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.

A Skin Testing Strategy for Non-IgE-Mediated Reactions Associated With Vancomycin.

BACKGROUND: Vancomycin infusion reaction (VIR), reportedly mediated through Mas-Related G Protein-Coupled Receptor-X2, is the primary vancomycin-induced immediate drug reaction. Clinically, distinguishing the underlying drug-induced immediate drug reaction mechanisms is crucial for future treatment strategies, including drug restriction, re-administration, and pretreatment considerations. However, the lack of validated diagnostic tests makes this challenging, often leading to unnecessary drug restriction. OBJECTIVE: To determine whether intradermal tests (IDTs) and, separately, the basophil activation test (BAT) differentiate VIR from vancomycin-tolerant subjects. METHODS: This was a cross-sectional study of vancomycin-exposed adults with and without a history of VIR. Data on demographics, allergy-related comorbidities, history of vancomycin exposures, and VIR characteristics were collected. IDT with vancomycin was performed. IDT dose-response EC50, IDT-related local symptoms, and BAT results were compared between groups. RESULTS: A total of 11 VIR and 10 vancomycin-tolerant subjects were enrolled. The most reported VIR symptoms were pruritus (82%), flushing (82%), hives (46%), angioedema (27%), and dyspnea (19%). The IDT dose-response mean EC50 was 328 µg/mL (95% CI, 296-367) in the VIR versus 1166 µg/mL (95% CI, 1029-1379) in the tolerant group (P < .0001). All VIR subjects reported IDT-related local pruritus compared with 60% of tolerant subjects (P = .0185). The %CD63+ basophils were consistently less than 2%, without significant differences between groups (P < .54). CONCLUSIONS: Variations in skin test methodologies could help identify other immediate drug reaction mechanisms beyond IgE. This skin test protocol holds the potential for identifying VIR, particularly in cases where patients have received multiple drugs while BAT is insufficient. Future studies will validate and delineate its predictive value, assessing the risk of VIR.

A case report and systematic literature review: insulin-induced type III hypersensitivity reaction.

Insulin-induced type III hypersensitivity reactions (HSRs) are exceedingly rare and pose complex diagnostic and management challenges. We describe a case of a 43-year-old woman with type 1 diabetes mellitus (DM), severe insulin resistance, and subcutaneous nodules at injection sites, accompanied by elevated anti-insulin IgG autoantibodies. Treatment involved therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) as bridge therapy, followed by long-term immunosuppression, which reduced autoantibody levels and improved insulin tolerance. Given the limited treatment guidelines, we conducted a comprehensive literature review, identifying 16 similar cases. Most patients were females with a median age of 36.5 years; 63% had type 1 DM, and 44% had concurrent insulin resistance (56% with elevated autoantibodies). Treatment approaches varied, with glucocorticoids used in 67% of cases. Patients with type 1 DM were less responsive to steroids than those with type 2 DM, and had a more severe course. Of those patients with severe disease necessitating immunosuppression, 66% had poor responses or experienced relapses. The underlying mechanism of insulin-induced type III HSRs remains poorly understood. Immunosuppressive therapy reduces anti-insulin IgG autoantibodies, leading to short-term clinical improvement and improved insulin resistance, emphasizing their crucial role in the condition. However, the long-term efficacy of immunosuppression remains uncertain and necessitates continuous evaluation and further research.

Randomized Multicenter Trial for the Validation of an Easy-to-Administer Algorithm to Define Penicillin Allergy Status in Sexually Transmitted Infection Clinic Outpatients.

BACKGROUND: Approximately 15% of patients in sexually transmitted infection (STI) clinics report penicillin allergies, complicating treatment for syphilis and gonorrhea. Nonetheless, >90% do not have a penicillin allergy when evaluated. We developed and validated an algorithm to define which patients reporting penicillin allergy can be safely treated at STI clinics with these drugs. METHODS: Randomized controlled trial to assess feasibility and safety of penicillin allergy evaluations in STI clinics. Participants with reported penicillin allergy answered an expert-developed questionnaire to stratify risk. Low-risk participants underwent penicillin skin testing (PST) followed by amoxicillin 250 mg challenge or a graded oral challenge (GOC)-amoxicillin 25 mg followed by 250 mg. Reactions were recorded, and participant/provider surveys were conducted. RESULTS: Of 284 participants, 72 (25.3%) were deemed high risk and were excluded. Of 206 low-risk participants, 102 (49.5%) underwent PST without reactions and 3 (3%) had mild reactions during the oral challenge. Of 104 (50.5%) participants in the GOC, 95 (91.3%) completed challenges without reaction, 4 (4.2%) had mild symptoms after 25 mg, and 4 (4.2%) after 250-mg doses. Overall, 195 participants (94.7%) successfully completed the study and 11 (5.3%) experienced mild symptoms. Of 14 providers, 12 (85.7%) completed surveys and 11 (93%) agreed on the safety/effectiveness of penicillin allergy assessment in STI clinics. CONCLUSIONS: An easy-to-administer risk-assessment questionnaire can safely identify patients for penicillin allergy evaluation in STI clinics by PST or GOC, with GOC showing operational feasibility. Using this approach, 67% of participants with reported penicillin allergy could safely receive first-line treatments for gonorrhea or syphilis. Clinical Trials Registration. Clinicaltrials.gov (NCT04620746).

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.

Examining cefazolin utilization and perioperative anaphylaxis in patients with and without a penicillin allergy label: A cross-sectional study.

STUDY OBJECTIVE: To compare the occurrence of cefazolin perioperative anaphylaxis (POA) in patients with and without a penicillin allergy label (PAL) to determine whether the prevalence of cefazolin POA differs based on the presence of a PAL. DESIGN: Cross-sectional study. SETTING: A large U.S. healthcare system in the Baltimore-D.C. region, July 2017 to July 2020. PATIENTS: 112,817 surgical encounters across inpatient and outpatient settings in various specialties, involving 90,089 patients. Of these, 4876 (4.3%) encounters had a PAL. INTERVENTIONS: Perioperative cefazolin administration within 4 h before surgery to 4 h after the procedure began. MEASUREMENTS: The primary outcome was cefazolin POA in patients with and without PALs. Potential POA cases were identified based on tryptase orders or diphenhydramine administrations within the initial cefazolin administration to 6 h postoperatively. Verification included two validation steps. The first checked for hypersensitivity reaction (HSR) documentation, and the second, led by Allergy specialists, identified POA and the probable culprit. The secondary outcome looked at cefazolin use trends in patients with a PAL, stratified by setting and specialty. MAIN RESULTS: Of 112,817 encounters, 1421 (1.3%) had possible cefazolin HSRs. Of these, 22 (1.5%) had POA, resulting in a 0.02% prevalence. Of these, 13 (59.1%) were linked to cefazolin and 9 (40.9%) attributed to other drugs. Only one cefazolin POA case had a PAL, indicating no significant difference in cefazolin POA prevalence between patients with and without PALs (p = 0.437). Perioperative cefazolin use in patients with PALs steadily increased from 2.6% to 6.0% between 2017 and 2020, specifically in academic settings. CONCLUSIONS: The prevalence of cefazolin POA does not exhibit significant differences between patients with and without PALs, and notably, the incidence remains remarkably low. Based on these findings, it is advisable to view cefazolin as an acceptable choice for prophylaxis in patients carrying a PAL.

Pharmacogenetics to prevent hypersensitivity reactions to antiepileptic drugs: is testing performed when indicated?

Extensive scientific evidence consistently demonstrates the clinical validity and utility of HLA-B*15:02 pre-screening in averting severe cutaneous adverse reactions (SCARs), namely Stevens-Johnson syndrome and toxic epidermal necrolysis, associated with carbamazepine or oxcarbazepine usage. Current practice guidelines and drug labeling actively advocate for pharmacogenetic pre-screening before initiating these antiepileptic drugs (AED), with particular emphasis on patients of Asian descent. However, there is a potential need to strengthen compliance with these recommendations. This retrospective study aimed to describe the pharmacogenetic pre-screening, documentation, and SCARs incidence for patients of Asian ancestry initiated on carbamazepine or oxcarbazepine at a large Northeastern USA healthcare system. Between 1 July 2016 and August 1, 2021, 27 patients with documented Asian heritage in the electronic health record (EHR) were included. The overall rate of HLA-B*15:02 pre-screening before carbamazepine or oxcarbazepine initiation was 4%. None who underwent pharmacogenetic pre-screening carried the associated HLA-B risk allele, and no SCARs were reported. Notably, pharmacogenetic results were not discretely entered into the EHR, and the results were only found as attached documents in the miscellaneous section of the EHR. There remains a significant opportunity for improving HLA-B*15:02 pre-screening for patients starting carbamazepine and oxcarbazepine to prevent SCARs in the USA.

Use of the Electronic Health Record for Monitoring Adverse Drug Reactions.

PURPOSE OF REVIEW: Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. The electronic health record (EHR) provides an opportunity to monitor ADRs, mainly through the utilization of drug allergy data and pharmacogenomics. This review article explores the current use of the EHR for ADR monitoring and highlights areas that require improvement. RECENT FINDINGS: Recent research has identified several issues with using EHR for ADR monitoring. These include the lack of standardization between EHR systems, specificity in data entry options, incomplete and inaccurate documentation, and alert fatigue. These issues can limit the effectiveness of ADR monitoring and compromise patient safety. The EHR has great potential for monitoring ADR but needs significant updates to improve patient safety and optimize care. Future research should concentrate on developing standardized documentation and clinical decision support systems within EHRs. Healthcare professionals should also be educated on the significance of accurate and complete ADR monitoring.

Prevention of Recurrent Attacks of Hereditary Angioedema (HAE): Berotralstat and Its Oral Bioavailability.

Hereditary angioedema (HAE) is a condition characterized by episodes of cutaneous and submucosal edema. Angioedema of the extremities and abdominal attacks are the most common manifestations of the disease. It can also affect the upper airways with the potential of becoming life-threatening. The two most common causes of HAE are a deficiency of C1 inhibitor (classified as type 1 HAE) or a dysfunction of C1 inhibitor (type 2 HAE). A malfunction or deficiency of C1 inhibitor leads to an overactivated plasma kallikrein (an inflammatory vasoactive peptide), that increases bradykinin, mediating the angioedema episodes in patients with HAE. To minimize the difficulties of this pathology and to improve patients' quality of life, prevention of this condition is essential. Berotralstat is a unique option for oral administration for routine prophylaxis. This drug acts by binding to kallikrein and reducing its plasma activity, lowering bradykinin levels. Open-label studies have demonstrated the effectiveness of a single daily dose of berotralstat 150 mg in preventing HAE attacks. This review aims to examine studies performed to elucidate the efficacy, safety, and tolerability of berotralstat.

Risk Factors for Vancomycin Drug Reaction With Eosinophilia and Systemic Symptoms Syndrome.

This case-control study uses single-institution data to explore risk factors associated with vancomycin drug reaction with eosinophilia and systemic systems (DRESS) syndrome.

Vancomycin Hypersensitivity Reactions Documented in Electronic Health Records.

BACKGROUND: Vancomycin, the most common antimicrobial used in US hospitals, can cause diverse adverse reactions, including hypersensitivity reactions (HSRs). Yet, little is known about vancomycin reactions documented in electronic health records. OBJECTIVE: To describe vancomycin HSR epidemiology from electronic health record allergy data. METHODS: This was a cross-sectional study of patients with 1 or more encounter from 2017 to 2019 and an electronic health record vancomycin drug allergy label (DAL) in 2 US health care systems. We determined prevalence and trends of vancomycin DALs and assessed active DALs by HSR phenotype determined from structured (coded) and unstructured (free-text) data using natural language processing. We investigated demographic associations with documentation of vancomycin red man syndrome (RMS). RESULTS: Among 4,490,618 patients, 14,426 (0.3%) had a vancomycin DAL with 18,761 documented reactions (2,248 [12.0%] free-text). Quarterly mean vancomycin DALs added were 253 ± 12 and deleted were 12 ± 2. Of 18,761 vancomycin HSRs, 7,903 (42.1%) were immediate phenotypes and 3,881 (20.7%) were delayed phenotypes. Common HSRs were rash (32% of HSRs) and RMS (16% of HSRs). Anaphylaxis was coded in 6% cases of HSRs. Drug reaction eosinophilia and systemic symptoms syndrome was the most common coded vancomycin severe cutaneous adverse reaction. RMS documentation was more likely for males (odds ratio, 1.30; 95% CI, 1.17-1.44) and less likely for blacks (odds ratio, 0.59; 95% CI, 0.47-0.75). CONCLUSIONS: Vancomycin causes diverse adverse reactions, including common (eg, RMS) and severe (eg, drug reaction eosinophilia and systemic symptoms syndrome) reactions entered as DAL free-text. Anaphylaxis comprised 6% of documented vancomycin HSRs, although true vancomycin IgE-mediated reactions are exceedingly rare. Improving vancomycin DAL documentation requires more coded entry options, including a coded entry for RMS.

Juntos: A Model for Language Congruent Care to Better Serve Spanish-Speaking Patients with COVID-19.

Coronavirus disease 2019 (COVID-19) exacerbated pre-existing health disparities and disproportionately affected the Latino community. Clinicians identified communication barriers as a major challenge in care for COVID-19 Latino patients with limited English proficiency (LEP). To address these challenges, Juntos (Together) consult service was established to promote language-congruent care with cultural sensitivity, identify barriers to safe discharge, and facilitate referral to appropriate resources. Spanish speaking volunteer health care providers worked synergistically with medical teams caring for LEP Latino patients. Volunteers were trained on consultant responsibilities and discharge planning resources. The program was evaluated by a satisfaction survey distributed to providers who requested a Juntos consult and Juntos volunteers. Between May 5 and July 30, 2020, 19 individuals volunteered time to the Juntos consult service, 12 (63%) Latinos, 14 (74%) physicians, and 5 (26%) staff. The service supported 127 patients, 76 (60%) males, mean age 42 (±16), 83 (65%) uninsured, and 91 (72%) without primary care. The most common referral sources were medical units (52, 41%) and intensive care units (47, 37%). The most common services offered were family engagement (55, 43%), goals of care (35, 28%), and mental status assessment (26, 20%). The majority of providers who consulted Juntos were very satisfied (48/59, 81%) with the care delivered. The Juntos service offered critical support tailored to the patients' and primary teams' needs. The experience reinforced the need for cultural-based communication to provide optimal care to LEP patients. The Juntos consult service could be a model for providing language-congruent care even beyond COVID-19, but to do so will require institutional investment and rigorous outcomes evaluation.