RESUMEN
This secondary analysis of adult patients in the Penicillin Allergy Clinical Decision Rule (PALACE) Study investigates the risk of self-reported penicillin allergy despite removal of penicillin allergy label.
Asunto(s)
Hipersensibilidad a las Drogas , Penicilinas , Autoinforme , Humanos , Penicilinas/efectos adversos , Masculino , Femenino , Adulto , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Persona de Mediana Edad , Etiquetado de MedicamentosRESUMEN
Cutaneous adverse drug reactions collectively are delayed drug reactions such as morbilliform drug eruption and severe cutaneous adverse reactions (SCARs). Morbilliform drug eruption may wane over time, be the result of drug viral interactions, and be amenable to slow reintroduction or rechallenge, whereas SCARs are HLA class I restricted, T-cell-mediated reactions that demonstrate durable immunity and warrant lifelong avoidance. SCARs such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption often occur in the setting of multiple drugs dosed together. Collectively, they lead to significant morbidity, mortality, and drug safety concerns that could severely limit future treatment options. Currently, no single or combination of diagnostic tests for SCARs such as ex vivo or in vitro testing, in vivo (skin) testing, or other adjunctive tests such as HLA typing have 100% negative predictive value. In this "Controversies in Allergy Review" article, we review the current literature on delayed skin testing (patch and delayed prick/intradermal test) and critically assess the evidence base of its utility across different drugs and clinical phenotypes of delayed hypersensitivity reactions.
RESUMEN
Risk stratification in drug allergy implies that specific risk categories (eg, low, moderate, and high) classify historical drug hypersensitivity reactions. These risk categories can be based on reaction phenotypic characteristics, the timing of the reaction and evaluation, the required reaction management, and individual characteristics. Although a multitude of frameworks have been described in the literature, particularly for penicillin allergy labels, there has yet to be a global consensus, and approaches continue to vary between allergy centers. Immune-mediated drug allergies can sometimes be confirmed using skin testing, but a negative drug challenge is required to demonstrate tolerance and remove the allergy from the electronic health record ("delabel" the allergy). Even for quintessential IgE-mediated drug allergy, penicillin allergy, recent data reveal that a direct oral challenge, without prior skin testing, is an appropriate diagnostic strategy in those who are considered low-risk. Drug allergy pathogenesis and clinical manifestations may vary depending on the culprit drug, and as such, the optimal approach should be based on risk stratification that considers individual patient and reaction characteristics, the likely hypersensitivity reaction phenotype, the drug class, and the patient's clinical needs. This article will describe low-risk drug allergy labels, focusing on ß-lactam and sulfonamide antibiotics, nonsteroidal anti-inflammatory drugs, iodinated contrast media, and common chemotherapeutics. This review will also address practical management approaches using currently available risk stratification and clinical decision tools.
Asunto(s)
Hipersensibilidad a las Drogas , Humanos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/terapia , Pruebas Cutáneas , Medición de Riesgo , Penicilinas/efectos adversos , Penicilinas/inmunología , Inmunoglobulina E , Antibacterianos/efectos adversos , Antibacterianos/inmunologíaRESUMEN
BACKGROUND: Cephalosporins, ß-lactam antibiotics, commonly cause allergic reactions. OBJECTIVE: To assess the clinical characteristics and management of pediatric patients with suspected cephalosporin allergy using direct graded oral challenges (GOCs). METHODS: Children referred for suspected cephalosporin allergy at 4 Canadian clinics were recruited over 10 years. Data on demographics, clinical reaction characteristics, and management were collected through a questionnaire. Patients underwent a direct GOC (initially 10% of the treatment dose, then 90% after 20 min), and reactions were monitored 1 week postchallenge. Families were contacted annually for up to 5 years to detect subsequent antibiotic reactions. Logistic regression analysis identified factors associated with positive GOC reactions. RESULTS: Among the 136 patients reporting cephalosporin allergy, 75 (55.1%) were males with a median age of 3.9 years (interquartile range 2.3-8.7). Cefprozil represented the most common cephalosporin linked to the index reaction (67.6% of cases). Of the 136 direct GOCs, 5.1% had an immediate and 4.4% a nonimmediate reaction, respectively. Positive GOCs conducted in children with a history of skin-limited nonsevere rashes were classified as mild, benign skin rashes. Positive GOCs were more likely in children with food allergies (adjusted odds ratio 1.14; 95% confidence interval [95% CI] 1.00-1.29). CONCLUSIONS: Direct GOCs are safe and effective for diagnosing pediatric cases that report nonvesicular skin-limited symptoms while being treated with cephalosporins.
Asunto(s)
Hipersensibilidad a las Drogas , Hipersensibilidad , Masculino , Humanos , Niño , Preescolar , Femenino , Cefalosporinas/efectos adversos , Pruebas Cutáneas/efectos adversos , Canadá/epidemiología , Antibacterianos/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/epidemiología , Hipersensibilidad a las Drogas/etiología , Monobactamas , Hipersensibilidad/complicaciones , Penicilinas/efectos adversosRESUMEN
Across all settings, women self-report more drug allergies than do men. Although there is epidemiologic evidence of increased drug allergy labeling in postpubertal females, the evidence base for female sex as a risk factor for true immune-mediated drug hypersensitivity reactions (DHRs), particularly in fatal drug-induced anaphylaxis, is low. A focus on the known immunologic mechanisms described in immediate and delayed DHR, layered on known hormonal and genetic sex differences that drive other immune-mediated diseases, could be the key to understanding biological sex variations in DHR. Particular conditions that highlight the impact of drug allergy in women include (1) pregnancy, in which a drug allergy label is associated with increased maternal and fetal complications; (2) multiple drug intolerance syndrome, associated with anxiety and depression; and (3) female-predominant autoimmune medical conditions in the context of mislabeling of the drug allergy or increased underlying risk. In this review, we describe the importance of drug allergy in the female population, mainly focusing on the epidemiology and risk, the mechanisms, and the associated conditions and psychosocial factors. By performing a detailed analysis of the current literature, we provide focused conclusions and identify existing knowledge gaps that should be prioritized for future research.
Asunto(s)
Anafilaxia , Hipersensibilidad a las Drogas , Embarazo , Femenino , Humanos , Masculino , Hipersensibilidad a las Drogas/etiología , Anafilaxia/tratamiento farmacológico , Factores de Riesgo , Autoinforme , Caracteres Sexuales , Antibacterianos/uso terapéutico , PenicilinasRESUMEN
Importance: Fewer than 5% of patients labeled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialized testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabeling. Objective: To determine whether a direct oral penicillin challenge is noninferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy. Design, Setting, and Participants: This parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial occurred in 6 specialized centers, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower than 3. PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies. Interventions: Patients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm). Main Outcome and Measure: The primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within 1 hour postintervention in the intention-to-treat population. Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp). Results: A total of 382 adults were randomized, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, -1.22 to 1.24 pp). The 1-sided 95% CI was below the noninferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, -0.45 pp; 95% CI, -4.87 to 3.96 pp). No serious adverse events occurred. Conclusions and Relevance: In this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label. Trial Registration: ClinicalTrials.gov Identifier: NCT04454229.
Asunto(s)
Hipersensibilidad a las Drogas , Hipersensibilidad , Adulto , Humanos , Femenino , Persona de Mediana Edad , Masculino , Reglas de Decisión Clínica , Penicilinas/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/etiología , Medición de Riesgo , Antibacterianos/efectos adversosRESUMEN
Inpatient direct oral challenge programs are increasingly deployed as part of antimicrobial stewardship initiatives to reduce the burden and impacts of penicillin allergy labels on antibiotic prescribing. Using data from a prospective, multicenter cohort inpatient penicillin allergy program, we identify the key targets for delabeling to aid health service implementation.
Asunto(s)
Hipersensibilidad a las Drogas , Hipersensibilidad , Humanos , Penicilinas/efectos adversos , Estudios Prospectivos , Pacientes Internos , Antibacterianos/efectos adversosRESUMEN
BACKGROUND: High-fidelity simulations based on real-life clinical scenarios have frequently been used to improve patient care, knowledge and teamwork in the acute care setting. Still, they are seldom included in the allergy-immunology curriculum or continuous medical education. Our main goal was to assess if critical care simulations in allergy improved performance in the clinical setting. METHODS: Advanced anaphylaxis scenarios were designed by a panel of emergency, intensive care unit, anesthesiology and allergy-immunology specialists and then adapted for the adult allergy clinic setting. This simulation activity included a first part in the high-fidelity simulation-training laboratory and a second at the adult allergy clinic involving actors and a high-fidelity mannequin. Participants filled out a questionnaire, and qualitative interviews were performed with staff after they had managed cases of refractory anaphylaxis. RESULTS: Four nurses, seven allergy-immunology fellows and six allergy/immunologists underwent the simulation. Questionnaires showed a perceived improvement in aspects of crisis and anaphylaxis management. The in-situ simulation revealed gaps in the process, which were subsequently resolved. Qualitative interviews with participants revealed a more rapid and orderly response and improved confidence in their abilities and that of their colleagues to manage anaphylaxis. CONCLUSION: High-fidelity simulations can improve the management of anaphylaxis in the allergy clinic and team confidence. This activity was instrumental in reducing staff reluctance to perform high-risk challenges in the ambulatory setting, thus lifting a critical barrier for implementing oral immunotherapy at our adult center.
RESUMEN
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.
RESUMEN
INTRODUCTION: Severe 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 ANALYSIS: Adult 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 DISSEMINATION: This 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 NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134).
Asunto(s)
Eosinofilia , Síndrome de Stevens-Johnson , Adolescente , Adulto , Australia/epidemiología , Eosinofilia/complicaciones , Humanos , Leucocitos Mononucleares , Estudios Prospectivos , Calidad de Vida , Sistema de Registros , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/etiología , Síndrome de Stevens-Johnson/terapiaRESUMEN
INTRODUCTION: Penicillin 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 ANALYSIS: This 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 DISSEMINATION: The 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 NUMBER: NCT04454229.