Direct Challenges for the Evaluation of Beta-Lactam Allergy: Evidence and Conditions for Not Performing Skin Testing.

In the western world, up to 10% of the general population and more than 15% of hospitalized patients report penicillin allergy. After a comprehensive evaluation, more than 95% of patients who report a penicillin allergy can subsequently tolerate this antibiotic. Traditionally, the most widely accepted protocol to evaluate beta-lactam (BL) allergy consisted of skin testing (ST) followed by a drug provocation test (DPT) in ST-negative patients. DPT is the gold standard for proving or excluding BL allergy and is considered the final and definitive step in the evaluation. Recently, studies have been published that support the use of direct DPTs without preceding ST for both pediatric and adult patients who report a low-risk historical reaction to BLs. However, these studies use various risk-stratification criteria to determine eligibility for a direct DPT. A standardized protocol for DPT is also lacking. In this review, we assess the current literature and evidence for performing direct DPT in the pediatric and adult populations. On the basis of this evidence, we also present risk-based algorithms for the evaluation of BL allergy in pediatric and adult populations based on a description of the historical reaction.

Tackling the Patient with Multiple Drug "Allergies": Multiple Drug Intolerance Syndrome.

As populations age, the prevalence of reported drug "allergy" increases, often leading to suboptimal care and increased morbidity because of unnecessary avoidance of safe and effective medications. Evaluation by a drug allergy specialist is often warranted when a patient has more than 2 unrelated drug "allergies" listed in the medical record. In this commentary, we clarify and propose standard terminology to use when evaluating patients with multiple drug allergy labels including and more specifically when diagnosing multiple drug intolerance syndrome and the much rarer multiple drug hypersensitivity syndrome. We review epidemiology and key features of multiple drug intolerance syndrome and multiple drug hypersensitivity syndrome. We summarize the methodologic and practical diagnostic workup and management of individuals with MDIS to assist with the accurate delabeling of drug "allergies" in the electronic health record.

Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing.

BACKGROUND: Unconfirmed penicillin allergy poses substantial public health consequences. The most widely accepted protocol to evaluate penicillin allergy is skin testing followed by an amoxicillin challenge. OBJECTIVE: To evaluate the safety of direct oral graded challenges to amoxicillin. METHODS: A prospective single-blind clinical trial with historical controls of patients ≥7 years old with historical non-life-threatening reactions to penicillin was conducted. Patients received placebo followed by a 2-step graded challenge to amoxicillin. The allergic reaction rate was compared with the rate observed in our previous study that included skin testing and with the currently reported penicillin allergy prevalence in the US population. RESULTS: Of the 155 participants who completed an amoxicillin challenge, 120 patients (77.4%) experienced no reaction whereas 31 patients (20%) experienced nonallergic reactions to either placebo (n = 16) or amoxicillin (n = 15). Four patients (2.6%) developed mild allergic reactions. Significantly (P = .03) fewer patients (4 of 155, 2.6%, 95% confidence interval [CI]: 1.0%, 6.5%) were determined to be allergic compared with 14 of 170 subjects (8.2%, 95% CI: 5.0%, 13.4%) in our previous study where patients were determined to be allergic based on either positive skin tests (n = 11) or allergic challenge reactions after negative skin tests (n = 3). This 2.6% reaction rate was also significantly less than the 10% reported US prevalence of penicillin allergy (P = .003). CONCLUSIONS: Placebo-controlled oral graded challenges to amoxicillin without prior skin testing may be safe for patients ≥7 years old with non-life-threatening historical reactions to penicillin. Amoxicillin can be tolerated by the majority of patients with self-reported penicillin allergy.

Evaluation of periprocedural hypersensitivity reactions.

BACKGROUND: Identifying the cause of periprocedural hypersensitivity reactions (HSRs) remains challenging because of the multitude of medications involved. Antibiotics are the most common cause in the United States, whereas neuromuscular blocking agents are most common in Europe. OBJECTIVE: To identify causative agents for periprocedural HSRs. METHODS: This study was a 7-year retrospective medical record review of patients evaluated between December 2009 and January 2017 at a drug allergy center in Bronx, New York for periprocedural HSRs, defined as occurring soon before, during, or soon after a medical procedure or operation with or without general anesthesia. Demographics, description of historical HSRs, results of testing to potential causative medications, and tolerance of subsequent anesthesia were reviewed. RESULTS: Thirty-four patients completed a comprehensive evaluation. Skin testing identified an IgE-mediated cause in 22 patients (64.7%). The most common causative class of medications was induction agents (n = 9 [36%]), with midazolam being the most frequently implicated (n = 6 [3 positive skin test results, 3 equivocal skin test results]). Cefazolin was the most common agent identified (n = 8 [32%]) followed by ondansetron (n = 3 [12%]). Sixteen of 22 contacted patients were exposed to subsequent anesthesia, including 3 patients with negative evaluations. One patient experienced a mild urticarial HSR. CONCLUSION: Induction agents were the most common causative agents in our patients, which differs from other studies. Given the variability in evaluations of periprocedural HSRs across the United States with data published on small sample sizes, there is a need to establish national guidelines to standardize evaluations and to create a national registry to allow for data sharing.

Identifying Allergic Drug Reactions Through Placebo-Controlled Graded Challenges.

BACKGROUND: 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. OBJECTIVE: To identify allergic drug reactions (ADRs) through a 3-step protocol composed of placebo followed by a 2-step graded drug challenge. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Safety and outcomes of test doses for the evaluation of adverse drug reactions: a 5-year retrospective review.

BACKGROUND: Graded challenges are the criterion standard for evaluating adverse drug reactions (ADR). Evidence-based guidelines regarding the optimal number of steps for challenges are lacking. OBJECTIVE: To determine the safety and outcomes of 1- or 2-step test doses among patients with ADRs seen by the allergy/immunology consult service and to compare the outcomes of 1- or 2-step test doses with multistep challenges performed during the same time period. METHODS: We conducted a retrospective chart review of all 1- or 2-step test doses and multistep challenges at a single academic center between 2008 and 2013. Patient demographics, symptoms of initial ADRs, and outcomes of test doses and multistep challenges were reviewed. ADRs were classified by type and were graded by severity. Outcomes of 1- or 2-step test doses were compared with multistep challenges. RESULTS: We identified 456 patients who underwent 497 one- or 2-step test doses (mean age, 51 years; 67.5% female patients). The most common drugs that prompted test doses were ß-lactams (62%). The majority of patients (n = 444 [89%]) did not experience any ADRs during test doses. ADRs that occurred during test doses (n = 53 [11%]) were most commonly non-immune-mediated (45%) or IgE-mediated (32%), with grade 1 or 2 severity (100%). Forty-nine percent of ADRs during test doses did not receive any treatment. The ADR rate during multistep challenges (10/82 [12%]) was similar to test doses. CONCLUSION: One- or 2-step test doses were safe for evaluation of ADRs. Multistep challenges did not confer added safety. Furthermore, 1- or 2-step test doses did not raise concern for induction of tolerance.