Insect sting allergy with negative venom skin test responses

Background: In our 1976 controlled venom immunotherapy trial, 33% of 182 patients with a history of systemic reactions to insect stings were excluded because of negative venom skin test responses. There have been reports of patients with negative skin test responses who have had severe reactions to subsequent stings. Objective: Our aim is to increase awareness about the patient with a negative skin test response and insect sting allergy and to determine the frequency and significance of negative skin test responses in patients with a history of systemic reactions to insect stings. Methods: We prospectively examined the prevalence of negative venom skin test responses in patients with a history of systemic reactions to stings. In patients who gave informed consent, we analyzed the outcome of retesting and sting challenge. Results: Of 307 patients with positive histories screened for our sting challenge study, 208 (68%) had positive venom skin test responses (up to 1 μg/mL concentration), and 99 (32%) had negative venom skin test responses. In 36 (36%) of the 99 patients with negative skin test responses, the venom RAST result was a low positive (1-3 ng/mL), or repeat venom skin test responses were positive; another 7 (7%) patients had high venom-specific IgE antibody levels (4-243 ng/mL). Notably, 56 (57%) of 99 patients with positive histories and negative skin test responses had negative RAST results. In patients with positive skin test responses, sting challenges were performed in 141 of 196 patients, with 30 systemic reactions. Sting challenges were performed on 37 of 43 patients with negative skin test responses and positive venom-specific IgE and in 14 of 56 patients with negative skin test responses and negative RAST results. There were 11 patients with negative skin test responses who had systemic reactions to the challenge sting: 2 had negative RAST results, and 9 had positive RAST results at 1 ng/mL. The frequency of systemic reaction was 21% in patients with positive skin test responses and 22% in patients with negative skin test responses (24% in those with positive RAST results and 14% in those with negative RAST results). Conclusions: Venom skin test responses can be negative in patients who will subsequently experience another systemic sting reaction. Venom skin test responses are negative in many patients with a history of systemic allergic reactions to insect stings and may be associated with positive serologic test responses for venom-specific IgE antibodies (sometimes strongly positive results). Venom skin test responses should be repeated when negative, along with a serologic IgE antivenom test. Better diagnostic skin test reagents are urgently needed.