Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort.

BACKGROUND: ß-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE. OBJECTIVE: We sought to identify genetic predisposing factors for immediate reactions to ß-lactam antibiotics. METHODS: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort. RESULTS: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to ß-lactams. CONCLUSIONS: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.

[Innovative immunotherapies of respiratory allergic diseases]. / Immunothérapies innovantes des maladies allergiques respiratoires.

Allergen immunotherapy (AIT) is an effective method in the treatment of respiratory allergic diseases (asthma, rhinitis and conjunctivitis). In addition to reducing symptoms, AIT can alter the course of allergic disease and remains efficient long after it has been discontinued by inducing specific tolerance to the allergen. In current clinical practice, immunotherapy is administered by subcutaneous or sublingual routes. The duration of efficacy is 7 to 12 years. It can prevent the development of both asthma and sensitization to new allergens. Despite recent progresses, other approaches are needed, especially for allergies (atopic dermatitis, food allergies). The new AIT improvement approaches involve the use of adjuvants or recombinant allergies, peptides and new routes of administration.

Advances in the Understanding of Drug Hypersensitivity: 2012 Through 2022.

Over the last decade there have been key advances in understanding mechanisms, risk, and consequences of both true immunological drug hypersensitivity and unverified drug allergy labels that have changed clinical practice. This has been facilitated by the widespread adoption of electronic health records (EHRs). The vast majority of EHR drug allergy labels are unverified and cause significant morbidity from unnecessary avoidance of optimal drug therapy. There has also been significant movement in our understanding of mechanisms of drug hypersensitivity that, in addition to advancing our understanding of the pathogenesis of immediate and delayed reactions, have guided preventive efforts, diagnostic procedures, and clinical management. More widespread adoption, including scale-up of "allergy" delabeling and appropriate management, specifically for antibiotics, opiates, radiocontrast, chemotherapeutics, biologics, and nonsteroidal anti-inflammatory medications, will be necessary to improve patient outcomes over the next decade. This will require further engagement and collaboration between primary care health care providers, allergists, and other specialists.

Digital Allergy Card: Design and Users' Perceptions.

This paper presents the design and the users' perceptions of a Digital Allergy Card for recording, sharing and tracing information on drug allergies.

Controversies in Drug Allergy: Drug Allergy Pathways.

Drug allergy pathways are standardized approaches for patients reporting prior drug allergies with the aim of quality improvement and promotion of antibiotic stewardship. At the International Drug Allergy Symposium during the 2018 American Academy of Allergy, Asthma, and Immunology/World Allergy Organization Joint Congress in Orlando, Florida, drug allergy pathways were discussed from international perspectives with a focus on beta-lactam allergy pathways and pragmatic approaches for acute care hospitals. In this expert consensus document, we review current pathways, and detail important considerations in devising, implementing, and evaluating beta-lactam allergy pathways for hospitalized patients. We describe the key patient and institutional factors that must be considered in risk stratification, the central feature of pathway design. We detail shared obstacles to widespread beta-lactam allergy pathway implementation and identify potential solutions to address these challenges.

The Limited Value of Prolonged Drug Challenges in Nonimmediate Amoxicillin (Clavulanic Acid) Hypersensitivity.

BACKGROUND: Misdiagnosis of amoxicillin (clavulanic acid) (AX(/CL)) hypersensitivity has serious consequences. A drug challenge (DC) is the final diagnostic to affirm or infirm AX(/CL) hypersensitivity. However, uncertainties remain whether a prolonged drug challenge (pDC) should benefit the diagnosis of a nonimmediate AX(/CL) hypersensitivity. OBJECTIVE: To assess the added value of a standardized 7-day pDC in the diagnosis of nonimmediate or unclear penicillin hypersensitivity. METHODS: A total of 132 patients with a history of a nonimmediate hypersensitivity reaction or an unclear reaction to AX(/CL) or an undefined penicillin with a negative diagnostic workup including a single-day DC (DC) with AX(/CL) were selected. In all these patients, an additional pDC with AX(/CL) was planned. Thirteen patients started the pDC immediately after the DC. To ensure that hypersensitivity symptoms manifesting during the pDC course do not result from the DC, in the remaining 119 patients, the pDC was scheduled after a washout of 1 week. RESULTS: A total of 128 patients (12 without washout, 116 with washout) completed the pDC. Three patients reacted with a mild maculopapular exanthema. However, the value of a pDC was evidenced in only 1 patient who reacted during her pDC after an uneventful washout. In 2 patients pDC was cancelled because they reacted during the washout. CONCLUSIONS: A pDC is of limited added value to the diagnostic algorithms of nonimmediate hypersensitivity reaction or unclear hypersensitivity reactions to AX(/CL). In our hands, the traditionally recommended diagnostic algorithm that offers a 1-day DC as a final diagnostic in patients with negative workup for AX(/CL) is appropriate.

Allergy to local anesthetics: Reality or myth?

The incidence of allergic reactions to local anesthetics is low. Most cases involve a psychogenic reaction rather than an allergic reaction. Additives and preservatives added to local anesthetics may cause allergic reactions. Vascular resorption of epinephrine-containing local anesthetics may produce cardiovascular signs similar to an allergic reaction. Diagnosis of allergy to local anesthetics must be established by skin testing and provocative challenge.

Drug allergy diagnosis.

Poorly documented and often self-reported drug hypersensitivity (DH) is a frequent problem in daily clinical practice and has a considerable impact on prescription choices. Little is known about the natural history of true DH. The suspicion of DH starts on clinical grounds. When assessing a patient with a presumed DH reaction in the symptomatic phase, it is mandatory to look for severity signs and, after doing so, to update the risk/benefit balance of exploring the suspected drug(s) on a case-by-case basis. With the help of allergy tests and a careful approach, a firm diagnosis is often possible.

Multiple drug hypersensitivity syndrome.

PURPOSE OF REVIEW: The multiple drug hypersensitivity syndrome (MDH) is a distinct clinical entity, different from cross-reactivity and flare-up reactions. Following its initial description in 1989 by Sullivan et al., several authors have addressed the issues surrounding this peculiar form of drug hypersensitivity. Whether this syndrome is single or can be further classified in several entities is still a matter of debate. RECENT FINDINGS: Case reports, case series or studies involving large populations on MDH are few. The use of this term in the literature is heterogeneous, and the definitions variable. Given the major advances in the study of drug hypersensitivities in general, and ongoing research regarding severe cutaneous adverse reactions in particular, careful study of the subgroup of patients with demonstrated immunological basis of MDH has enabled the generation of possible pathogenetic hypotheses. Together with the studies (despite their limitations) to estimate the prevalence of this syndrome in adult and paediatric patients these emerging data need confirmation through larger studies with well defined populations. SUMMARY: Bringing together the experience of groups involved in the field of drug allergy should help to move knowledge regarding this peculiar form of drug hypersensitivity forward.