, due to potential allergic reactions, the use of hyaluronidase with local anesthetics in pain management might be reconsidered. However, interestingly, many other authors have insisted that hyaluronidase with local anesthetics reduces the anesthetic volume needed and improves the efficacy of local anesthesia [12-14]. Since symptoms in most cases, including this report, are benign, infrequent and not prolonged, risk of complication might not be significant. Delaere et al. [2] carefully recommended the use of hyaluronidase in spite of potential allergic responses.

In conclusion, although symptoms are usually benign and improve within a few days, an allergic reaction to hyaluronidase can occur in pain practice. Therefore, extra caution has to be urged to avoid hyaluronidase injection into patients with this allergy. Additionally, allergic reaction should be considered in the differential diagnosis of patients who demonstrate characteristic clinical symptoms and signs after hyaluronidase administration.