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IntroductionPenicillin allergies are highly prevalent in the healthcare setting and associated with the prescription of second-line inferior antibiotics. More than 85% of all penicillin allergy labels can be removed by skin testing and 96%–99% of low-risk penicillin allergy labels can be removed by direct oral challenge. An internally and externally validated clinical assessment tool for penicillin allergy, PEN-FAST, can identify a low-risk penicillin allergy without the need for skin testing; a score of less than 3 has a negative predictive value of 96.3% (95% CI, 94.1 to 97.8) for the presence of a penicillin allergy. It is hypothesised that PEN-FAST is a safe and effective tool for assessing penicillin allergy in an outpatient clinic setting.Methods and analysisThis is an international, multicentre randomised control trial using the PEN-FAST tool to risk-stratify penicillin allergy labels in adult outpatients. The study’s primary objective is to evaluate the non-inferiority of using PEN-FAST score-guided management with direct oral challenge compared with standard care (defined as prick and intradermal skin testing followed by oral penicillin challenge). Participants will be randomised 1:1 to the intervention arm (direct oral penicillin challenge) or standard of care arm (skin testing followed by oral penicillin challenge, if skin testing is negative). The sample size of 380 randomised patients (190 per treatment arm) is required to demonstrate non-inferiority.Ethics and disseminationThe study will be performed according to the guidelines of the Helsinki Declaration and is approved by the Austin Health Human Research Ethics Committee (HREC/62425/Austin-2020) in Melbourne Australia, Vanderbilt University Institutional Review Board (IRB #202174) in Tennessee, USA, Duke University Institutional Review Board (IRB #Pro00108461) in North Carolina, USA and McGill University Health Centre Research Ethics Board in Canada (PALACE/2022-7605). The results of this study will be published and presented in various scientific forums.Trial registration numberNCT04454229.

Background Acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions. These rare conditions differ in clinical presentation, pathological features, treatment and prognosis, but overlap has been described implying a challenging clinical management. Case presentation We describe a case of overlap between TEN and AGEP probably secondary to beta-lactams in a 77-year-old patient treated for a complicated cholangitis. We review the diagnosis and the management of these two conditions. The diagnosis of TEN was suggested by the initial clinical presentation with severe hemodynamic instability, skin detachment, positive Nikolsky sign and mucosal involvement. However, the skin biopsy as well as the rapid improvement of the skin lesions were discriminative for AGEP. This indicated an overlap presentation. Unfortunately, the patient refused allergy investigations in order to find the culprit drug. Medical photographs, proper physical examination and histopathological results are integrated. Conclusion Despite clinical features indicating a diagnosis of TEN, histopathology was conclusive for AGEP thus indicating a possible clinical-pathological overlap between the two conditions, a scarcely described situation in the medical literature. To our knowledge, this is one of the few cases that portrays a TEN–AGEP overlap probably secondary to Piperacillin Tazobactam. Understanding the immunological implications of these conditions can help us better distinguish and manage these severe reactions.

IntroductionSevere cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand.Methods and analysisAdult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data.Ethics and disseminationThis study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12619000241134).

Roughly 1% to 5% of patients with coronary artery disease report adverse effects from acetylsalicylic acid (ASA). Patients with ASA-exacerbated respiratory disease (AERD) should avoid ASA if desensitization is not possible. Patients with a history of urticaria or angioedema after intake of COX-1 inhibitors may tolerate low doses of ASA. Patients who report isolated gastrointestinal effects or have tolerated another COX-1-inhibiting nonsteroidal anti-inflammatory (NSAID) medication may not have ASA allergy. Desensitization and questions about the safety of ASA administration require consultation with an allergy and immunology specialist.

Delayed drug T-cell immune-mediated hypersensitivity reactions have a large clinical heterogeneity varying from mild maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and severe skin necrosis and blistering as seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Given the knowledge gaps related to the immunopathogenesis of these conditions, the absence of validated diagnostic tools and the significant associated morbidity and mortality, patients with SCARs often have limited drug choices. We performed a comprehensive review aiming to evaluate in vivo diagnostic tools such as delayed intradermal skin and patch testing and ex vivo/in vitro research assays such as the lymphocyte transformation test (LTT) and the enzyme-linked ImmunoSpot (ELISpot) assay. We searched through PubMed using the terms “drug allergy,” “ in vivo ” and “ ex vivo ” for original papers in the last 10 years. A detailed meticulous approach adapted to the various clinical phenotypes is recommended for the diagnostic and management of delayed drug hypersensitivity reactions. This review highlights the current diagnostic tools for the delayed drug hypersensitivity phenotypes.

Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions (HSRs) with varying mechanisms and clinical presentations. This type of adverse drug reaction (ADR) not only affects patient quality of life, but may also lead to delayed treatment, unnecessary investigations, and increased morbidity and mortality. Given the spectrum of symptoms associated with the condition, diagnosis can be challenging. Therefore, referral to an allergist experienced in the diagnosis and management of drug allergy is recommended if a drug-induced allergic reaction is suspected. Diagnosis relies on a careful history and physical examination and, in some instances, skin testing or in vitro testing and drug challenges. The most effective strategy for the management of allergist-confirmed drug allergy is avoidance or discontinuation of the offending drug. When available, alternative medications with unrelated chemical structures should be substituted. Cross-reactivity among drugs should also be taken into consideration when choosing alternative agents. Additional therapy for drug HSRs may include topical corticosteroids, oral antihistamines and, in severe cases, systemic corticosteroids and other immunomodulators. In the event of anaphylaxis, the treatment of choice is intramuscular epinephrine. If a patient with a history of anaphylaxis requires a specific drug and there is no acceptable alternative, desensitization to that drug may be considered. This article provides a background on drug allergy and strategies for the diagnosis and management of some of the most common drug-induced allergic reactions. Key take-home messages Drug allergy encompasses a spectrum of immunologically mediated hypersensitivity reactions (HSRs) with varying mechanisms and clinical presentations. Risk factors for drug allergy include age (more common in young/middle-aged adults), gender (more common in females), genetic polymorphisms, certain viral infections (HIV and herpes viruses) and drug-related factors (topical and IV/intramuscular routes of administration are more immunogenic than oral administration). The skin is the organ most frequently affected by drug-induced allergic reactions; however, many other organ systems may be involved, including multi-organ reactions such as anaphylaxis. Referral to an allergist is important for the appropriate diagnosis and treatment of drug allergy. Diagnosis requires a thorough drug history, including dates of administration, drug formulation, dosage and route of administration, as well as clinical symptoms and their timing and duration in relation to drug exposure; skin testing and graded challenges may also be required. The mainstay of treatment is avoidance of the offending drug; alternative medications with unrelated chemical structures should be substituted when possible. If a particular drug to which the patient is allergic is indicated, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug.

Background The use of in vivo and ex vivo diagnostic tools for delayed hypersensitivity reactions (DHRs) associated with iodinated contrast media (ICM) is currently ill-defined. Objective To evaluate the role of in vivo and ex vivo diagnostic tools for DHRs occurring >6 h following intravenous low-osmolality ICM. Methods We conducted a prospective, multicenter, international cohort study. The patients were recruited from two tertiary care adult allergy clinics, Austin Health, Australia and the McGill University Health Centre, Canada. Eligible participants were adults who reported a DHR after receiving ICM. In vivo testing (skin testing and intravenous challenge) was performed to identify an alternative agent. Ex vivo testing using interferon-γ enzyme-linked ImmunoSpot assay was performed in four Australian patients to explore its diagnostic performance. Results The culprit ICM was identified by dIDT in 17/20 (85%) while in 3/20 (15%) a challenge was necessary to confirm delayed hypersensitivity. All patients with a positive dIDT to iohexol were positive to iodixanol (15/15; 100%) while 3/4 (75%), 3/4 (75%), 4/6 (67%), and 3/5 (60%) were positive to iopromide, ioversol, iopamidol, and iobitridol, respectively. Overall, 7/20 (35%) patients tolerated a challenge with an alternative ICM. The IFN-γ release assay was negative for the implicated ICM in 4 patients with confirmed DHR through a positive dIDT. Conclusion dIDT allowed confirmation of T cell-mediated allergy to the implicated ICM in 85% of patients with a strong clinical suspicion of DHR and identification of non-cross-reactive ICM in 35% of patients. The IFN-y ELISpot was not useful in the four patients tested.