Near-fatal anaphylaxis after Hymenoptera venom immunotherapy
Authors: Bruce L. Wolf, Robert G. Hamilton
Journal: Journal of Allergy and Clinical Immunology (1998)

Since Food and Drug Administration licensure in 1979, Hymenoptera venom extracts have been qualified for commercial release on the basis of tests for sterility, moisture content, protein content, and hyaluronidase enzymatic activity. Considering the potential risk for anaphylaxis associated with testing and escalating doses to maintenance, it is remarkable that no deaths have been reported from Hymenoptera venom immunotherapy (VIT). This report describes a case of near-fatal anaphylaxis that occurred in a patient receiving VIT after switching manufacturer's venom extract. A 55-year-old man was stung by a Polistes wasp, and he experienced syncope and documented hypoxemia. Our initial intradermal skin test identified only sensitivity to both honeybee venom (HBV; 9-mm induration and 10-mm erythema at 1.0 μg/mL) and Polistes wasp venom (PWV; 7-mm induration and 8-mm erythema at 0.1 μg/mL). Intradermal skin tests with the vespid venoms were negative. VIT was administered according to Bayer Corporation's protocol. The subject had been receiving monthly maintenance injections of Bayer HBV and PWV, each at 100 μg, for 13 months without incident. When the national shortage of Bayer PWV occurred, ALK PWV was substituted. Each lyophilized, single-dose vial of 100 μg was reconstituted with 1.2 mL of sterile human serum albumin containing 0.4% phenol and gently rocked to insure complete dissolution. Within minutes after injection of 100 μg of Bayer HBV and ALK PWV (both from new vials) the subject became lightheaded and experienced syncope. Quickly regaining consciousness, he remained hypotensive (74/–) despite being placed in a Trendelenburg position and receiving subcutaneous adrenaline twice, inhaled oxygen, and 1 L of normal saline intravenously. He was taken to an emergency department within 30 minutes of the reaction and was given 200 mg of intravenous hydrocortisone, 300 mg of intravenous Tagamet, and 25 mg of Benadryl by mouth before his blood pressure normalized. Serum collected at 2 hours after the reaction was evaluated for serum tryptase and found to be elevated at 37.5 μg/mL (normal range for adults, 5.6 to 13.5 μg/mL). HBV- and PWV-specific IgE and IgG antibodies were measured in the same serum specimen by RAST analysis in the Johns Hopkins University DACI Laboratory as previously reported.1Golden DBK Lawrence ID Hamilton RG Sobotka AK Valentine MD Lichtenstein LM. Clinical correlation of the venom specific IgG antibody level during maintenance venom therapy.J Allergy Clin Immunol. 1992; 90: 386-393Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 2Hamilton RG Wisenauer JA Golden DBK Valentine MD Adkinson Jr., NF Selection of Hymenoptera venoms for immunotherapy based on patient's IgE antibody cross-reactivity.J Allergy Clin Immunol. 1993; 92: 651-659Abstract Full Text PDF PubMed Scopus (69) Google Scholar The IgE anti-HBV and PWV levels were 5 and 12 ng/mL, respectively. The results of repeat intradermal skin tests weeks after the reaction were positive for HBV (10.5-mm induration and 11-mm erythema at 1 μg/mL) and PWV (10-mm induration and 11-mm erythema at 0.1 μg/mL). The levels of IgG anti-HBV and PWV were 2.9 and 9.8 μg/mL, respectively. Levels of IgG anti-venom greater than 3.5 μg/mL have been associated with reduced risk for reaction on re-sting in individuals receiving VIT.1Golden DBK Lawrence ID Hamilton RG Sobotka AK Valentine MD Lichtenstein LM. Clinical correlation of the venom specific IgG antibody level during maintenance venom therapy.J Allergy Clin Immunol. 1992; 90: 386-393Abstract Full Text PDF PubMed Scopus (83) Google Scholar RAST inhibition was performed twice to determine the relative potency of the different venom extracts by using the subject's serum as the IgE anti-venom source according to previously described methods.2Hamilton RG Wisenauer JA Golden DBK Valentine MD Adkinson Jr., NF Selection of Hymenoptera venoms for immunotherapy based on patient's IgE antibody cross-reactivity.J Allergy Clin Immunol. 1993; 92: 651-659Abstract Full Text PDF PubMed Scopus (69) Google Scholar Previously administered venoms were maintained at 4°C for 6 weeks before testing the residual 0.2 mL. On the basis of the labeled protein content, all new extract vials should have contained 120 μg and were reconstituted with 1.2 mL of phenol saline to a final protein concentration of 100 μg/mL. Table I summarizes the relative potencies of the different venom preparations as measured by RAST inhibition.Table IRelative venom potencies on the basis of RAST-inhibition analysesVenomSourceStatusLot noVenom content (μg/mL),* mean ± 1 SDPWVALKFreshly reconstituted01948989100†PWVALKAdministered at injection0194898937 ± 16PWVBayerFreshly reconstituted521930185 ± 17HBVBayerFreshly reconstituted5219501100†HBVBayerAdministered at injection5219501210 ± 25*Two separate analyses were performed. †Newly reconstituted venom used as reference and given the reported potency of 100 μg/mL. Open table in a new tab In this case near-fatal anaphylaxis was totally unexpected with a patient who had achieved maintenance and in whom immunologic protection was considered to be near 100%. Initially we suspected that differences in the potency of the venom from the new company might have been causal. However, it appears from the relative potency data that the HBV from a single source may have contributed to the reaction rather than the new source of PWV. If so, it reminds us that in every case VIT, especially HBV at a maintenance level of 100 μg/mL, may not be protective.3Bousquet J Menardo JL Velasquez G Michel FB. Systemic reactions during maintenance immunotherapy with honey bee venom.Ann Allergy. 1988; 61: 63-68PubMed Google Scholar, 4Muller U Helbling A Berchtold E. Immunotherapy with honeybee venom and yellow jacket venom is different regarding efficacy and safety.J Allergy Clin Immunol. 1992; 89: 529-535Abstract Full Text PDF PubMed Scopus (257) Google Scholar, 5Yunginger JW Dahlberg ME Jones RT Parker JL Carey TL. Diagnostic and therapeutic importance of individual honey bee venom allergens.J Allergy Clin Immunol. 1982; 69: 139-142Abstract Full Text PDF Google Scholar Why the patient did not experience anaphylaxis to previous HBV injections is unclear. Some may speculate that differences in the RAST-inhibition analyses might be explained by error in reconstitution of the unidose vial. However, because 1 mL of venom was administered from a vial containing 120 μg of venom and 0.2 mL was left for testing, this is not the explanation. Likewise, it is possible but unlikely that subsequent changes in allergen concentration could have occurred secondary to adherence to the vial itself after reconstitution. Of greatest relevance in this case, and of broader concern, is the issue of extract standardization. The Food and Drug Administration defines acceptable ranges for levels of hyaluronidase (HBV, 40 to 110 U/100 mL; PWV, 45 to 165 U/100 mL) in Hymenoptera venom extracts. Individual manufacturers also use phospholipase measurements (eg, phospholipase A2 in HBV 150 to 400 U/mg and phospholipase A1/2 in PWV 10 to 300 U/mg) as a secondary reference parameter. The actual potency range, as well as the intralot and interlot variation of commercial venom products, should be clearly noted for review by those administering and receiving extracts as an integral part of VIT. We thank Dr David B. K. Golden for his critical review of this report and Mr Jack Wisenauer, MLT, for his excellent technical assistance in the performance of the RAST-inhibition analyses.