Non-IgE-mediated drug-induced hypersensitivity reactions in pediatrics.

PURPOSE OF REVIEW: Despite their prevalence and potential severity, non-IgE-mediated drug-induced hypersensitivity reactions (DHRs) are under-researched and poorly defined, particularly in children. Presentations range from mild cutaneous reactions to severe systemic diseases, with pathophysiological mechanisms and reliable diagnostic markers not well established. The lack of validated tests often leads to permanent drug restrictions, reliance on second-line drugs, and increased costs. Focusing on recent advancements and areas needing further research, this review aims to enhance children's recognition, diagnosis, and management of non-IgE-mediated DHRs. RECENT FINDINGS: Recent studies have enhanced the understanding of immediate and delayed non-IgE-mediated drug reactions. Key findings include the Mas-related G protein-coupled receptor X2 in mast cells and the identification of HLA alleles linked to severe cutaneous adverse reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Improved diagnostic techniques, including skin testing, show promise in identifying immediate and delayed non-IgE DHRs. Additionally, research highlights the impact of cofactors, drug metabolites, and co-infections on these DHRs and explores potential biomarkers for predicting reaction severity. SUMMARY: Non-IgE-mediated DHRs are a significant cause of morbidity and treatment changes in pediatric patients. Recent research underscores their clinical presentations and mechanisms, paving the way for more precise diagnostic and therapeutic strategies to improve patient outcomes.

Patient Perceptions of Penicillin Allergy Testing in a Public Health System.

BACKGROUND: Documented penicillin allergies are associated with increased morbidity, increased hospital stay, and an increase in resistant infections. Penicillin allergy evaluations using a direct oral challenge with or without skin testing has been recommended as a delabeling strategy for patients with penicillin reaction histories. Barriers for achieving equitable access, however, exist. Understanding patient perceptions regarding their penicillin allergy across diverse populations is crucial to mitigate potential obstacles to penicillin allergy testing (PAT) and the use of penicillin-like antibiotics after delabeling. OBJECTIVE: The objective of this study was to gather perceptions of patients delabeled of their penicillin allergy after testing through a PAT program. METHODS: Patients who underwent PAT and had a subsequent allergy removal due to a negative result were interviewed using closed and open-ended questions. RESULTS: A total of 100 patient interviews were completed. Awareness of the risks associated with unnecessary penicillin avoidance and PAT was low. Initial concerns regarding PAT were common but were frequently alleviated with targeted education. Most patients undergoing testing reported a positive experience and would recommend PAT to others. A minority of patients continued to have discordant perceptions regarding their penicillin allergy label with mistrust in the negative result being a critical theme identified. CONCLUSIONS: Future interventions increasing the awareness of penicillin allergy labels and the risks and benefits of PAT in the general population are needed and must consider health literacy levels, languages, and cultural contexts. Measures to offer PAT within a clinical setting that has built high levels of patient trust will likely achieve the greatest long-term success.

Cephalosporin Allergy: Updates on Diagnostic Testing.

PURPOSE OF REVIEW: Cephalosporins are one of the most prescribed antibiotics worldwide and are implicated in a wide range of hypersensitivity reactions (HSR). This review summarizes recent updates in cephalosporin hypersensitivity with a focus on diagnostic testing. RECENT FINDINGS: Reported testing strategies to evaluate different immediate and delayed cephalosporin HSR have included skin testing, in vitro testing, and diagnostic drug challenges. However, the diagnostic performance of in vivo and in vitro tests remains unclear across different hypersensitivity endotypes; adequately powered studies investigating the true positive and negative predictive value of these diagnostic modalities are needed using the reference standard of drug challenges to define cephalosporin hypersensitivity. Refinement of diagnostic testing should be guided by growth in our understanding of cephalosporin antigenic determinants. This growth will be crucial in driving further clarification of cross-reactivity between cephalosporins, and potentially delineating streamlined evaluation processes resulting in reduced unnecessary antibiotic avoidance.

Non-IgE-Mediated Immediate Drug-Induced Hypersensitivity Reactions.

Immediate drug-induced hypersensitivity reactions (IDHSRs) have conventionally been attributed to an immunoglobulin E (IgE)-mediated mechanism. Nevertheless, it has now been acknowledged that IDHSRs can also occur independently of IgE involvement. Non-IgE-mediated IDHSRs encompass the activation of effector cells, both mast cell-dependent and -independent and the initiation of inflammatory pathways through immunogenic and nonimmunogenic mechanisms. The IDHSRs involve inflammatory mediators beyond histamine, including the platelet-activating factor, which activates multiple cell types, including smooth muscle, endothelium, and MC, and evidence supports its importance in IgE-mediated reactions in humans. Clinically, distinguishing IgE from non-IgE mechanisms is crucial for future treatment strategies, including drug(s) restriction, readministration approaches, and pretreatment considerations. However, this presents significant challenges because certain drugs can trigger both mechanisms, and their presentations can appear similarly, ranging from mild to life-threatening symptoms. Thus, history alone is often inadequate for differentiation, and skin tests lack a standardized approach. Moreover, drug-specific IgE immunoassays have favorable specificity but low sensitivity, and the usefulness of the basophil activation test remains debatable. Lastly, no biomarker reliably differentiates between both mechanisms. Whereas non-IgE-mediated mechanisms likely predominate in IDHSRs, reclassifying most drug-related IDHSRs as non-IgE-mediated, with suggested prevention through dose administration adjustments, is premature and risky. Therefore, continued research and validated diagnostic tests are crucial to improving our capacity to distinguish between these mechanisms, ultimately enhancing patient care.

Clinical Phenotypes of Immediate First-Dose Reactions to mRNA COVID-19: A Multicenter Latent Class Analysis.

BACKGROUND: Although immediate potentially allergic reactions have been reported after dose 1 of mRNA coronavirus disease 2019 (COVID-19) vaccines, comprehensively defined subtypes have not been clearly distinguished. OBJECTIVE: To define distinct clinical phenotypes of immediate reactions after dose 1 of mRNA COVID-19 vaccination, and to assess the relation of clinical phenotype to mRNA COVID-19 vaccine second dose tolerance. METHODS: This retrospective study included patients with 1 or more potentially allergic symptoms or signs within 4 hours of receiving dose 1 of an mRNA COVID-19 vaccine and assessed by allergy/immunology specialists from 5 U.S. academic medical centers (January-June 2021). We used latent class analysis-an unbiased, machine-learning modeling method-to define novel clinical phenotypes. We assessed demographic, clinical, and reaction characteristics associated with phenotype membership. Using log-binomial regression, we assessed the relation between phenotype membership and second dose tolerance, defined as either no symptoms or mild, self-limited symptoms resolving with antihistamines alone. A sensitivity analysis considered second dose tolerance as objective signs only. RESULTS: We identified 265 patients with dose-1 immediate reactions with 3 phenotype clusters: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. A total of 223 patients (84%) received a second dose and 200 (90%) tolerated their second dose. Sensory cluster (all patients had the symptom of numbness or tingling) was associated with a higher likelihood of second dose intolerance, but this finding did not persist when accounting for objective signs. CONCLUSIONS: Three novel clinical phenotypes of immediate-onset reactions after dose 1 of mRNA COVID-19 vaccines were identified using latent class analysis: (1) Limited or Predominantly Cutaneous, (2) Sensory, and (3) Systemic. Whereas these clinical phenotypes may indicate differential mechanistic etiologies or associations with subsequent dose tolerance, most individuals proceeding to their second dose tolerated it.

Penicillin Allergy Evaluation and Health Equity: A Call to Action.

Allergists have been at the forefront of addressing the burden of unverified penicillin allergy labels. Coordinated national efforts with infectious diseases, antimicrobial stewardship experts, and pharmacy societies to advocate for formal evaluation of patient-reported penicillin allergy have resulted in improvements in delabeling efforts. Given the poorer health outcomes associated with the penicillin allergy label and the potential health benefits that can be gained with delabeling, improving access to penicillin allergy evaluation is of the utmost importance. Health disparities are widely recognized to impact all aspects of health care, and multilevel interventions at the patient, clinician, and systems level are required to ensure equitable care delivery. Structural racism underpins many social determinants of health and is a key driver of racial and ethnic health disparities. In this Rostrum, we use a conceptual framework from the 2015 National Academy of Medicine report Improving Diagnosis in Health Care to explore how inequities are related to the evaluation of penicillin allergy. We use the National Institute on Minority Health and Health Disparities Strategies to Advance Health Disparities to elucidate areas of important study. Building upon existing efforts to address disparities in Allergy/Immunology, we highlight the urgent importance of understanding and eliminating health disparities in penicillin allergy evaluation and delabeling.

Adverse Reactions to Biologic Medications Used in Allergy and Immunology Diseases.

PURPOSE OF REVIEW: The use of biologic therapies has risen exponentially over recent years, allowing for unprecedented disease control within numerous areas of Allergy/Immunology. With this expanded use, awareness and understanding of adverse reactions to biologic agents have also increased. RECENT FINDINGS: Multiple biologic adverse reaction phenotypes have been described, but significant overlap in clinical features across phenotypes exists. Given considerable phenotypic overlap, a targeted testing approach may not always be clear, and more recent classifications focus on management decision making using tools of diagnostic challenges and rapid drug desensitizations, guiding clinicians in developing a management plan when the exact underlying mechanism is not clearly known. With increased clinical experience with omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, tezepelumab, rituximab, and TNF-inhibitors, there is a growing appreciation to the spectrum and particularities of adverse reactions to these agents which are outlined in this review. Our understanding of the clinical presentation and management of adverse reactions to biologic medications encountered in Allergy/Immunology has grown. Opportunities remain to further define optimal diagnostic and management strategies for these reactions.

A Review of Adverse Reactions to Biologics Used in Allergy-Immunology Practice.

Biologic agents have become an integral therapeutic option for practicing allergists-immunologists for the management of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and various immunologic conditions. As these agents vary considerably from traditional small-molecule drugs, various adverse reactions have been noted. A different approach must be used to classify these reactions beyond the classic Gell-Coombs classification system as it does not capture many of the adverse events seen with biologic therapy. This article addresses the available literature on proposed classification systems and diagnostic modalities for adverse events associated with biologics and reviews each approved agent used frequently in allergy-immunology practice.

Safety of subcutaneous immunotherapy in patients with severe asthma.

BACKGROUND: Severe asthma (SA) has been identified as a risk factor for severe systemic reactions (SR) to allergen subcutaneous immunotherapy (SCIT). However, the incidence and characterization of SRs in SA in comparison to less severe or no asthma is not known. OBJECTIVE: The objective of this study was to characterize the incidence of SRs in patients with SA receiving SCIT in comparison to patients with no asthma or less SA. METHODS: A retrospective cohort study was performed on patients receiving SCIT from a multicenter national network of private allergy practices between January 2015 and December 2019. Demographics, asthma severity (International Classification of Diseases-10 codes), concomitant medications, aeroallergen skin testing, measures of asthma control with the asthma control test and forced expiratory volume in 1 second values, SCIT prescription, and an SR standardized form were assessed. RESULTS: A total of 65,855 patients, with 1072 patients having SA receiving SCIT, were included with a total of 4415 SRs (19.9 SR per 10,000 injection visits). Severe asthma had 23.9 SRs per 10,000 injection visits (incidence rate, 0.239; 95% confidence interval [0.189-0.298]). There were 155 grade III or IV SRs; 5 (3.2%) occurred in the SA group. There was no difference in rates of grade III or IV SRs between SA and no asthma and in rates of total SRs between SA and less SA. CONCLUSION: In a large cohort of patients with SA undergoing multiallergen SCIT drawn from a diverse outpatient allergy population, the diagnosis of SA was not associated with increased moderate-severe SRs compared with patients without asthma and any severity of asthma.

Sulfonamide Hypersensitivity.

Sulfonamides, particularly antimicrobial sulfonamides, have been implicated as a common cause of a spectrum of hypersensitivity reactions. Immediate IgE-mediated reactions have been reported but are much less common than delayed cutaneous reactions. Delayed cutaneous reactions range from benign exanthems to severe cutaneous reactions such as Stevens Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms. Sulfonamides can be subclassified as antimicrobial sulfonamides and non-antimicrobial sulfonamides, which are also distinguished by key structural differences, resulting in very low risk of cross-reactivity between these two subclasses. Immediate and delayed skin testing and in vitro testing remain limited as options in evaluating antimicrobial sulfonamide hypersensitivity. Drug challenges continue to play an important role in the evaluation of both immediate and delayed reactions, with a growing body of evidence for the safety of direct challenges regardless of human immunodeficiency virus infection status. While numerous "desensitization" protocols have been described for the management of antimicrobial sulfonamide hypersensitivity, there is limited evidence that such procedures are successful because of an induction of tolerance.

A 2-year-old girl with periprocedural anaphylaxis.

Periprocedural or perioperative anaphylaxis is rare, with an estimated incidence of 1 in 10,000 to 40,000 sedation cases. During such procedures, patients are often exposed to numerous medications, such as antimicrobials, neuromuscular blocking agents, sedative and/or hypnotics, and opioids. The most commonly implicated agents include antibiotics (in the United States) and neuromuscular blocking agents (in Europe). In this article, we explore the differential diagnosis and laboratory investigation of a case of periprocedural anaphylaxis.

POPs Case Report: A 2-year-old girl with periprocedural anaphylaxis.

Periprocedural or perioperative anaphylaxis is rare, with an estimated incidence of 1 in 10,000 to 40,000 sedation cases.During such procedures, patients are often exposed to numerous medications, such as antimicrobials, neuromuscular blockingagents, sedative and/or hypnotics, and opioids. The most commonly implicated agents include antibiotics (in the UnitedStates) and neuromuscular blocking agents (in Europe). In this article, we explore the differential diagnosis and laboratoryinvestigation of a case of periprocedural anaphylaxis.