Safety of test doses for the evaluation of adverse drug reactions


Published Online: September 13, 2014

Graded challenges are considered the gold standard for the evaluation of adverse drug reactions. They are defined as the administration of progressively increasing doses of a medication to verify that a patient does not experience an immediate adverse drug reaction. Graded challenges can exclude hypersensitivity in patients with a low-risk history of an adverse drug reaction and also allow for the evaluation of cross-reactivity of structurally-related compounds among different drug classes. They are not recommended for patients with a history consistent with a severe non-IgE-mediated reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, hepatitis, or hemolytic anemia. Despite the widespread use of graded challenges, there are no evidence-based guidelines delineating the optimal number of steps.

In an article recently published in The Journal of Allergy and Clinical Immunology: In Practice, Iammatteo et al. sought to determine the safety of test doses among patients with a history of adverse drug reactions. A test dose is considered a subset of graded challenges and is defined as a challenge with one or two steps. A one-step test dose is defined as the administration of the full dose of a medication followed by a specific time period (i.e., 60 minutes) of observation, while a two-step test dose is defined as 1/10th of the full dose for a parenteral medication or ¼ of a pill for an oral medication followed by administration of the full dose after a specific period of observation. Iammatteo and colleagues compared the outcomes of one- or two-step test doses with multi-step graded challenges comprised of three or four steps performed during the same time period.

A retrospective chart review of all one- or two-step test doses and multi-step challenges at a single academic center was performed between May 2008 and May 2013. Adverse drug reactions were classified by type and graded by severity. Iammatteo et al. identified 456 patients who underwent 497 one- or two-step test doses (mean age, 51 years; 67.5% female). Beta-lactams (62%) were the most common drug prompting test doses followed by NSAIDs (12%).  The majority of patients (n=444, 89%) did not experience any adverse drug reactions during test doses. Adverse drug reactions that occurred during test doses (n=53, 11%) were most commonly non-immune-mediated (45%), including localized tingling sensation, nausea, drowsiness, chills, dry throat and headache. Less commonly seen reactions (32 %) appeared to be IgE-mediated , such as hives (n=5), pruritus (n=6), and angioedema (n=1). All reactions were either grade 1 or 2 severity, which included skin symptoms or measurable but non-life-threatening reactions. No anaphylactic reactions occurred. Forty-nine percent of adverse drug reactions during test doses did not receive any treatment. The adverse drug reaction rate during multi-step challenges (n=10/82, 12%) was similar to the reaction rate with test doses.

The authors concluded that one- or two-step test doses are safe in appropriately selected patients for the evaluation of adverse drug reactions. The overwhelming majority of test doses do not result in adverse drug reactions. Furthermore, when reactions did occur, they were mild and often did not require any treatment. Multi-step challenges do not confer additional safety, but may be performed when caution is required, such as in patients with anxiety or multiple co-morbid conditions.


The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.

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