Use of Rapid Drug Desensitization in Delayed Hypersensitivity Reactions to Chemotherapy and Monoclonal Antibodies

Background:Rapid drug desensitization (RDD) allows first-line therapies in patients with immediate drug hypersensitivity reactions (DHR) to chemotherapeutic drugs (ChD) and monoclonal antibodies (mAb). Desensitization in delayed drug reactions has traditionally used slow protocols extending up to several weeks; RDD protocols have been scarcely reported.Patients and Method:We retrospectively analyzed the patients referred to the Allergy Department, who had experienced a delayed DHR (> 6 h) related to a ChD or mAb and underwent an RDD protocol. The rate of successful administration of the offending drug and the presence of adverse reactions were evaluated.Results:A total of 93 RDDs were performed in 11 patients (including 6 men and 5 women, with a median age of 61 years). The primary DHR were maculopapular exanthema (MPE) (8), generalized delayed urticaria (1), MPE with pustulosis and facial edema (1), and facial edema with desquamative eczema (1). The meantime for the onset of symptoms was 3 days (range 1–16 days). RDD was performed using a protocol involving 8–13 steps, with temozolomide (25), bendamustine (4), rituximab (9), infliximab (24), gemcitabine (23), and docetaxel (8), within 4.6–6.5 h. Sixteen breakthrough reactions were reported during the RDD (17.2 %) in 5 patients; all were mild reactions including 11 delayed and 5 immediate reactions. All patients completed their treatment.Conclusions:RDD is a potentially safe and effective procedure in patients suffering from delayed reactions to ChD and mAb. It allows them to receive full treatment in a short period, thereby reducing time and hospital visits.

Converter Phenotype: A New Profile That Is Not Exclusive to Taxanes

Introduction: Phenotype I hypersensitivity reactions are the most commonly reported drug reactions; however, precision medicine has made it possible to characterize new phenotypes. A recent communication proposed the existence of a “converter phenotype,” which would affect patients who present non-immediate hypersensitivity reactions and in subsequent exposures develop immediate hypersensitivity reactions. This study aimed to describe the clinical characteristics of converter phenotype reactions and their evolution during desensitization to chemotherapeutic drugs and monoclonal antibodies.Methods: We retrospectively reviewed our database of patients undergoing desensitization to chemotherapy or biological agents and selected those with a converter phenotype. Demographic and clinical characteristics of the patients, the results of skin tests, tryptase and IL-6 levels, and desensitization outcomes were assessed.Results: Of 116 patients evaluated, 12 (10.3%) were identified as having a converter phenotype. The median interval between drug exposure and reaction was 90.6 h (range 8-288 h). After the conversion, phenotype I was the most frequent (58.3%), followed by cytokine release reactions (33.3%). Fifty-one desensitizations were undertaken and all treatments completed, with 10 (19.6%) breakthrough reactions. No new changes in the phenotype were detected.Conclusions: The symptoms of non-immediate drug hypersensitivity reactions may indicate the need for an early allergological evaluation to assess the risk of future immediate drug reactions. Clinical characteristics, skin test results, and biomarkers can help predict responses to rapid drug desensitization, guiding clinicians on how to optimize therapy delivery while maintaining patient safety.

Genotyping for HLA Risk Alleles to Prevent Drug Hypersensitivity Reactions: Impact Analysis

Human Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA risk alleles incorporated in the Dutch Pharmacogenetics Working Group (DPWG) guidelines in The Netherlands. We estimated the number of hypersensitivity reactions and associated deaths that can be avoided annually by genotyping for these HLA risk alleles. Additionally, the cost-effectiveness was estimated. Nationwide implementation of genotyping HLA risk alleles before initiating drugs with an actionable drug–gene interaction can potentially save the life of seven allopurinol initiators and two flucloxacillin initiators each year in The Netherlands. Besides these deaths, 28 cases of abacavir hypersensitivity, 24 cases of allopurinol induced SCARs, 6 cases of carbamazepine induced DRESS and 22 cases of flucloxacillin induced DILI can be prevented. Genotyping HLA-B*5701 in abacavir initiators has a number needed to genotype of 31 to prevent one case of abacavir hypersensitivity and is cost-saving. Genotyping HLA-B*5801 in allopurinol initiators has a number needed to genotype of 1149 to prevent one case of SCAR but is still cost-effective. Genotyping before initiating antiepileptic drugs or flucloxacillin is not cost-effective. Our results confirm the need for mandatory testing of HLA-B*5701 in abacavir initiators, as indicated in the drug label, and show genotyping of HLA-B*5801 in allopurinol initiators should be considered.

Study of indicators of the immune status in HIV-infected patients with concurrent allergic pathology

Aim. To study the indicators of the immune status and manifestations of allergic diseases in HIV-infected patients in the Novgorod region. Methods. We studied the data of HIV-infected patients living in the Novgorod region for the years 20002021. A total of 1020 cases of HIV infection were studied, in which 121 (12%) patients were diagnosed with allergic reactions. In patients with allergic manifestations, the human immunodeficiency virus type 1 ribonucleic acid content was measured by the polymerase chain reaction method, and the indicators of the immune status (the content of lymphocytes, eosinophils, basophils, the levels of CD3+, CD3+CD4+, CD3+CD8+ cells, immunoregulatory index) were assessed. For statistical analysis, the Student's test (t) was used to assess the statistical significance of differences in immune status indicators, and the Pearson 2 test to assess the statistical significance of differences in allergic manifestations in patients with HIV. Results. The subjects of the study were divided into 2 groups based on the levels of HIV viral load. Analysis of these groups using the Pearson 2 test showed a statistically significant (p 0.012) correlation between high viral load and the development of drug hypersensitivity reaction in HIV-infected patients. The following etiology of allergic reactions was determined among the subjects: drug (59%), food (19%), pollen (5.7%), household (5.7%), chemical (1.9%), unspecified (6.7%). The study of the immune status in two groups did not reveal statistically significant differences (p 0.05). The study of the immune status indicators in HIV-infected patients with drug hypersensitivity reactions and different levels of viral load revealed a significantly higher level of CD3+ cells (p 0.003) in patients with drug hypersensitivity reactions and detectable viral load. Conclusion. The study revealed statistically significant differences in the immune status of HIV-infected patients with drug hypersensitivity reactions living in the Novgorod region compared with HIV-infected patients without drug allergies.

Multiepitope Dendrimeric Antigen-Silica Particle Composites as Nano-Based Platforms for Specific Recognition of IgEs

β-lactam antibiotics (BLs) are the drugs most frequently involved in drug hypersensitivity reactions. However, current in vitro diagnostic tests have limited sensitivity, partly due to a poor understanding of in vivo drug–protein conjugates that both induce the reactions and are immunologically recognized. Dendrimeric Antigen-Silica particle composites (DeAn@SiO2), consisting on nanoparticles decorated with BL-DeAns are promising candidates for improving the in vitro clinical diagnostic practice. In this nano-inspired system biology, the synthetic dendrimer plays the role of the natural carrier protein, emulating its haptenation by drugs and amplifying the multivalence. Herein, we present the design and synthesis of new multivalent mono- and bi-epitope DeAn@SiO2, using amoxicillin and/or benzylpenicillin allergenic determinants as ligands. The homogeneous composition of nanoparticles provides high reproducibility and quality, which is critical for in vitro applications. The suitable functionalization of nanoparticles allows the anchoring of DeAn, minimizing the nonspecific interactions and facilitating the effective exposure to specific IgE; while the larger interaction area increments the likelihood of capturing specific IgE. This achievement is particularly important for improving sensitivity of current immunoassays since IgE levels in BL allergic patients are very low. Our data suggest that these new nano-based platforms provide a suitable tool for testing IgE recognition to more than one BL simultaneously. Immunochemical studies evidence that mono and bi-epitope DeAn@SiO2 composites could potentially allow the diagnosis of patients allergic to any of these drugs with a single test. These organic–inorganic hybrid materials represent the basis for the development of a single screening for BL-allergies.

ANAMNESTIC, CLINICAL AND LABORATORY DATA ANALYSIS OF PATIENTS FOR DRUG HYPERSENSITIVITY REACTIONS

The current development of the pharmaceutical industry in the synthesis of new chemical compounds, standardized treatment protocols, and disease prevention can lead to a progressive increase in drug hypersensitivity reactions, which often have serious consequences for human health. Increasing evidence of involvement of infections, including Herpesviridae viruses, in the development of drug hypersensitivity reactions is known.The method of flow cytometry can be used, in particular, the basophil activation test to diagnose drug hypersensitivity reactions. The anamnestic, clinical, andlaboratory data of 368 people were analyzed for the selection of patients at risk of drug hypersensitivity for the basophil degranulation test execution. It was found that among patients hypersensitivity reactions were most often detected to antibiotics (50.0%), radiopaque substances (27.7%), perioperative drugs, local anesthetics - 13.6% each. Clinical manifestations of these reactions were urticaria with angioneurotic edema (40.6%), urticaria (28.1%), anaphylaxis (21.9%), obstructive bronchitis chenges (9.37%). According to anamnestic and clinical-laboratory data, patients with a high risk of drug hypersensitivity reactions revealed frequent manifestations of herpesvirus infection HSV1 (34.4%), active chronic persistence of EBV (59.4%), accompanied by manifestations of EBV-associated secondary immune disorders and prevalence of chronic EBV infection in all patients.

Non-immediate drug hypersensitivity reactions secondary to intravitreal anti-vascular endothelial growth factors

Purpose To describe a series of non-immediate drug hypersensitivity reactions after intravitreal anti-vascular endothelial growth factors (anti-VEGFs). Patients and methods Retrospective report of 6 patients with cutaneous non-immediate drug hypersensitivity reactions following intravitreal anti-VEGF injections, 4 after ranibizumab, 1 after bevacizumab and 1 after aflibercept. Results Clinical manifestations ranged from mild maculopapular rash, purpura to severe generalized erythroderma, with or without systemic involvement such as microscopic hematuria and proteinuria or fever. In two out of the six patients, reintroduction of either the same or an alternative anti-VEGF drug did induce a recurrence of the drug hypersensitivity reaction, while 4 patients showed no recurrence. Conclusion Cutaneous non-immediate drug hypersensitivity reactions secondary to intravitreal anti-VEGF may occur. Continuation of the same drug or switch to another anti-VEGF may either induce recurrence or be well supported by the patient. The decision of drug discontinuation should be guided by the severity of the disease.

Diagnosing and Managing Patients with Reactions to Radiocontrast Media

Purpose of the review Iodinated radio contrast media (RCM) belong to the most common elicitors of drug hypersensitivity reactions (HR). Urticaria or anaphylaxis may occur ≤ 1(−6) hour(s) (immediate HR) and exanthems (non-immediate HR) develop > 6 h after application of RCM. Evidence for an immunologic mechanism of RCM HR against the different RCM benzene ring molecules and the benefit of allergological testing in patients with previous hypersensitivity reactions is progressively increasing. Recent findings Positive skin tests can confirm allergy in patients with previous reactions to RCM and help to select alternative better tolerated RCMs. Severe hypersensitivity reactions are mainly caused by an allergic mechanism, whereas the majority of non-severe reactions appear to be non-allergic. Skin testing is highly recommended to help identify allergic hypersensitivity reactions and to select alternatives. Using structurally different RCM is more effective than premedication for the prevention of future reactions. Drug provocation tests to RCM have been increasingly used, but are not yet standardized among different centers. Summary In patients with previous severe hypersensitivity reactions to RCM, skin testing is recommended. For future RCM-enhanced examinations in patients with previous reactions, structurally different, skin test-negative preparations should be applied. Drug provocation tests do confirm or exclude RCM hypersensitivity or may demonstrate tolerability of alternative RCMs.

Skin Resident Memory T Cells May Play Critical Role in Delayed-Type Drug Hypersensitivity Reactions

Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (TRM) are a unique T cell population potentially well situated to act as key mediators in disease pathogenesis, but significant obstacles to defining, identifying, and testing TRM in dtDHR preclude definitive conclusions at this time. Deeper mechanistic interrogation to address these unanswered questions is necessary, as involvement of TRM in disease has significant implications for prediction, diagnosis, and treatment of disease.