Identifying Allergic Drug Reactions Through Placebo-Controlled Graded Challenges

Graded challenges are performed to exclude hypersensitivity reactions in patients with a low likelihood of drug allergy. Literature regarding optimal protocols with a defined number of steps and use of placebo is lacking.

To identify allergic drug reactions (ADRs) through a 3-step protocol composed of placebo followed by a 2-step graded drug challenge.

We performed a 5-year retrospective chart review of all patients with historical ADRs who underwent single-blind, placebo-controlled graded drug challenges between October 2010 and November 2015 at an outpatient drug allergy clinic. Patients' demographic characteristics and description of historical reaction were obtained. Outcomes of challenges to drug versus placebo were compared by drug class.

Two hundred twenty-nine patients underwent at least 1 single-blind placebo-controlled graded challenge. The most commonly challenged drug class was beta-lactams (70.8%) followed by nonsteroidal anti-inflammatory drugs (17.5%). The reaction rate to drug and placebo was similar during beta-lactam challenges (9.4% vs 8.2%; P = .9) and during nonsteroidal anti-inflammatory drug challenges (14% vs 7%, P = .5), respectively. Only 10 patients (4.4%) had objective findings during drug challenges. Patients who reacted to placebo before beta-lactam challenges had an increased number of drug allergies (4.3 ± 1.0) compared with nonreactors (2.4 ± 0.1) and to beta-lactam reactors (3.3 ± 0.7) (P = .002). All placebo reactors were female (20 of 183 vs 0 of 46 males; P = .02).

Two-step graded challenges are safe in appropriately selected patients with a low risk of reaction. Placebo should be considered to reduce false-positive results, especially in females and in patients with multiple drug allergies.