EAACI/ENDA position paper on drug provocation testing.

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low-risk patients. The task force suggests a strict definition of such low-risk patients in children and adults. Based on experience and evidence from studies of allergy to beta-lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non-steroidal anti-inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources.

Use, misuse, and pitfalls of the drug challenge test in the diagnosis of the Brugada syndrome.

The diagnosis of Brugada syndrome (BrS) requires the presence of a coved (Type 1) ST segment elevation in the right precordial leads of the electrocardiogram (ECG). The dynamic nature of the ECG is well known, and in patients with suspected BrS but non-diagnostic ECG at baseline, a sodium channel blocker test (SCBT) is routinely used to unmask BrS. There is little doubt, however, that in asymptomatic patients, a drug-induced Brugada pattern is associated with a much better prognosis compared to a spontaneous Type 1 ECG. The SCBT is also increasingly used to delineate the arrhythmogenic substrate during ablation studies. In the absence of a "gold standard" for the diagnosis of BrS, sensitivity and specificity of the SCBT remain elusive. By studying patient groups with different underlying diseases, it has become clear that the specificity of the test may not be optimal. This review aims to discuss the pitfalls of the SCBT and provides some directions in whom and when to perform the test. It is concluded that because of the debated specificity and the overall very low risk for future events in asymptomatic individuals, patients should be properly selected and counseled before SCBT is performed and that SCBT should not be performed in asymptomatic patients with a Type 2 Brugada pattern and no family history of BrS or sudden death.

United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.

BACKGROUND: There is no accepted grading system classifying the severity of immediate reactions to drugs. OBJECTIVE: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium. METHODS: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research. RESULTS: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis. CONCLUSION: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice.

Arrhythmias induced by dextrose-insulin challenge test in nondiagnostic Brugada ECG patterns.

INTRODUCTION: Dynamic ECG changes in Brugada syndrome (BrS) are influenced by several factors, may not be apparent, and can be unmasked by a drug test. METHODS AND RESULTS: Four of six patients with nondiagnostic Brugada ECG index patterns underwent a dextrose-insulin challenge test that resulted in J-ST segment elevation and triggered arrhythmias. CONCLUSION: Insulin action may be due in part to an outward shift in the K+ current at the end of action potential phase 1 and the dispersion of repolarization, leading to local re-entry with arrhythmogenicity. This effect is likely a phenomenon-specific to BrS.

Meropenem allergy testing performed at the bedside of hospitalized patients labelled with a penicillin allergy.

BACKGROUND: Meropenem is a widely prescribed beta-lactam for hospitalized patients. There are few data on meropenem allergy assessments in inpatients with a reported history of penicillin allergy who require a treatment with meropenem. This can lead to the use of less effective second-line antibiotics that may increase antibiotic resistances. We aimed to evaluate the clinical outcomes of a meropenem allergy assessment in admitted patients with a reported history of penicillin allergy that required meropenem for the treatment of an acute infection. METHODS: A retrospective analysis was performed on 182 inpatients labelled with a penicillin-allergy who received meropenem after an allergy assessment. The allergy study was performed bedside if meropenem was required urgently. The study included skin prick tests (SPTs) followed by an intradermal skin test (IDT) to meropenem, and a meropenem drug challenge test (DCT). If a non-immediate reaction to a beta-lactam was suspected, it was initiated with patch tests. RESULTS: The median age of the patients was 59.7 years (range 28-95) and 80 (44%) were women. A total of 196 sets of diagnostic workups were performed, with 189 (96.4%) of them being tolerated. Only two patients had a positive meropenem IV DCT, both presenting a non-severe cutaneous reaction that completely resolved after treatment. CONCLUSIONS: This study evidenced that a bedside meropenem allergy assessment of hospitalized patients labelled with a 'penicillin allergy' who require a broad-spectrum antibiotic for empiric coverage is a safe and effective procedure, avoiding the use of second-line antimicrobial agents.

Impact of antibiotic allergy labels on patient outcomes in a tertiary paediatric hospital.

AIMS: Antibiotic allergies are reported in 5-15% of children. This study aimed to evaluate the impact of common ß-lactam antibiotic allergy labels (AALs) on hospital treatment, focusing on length of stay and appropriateness of antibiotic prescribing. METHODS: This was a retrospective cohort study over 21 months at the Royal Children's Hospital Melbourne, Australia. A subset of children with the most common ß-lactam allergies, and who required admission for intravenous antibiotics over a 12-month period, was analysed for appropriateness of prescribing. Non-allergic patients were matched to evaluate associations between AALs and hospital treatment. RESULTS: There were 98 912 children admitted over the study period, of whom 938 (1%) had at least one AAL on first admission. Of all encounters, 5145 (2.5%) were for children with AALs. The most common AALs were to amoxicillin and amoxicillin-clavulanic acid combinations (40.8%), cefalexin (14.4%) and trimethoprim-sulfamethoxazole (9.7%). For the subset, there were 66 admissions for children who required intravenous antibiotics. Documentation was adequate for 27% of AALs. Inappropriate prescribing occurred in almost half (47%). Hospital stay was longer for children with AALs (median 4.7 days; IQR 2.3-9.2) compared to non-allergic controls (median 3.9 days; IQR 1.9-6.8; P = .02). Children with AALs were more likely to receive restricted antibiotics (aOR 3.03; 95% CI, 1.45-6.30; P = .003). CONCLUSION: This is the first study to demonstrate high rates of inappropriate prescribing in children with AALs. Children with AALs were significantly more likely to receive restricted antibiotics and had a longer length of stay compared with non-allergic controls.

Oral amoxicillin challenge for low-risk penicillin allergic patients.

BACKGROUND: Penicillin allergy is the most reported adverse drug reaction (ADR). Being labelled with 'penicillin allergy' is associated with suboptimal antibiotic therapy and poor patient outcomes. Most labelled with 'penicillin allergy' are at low risk of harm from penicillins and guidelines recommend testing for accurate diagnosis. Although skin testing is recommended to exclude immunoglobulin E (IgE)-mediated reactions, there is limited access in most settings. AIMS: To evaluate oral amoxicillin challenge without prior skin testing for patients labelled with 'penicillin allergy' assessed as low risk during hospital admission. METHODS: General Medical inpatients with a 'penicillin allergy' label were assessed. For those who had tolerated a penicillin since the index event, the ADR label was removed. Those assessed as 'low risk' were administered 250 mg amoxicillin orally without prior skin testing. The durability of de-labelling was subsequently assessed by review of clinical records. RESULTS: Of 224 patients with a history of a penicillin ADR, 162 (72%) were low risk. A further 12 were excluded and of the remaining 150, 56 (37%) had tolerated penicillins since their index reaction and were de-labelled without challenge, 15 (10%) with a non-allergic history were de-labelled. The remaining 79 were offered an oral amoxicillin challenge; 38 declined and 41 tolerated amoxicillin. Overall, 112 of the 224 (50%) patients had their ADR label removed. CONCLUSIONS: A careful ADR history enables de-labelling of many patients. An oral amoxicillin challenge without prior skin testing is safe and feasible for low-risk penicillin allergic patients while in hospital.

Penicillin Allergy Testing Is Cost-Saving: An Economic Evaluation Study.

BACKGROUND: Having a penicillin allergy label is associated with the use of less appropriate and more expensive antibiotics and increased healthcare utilization. Penicillin allergy testing results in delabeling most allergy claimants and may be cost-saving. This study aimed to project whether penicillin allergy testing in patients reporting a penicillin allergy is cost-saving. METHODS: In this economic evaluation study, we built decision models to project the economic impact of 2 strategies for a patient with a penicillin allergy label: (1) perform diagnostic testing (drug challenges, with or without skin tests); and (2) do not perform diagnostic testing. The health service perspective was adopted, considering costs with penicillin allergy tests, and with hospital bed-days/outpatient visits, antibiotic use, and diagnostic testing. Twenty-four base case decision models were built, accounting for differences in the diagnostic workup, setting (inpatient vs outpatient) and geographic region. Uncertainty was explored via probabilistic sensitivity analyses. RESULTS: Penicillin allergy testing was cost-saving in all decision models built. For models assessing the performance of both skin tests and drug challenges, allergy testing resulted in average savings (in United States [US] dollars) of $657 for inpatients (US: $1444; Europe: $489) and $2746 for outpatients (US: $256; Europe: $6045). 75% of simulations obtained through probabilistic sensitivity analysis identified testing as the less costly option. CONCLUSIONS: Penicillin allergy testing was projected to be cost-saving across different scenarios. These results are devised to inform guidelines, supporting the adoption of policies promoting widespread testing of patients with a penicillin allergy label.

Hypersensitivity Reactions to Cancer Chemotherapy: Practical Recommendations of ARADyAL for Diagnosis and Desensitization.

Rapid drug desensitization has enabled first-line therapies in patients with drug hypersensitivity reactions to chemotherapeutic drugs including monoclonal antibodies. Desensitization is a safe and highly effective procedure, not only for IgE-mediated reactions, but also for those mediated by non-IgE mechanisms. The likelihood of breakthrough reactions during desensitization is low, and most are mild; in fact, moderate-to-severe reactions are infrequent. In this document, 16 allergy departments belonging to the Spanish research network ARADyAL present a review of the available scientific evidence and provide general guidelines for the diagnosis and management of drug hypersensitivity reactions to chemotherapeutic drugs and monoclonal antibodies. Emphasis is placed on the desensitization procedure.

The utility of drug challenge testing in Brugada syndrome: A systematic review and meta-analysis.

INTRODUCTION: Brugada syndrome (BrS) is associated with ventricular arrhythmia leading to sudden cardiac death. Risk stratification is challenging, as major arrhythmic events (MAEs) are rare. We assessed the utility of drug challenge testing in BrS by a systematic review and meta-analysis. METHODS AND RESULTS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2019. Included studies compared the incidence of MAE between spontaneous and drug challenge-induced Type 1. Mixed-effects Poisson regression was used to calculate the incidence rate ratio (IRR). Eighteen studies from 2006 to 2018 were included (4099 patients, mean follow-up: 4.5 years). Pooled annual incidences of MAE in spontaneous, drug challenge induced (regardless of symptoms), asymptomatic drug challenge induced, and symptomatic drug challenge-induced Type 1 were 23.8 (95% confidence interval [CI]: 19.8-27.8), 6.5 (95% CI: 3.9-9.1), 2.1 (95% CI: -0.3 to 4.4), and 19.6 (95% CI: 9.9-29.3) per 1000 person-years, respectively. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type 1 was not statistically different (IRR = 1.0; 95% CI: 0.6-1.7). CONCLUSIONS: The incidence of MAE in drug challenge-induced Type 1 in asymptomatic patients is low. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type 1 was similar.

Drug Challenge Tests With General Anesthetics: Predictive Value of Skin Tests.

BACKGROUND: The study of perioperative drug reactions remains a major challenge for both diagnosis and therapy. The lack of a standard assessment of allergy to general anesthetics and of data establishing the true value of skin tests for most drugs used in induction and maintenance of anesthesia, as well as the lack of commercially available reagents for in vitro tests, renders the study of these reactions problematic. The aims of this study were to provide a diagnostic protocol for drug challenge testing with general anesthetics, to establish an etiological diagnosis that is as specific as possible, and to determine the predictive value of skin tests. METHODS: Twenty-nine patients with perioperative drug reactions were included in the study from November 2008 to December 2018. RESULTS: We confirmed the high negative predictive value of the tests (96%-100%) in the case of propofol, rocuronium, and fentanyl. To our knowledge, this is the first study to describe drug challenge testing with general anesthetics and, therefore, to establish the true negative predictive value of skin tests, which leads to a definitive diagnosis and safer surgery. CONCLUSIONS: After assessing risks and benefits and considering the importance of this group of drugs, we conclude that drug challenge testing with general anesthetics is necessary. We propose a protocol for perioperative drug reactions that enables us to make a highly accurate etiological diagnosis with minimum risk for the patient.

Recurrent syncope after a finger injury and induced monomorphic ventricular tachycardia: Really Brugada syndrome?

Brugada syndrome is an arrhythmogenic disease with often fatal outcome in otherwise healthy and young individuals. Anamnesis and ECG are cornerstones in a syncope workup. In our case, a 27-year-old male presented to the emergency department due to recurrent syncope. Repeated 12­lead-ECGs revealed a type 2 Brugada pattern. A positive drug challenge suggested a Brugada syndrome and electrophysiological testing reproducibly induced monomorphic ventricular tachycardia. Consequently, an ICD was implanted for secondary prevention. On 2-year follow-up, the patient remained free from other arrhythmic events or ICD interventions.

Skin tests and challenge-based drug allergy diagnosis: a retrospective study of patients with confirmed drug allergy.

Summary: Objectives. To describe clinical manifestations and performed diagnostic workup, focusing drug challenge tests (DCT), in patients with drug allergy. Methods. Retrospective study including all patients with skin tests (STs) or DCT-based drug allergy diagnosis, between 01/2014 - 06/2018 in a Portuguese allergy unit. Data were collected from electronic and paper-based clinical records. Results. We had 75 drug allergy diagnoses. Most index reactions were mild and major or equal 1 hour after drug intake. 59 (78%) diagnoses were based on DCTs, all based on multistep protocols with major or equal 3 predicted steps. Only 10% of the DCT were positive during up-dosing; timing and severity of the index reaction predicted DCT interruption during up-dosing. Conclusions. Most drug allergy diagnoses were based on multistep DCT. The identified predictors of DCT interruption during up-dosing can support the development of more personalized DCTs protocols.

Open-field PET: Simultaneous brain functional imaging and behavioural response measurements in freely moving small animals.

A comprehensive understanding of how the brain responds to a changing environment requires techniques capable of recording functional outputs at the whole-brain level in response to external stimuli. Positron emission tomography (PET) is an exquisitely sensitive technique for imaging brain function but the need for anaesthesia to avoid motion artefacts precludes concurrent behavioural response studies. Here, we report a technique that combines motion-compensated PET with a robotically-controlled animal enclosure to enable simultaneous brain imaging and behavioural recordings in unrestrained small animals. The technique was used to measure in vivo displacement of [11C]raclopride from dopamine D2 receptors (D2R) concurrently with changes in the behaviour of awake, freely moving rats following administration of unlabelled raclopride or amphetamine. The timing and magnitude of [11C]raclopride displacement from D2R were reliably estimated and, in the case of amphetamine, these changes coincided with a marked increase in stereotyped behaviours and hyper-locomotion. The technique, therefore, allows simultaneous measurement of changes in brain function and behavioural responses to external stimuli in conscious unrestrained animals, giving rise to important applications in behavioural neuroscience.

Antibiotic Allergy in Children: More than Just a Label.

Within the broad category of adverse drug reactions in children, there has been a recent focus specifically on the evaluation of children with antibiotic allergy, in particular, beta-lactam allergy. The potential consequences of being labeled beta-lactam allergy are increasingly recognized. Appropriate evaluation of children with suspected reactions to antibiotics is essential as it is increasingly being recognized that the label of "penicillin allergy" is associated with adverse health and economic outcomes. This review will focus on the 3 main classes of antibiotics reported to cause allergic reactions in children: beta lactams (penicillin derivatives and cephalosporins), macrolides, and sulfonamides. This article is a narrative review of the prevalence, diagnosis, and management of different types of antibiotic allergies in children. Our review reveals that antibiotic allergy is often overreported and not appropriately diagnosed in the pediatric age groups. There is a recent shift in the diagnostic paradigm from the use of skin tests and if negative challenges to the use of challenge only in the pediatric age group. Larger studies to establish the usefulness and safety of this new approach as well as updated guidelines are needed.

Pediatric Drug Hypersensitivity.

PURPOSE OF REVIEW: Pediatric drug hypersensitivity is a rapidly evolving field. The purpose of this paper is to review the current state of pediatric drug hypersensitivity and highlight new developments in diagnosis and management. RECENT FINDINGS: This paper will discuss the safety and use of risk stratification to proceed directly to oral challenge without prior skin testing for ß-lactam reactions. We review unique aspects of pediatric drug challenges and desensitizations. It is important to accurately diagnose pediatric drug hypersensitivity reactions through a detailed history, physical examination, and available diagnostic testing. Understanding of the underlying mechanism leads to appropriate classification which is necessary to direct management. The decision to perform drug challenge, desensitization, or recommend avoidance of a medication can have a significant impact on a patient's treatment. Utilization of weight-based dose and infusion rate adjustments for current drug challenge and desensitization protocols optimize success.

Low frequency of acetyl salicylic acid hypersensitivity in mastocytosis: The results of a double-blind, placebo-controlled challenge study.

BACKGROUND: Patients with mastocytosis are at increased risk of anaphylaxis. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is often discouraged because of this reason. However, the actual prevalence and severity of NSAID-related hypersensitivity among patients with mastocytosis is unknown. METHODS: A double-blind, placebo-controlled acetylsalicylic acid (ASA) challenge up to a cumulative dose of 520 mg was performed among adult patients with mastocytosis. In addition, a retrospective search of the entire outpatient cohort was performed to obtain "real-life" data on NSAID hypersensitivity. RESULTS: Fifty patients underwent an ASA challenge. Seventy percent had indolent systemic mastocytosis, 18% had mastocytosis in the skin, and 12% had advanced mastocytosis. The ASA challenge was positive in 1 patient who developed urticaria. The additional retrospective chart review revealed that 8 of 191 patients had a history of NSAID-related hypersensitivity reaction(s), of whom 3 reported severe systemic reactions. All 8 patients had already experienced NSAID-related hypersensitivity reactions before mastocytosis was diagnosed. CONCLUSIONS: The frequency of ASA hypersensitivity was 2% in a prospective challenge study and 4.1% in a retrospective chart review of 191 patients with mastocytosis. NSAIDs can be administered safely to most patients with mastocytosis. Extra caution should be taken in patients with a history of hypersensitivity reactions to other drugs, or traditional risk factors for NSAID hypersensitivity.

Impact of electrocardiogram screening during drug challenge test for the prediction of T-wave oversensing by a subcutaneous implantable cardioverter defibrillator in patients with Brugada syndrome.

Screening tests conducted at rest may be inadequate for the prediction of the T-wave oversensing (TWOS) in subcutaneous implantable cardioverter defibrillator (S-ICD) candidates with Brugada syndrome (BrS) because of the dynamic nature of electrocardiogram (ECG) morphology. We evaluated the utility of ECG screening during drug challenge (DC) for prediction of TWOS in BrS patients implanted with an S-ICD. The study enrolled 6 consecutive BrS patients implanted with an S-ICD. In addition to baseline ECG screening, pre-implant screening during DC using a sodium channel blocker was performed in all patients. All patients underwent appropriate morphological analysis on baseline ECG screening; however, 2 BrS patients (33%) showed inappropriate sensing during DC. During 243 days of follow-up after S-ICD implantation, no patient experienced an appropriate shock. TWOS was confirmed during exercise testing in one of 2 patients who showed inappropriate sensing during DC. However, one patient with appropriate sensing during DC experienced recurrent episodes of inappropriate shocks due to TWOS during exercise. The present initial experience indicates that further studies are needed to detect the risk for TWOS from an S-ICD in BrS patients.