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.

Risk predictive tools of perioperative drug hypersensitivity reaction: A case-control study

Objective We aimed to determine the risk factors of perioperative drug hypersensitivity reaction (DHR) and develop a predictive score for use in clinical practice. Methods A case-control study was conducted in patients who underwent anesthesia at a tertiary hospital in Thailand, between 2015–2018. DHR cases were graded clinically from 1 to 4 according to the World Federation of Societies of Anesthesiologists by two anesthesiologists. Controls were randomly matched with cases (ratio 2:1) by age group and month and type of surgery. Patient and anesthesia-related factors and agents given intraoperatively were recorded. A risk score was derived from the coefficients of the significant predictors of the final multivariate logistic regression model. Risk scores, adjusted odds ratios (OR) for perioperative DHR and 95% confidence intervals (CI) were determined. Results Overall, 325 cases and 650 controls were recruited. The severity of DHR was grade 1 (72.9%), grade 2 (24%), and grade 3 (3.1%). Our risk predictive tools for perioperative DHR provided a sensitivity of 62% and specificity of 65%. Predictive scores of subgroups of moderate to severe DHR showed high specificity (80%) but low sensitivity (47%). Common predictors of overall DHR and moderate to severe DHR were history of drug allergy to 2 or more drug categories (score 2.5–3.5), being allergic to analgesics (score 2.5–4.0), and intraoperative morphine use (score of 1). The sole predictor of high-risk perioperative DHR (score ≥3.5) was airway management with an endotracheal tube intubation (OR 5.6, 95% CI 2.2–14.4) whereas history of allergic rhinitis (OR 11.7, 95% CI 1.3–105.1) was a predictor of high-risk moderate to severe DHR (score ≥2.5). Conclusions Our predictive tool for perioperative DHR provided a modest predictive ability. History of drug allergies, rhinitis, morphine use and endotracheal intubation were significant risk factors of DHR after adjusting for age and type of surgery.

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.

DRESS/DIHS syndrome induced by sulfasalazine

Among the manifestations of drug hypersensitivity, DRESS/DIHS syndrome is of particular importance. The clinical manifestations include rash, enlarged lymph nodes, fever, hepatitis, leukocytosis with eosinophilia, as well as the involvement of other organs and systems. The most common causative agents include anticonvulsants, antidepressants, sulfanilamides, non-steroidal anti-inflammatory drugs, and allopurinol, but the list is constantly expanding. The exact pathogenesis of DRESS/DIHS syndrome is currently unclear. Timely diagnosis and adequate therapy can improve prognosis of this disease. In our clinical case, DRESS syndrome developed after the patient was administered sulfasalazine for erosive proctosigmoiditis. In order to ensure adequate prevention, early diagnosis, and proper management of DRESS syndrome, it is necessary to raise awareness of practitioners of different specialties about the possibility of developing this undesirable reaction to pharmacotherapy.

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.

Refractory cytokine release reaction to Nivolumab: Following desensitization algorithms to optimize the management of drug hypersensitivity

Introduction Nivolumab is a fully human IgG4 monoclonal antibody (moAb) against programmed cell death protein 1, approved for the treatment of over ten types of cancer. The use of this and other moAbs has augmented considerably in recent years and this in turn has caused an increase of hypersensitivity reactions (HSR). Case report We present the case of a patient with metastatic renal cell cancer (RCC) who developed a grade 3 cytokine release reaction (CRR) to nivolumab. The maintenance of the symptoms despite of the administration of symptomatic treatment and slowing down the infusion rate of nivolumab during the 1st and 2nd reaction required an allergy evaluation of our patient. Management and outcome Skin testing to Nivolumab with negative results and baseline tryptase within the normal range were observed during the allergy workout. A desensitization protocol with specific premedication was applied to reintroduce the moAb, with no further issues. Moreover, a follow up of the patient in the oncology setting was done showing disease stabilization. Discussion The CRR should be treated by desensitization, in contrast to infusion reactions. The diagnosis of CRR phenotype is based on the clinical presentation and recently, and elevation of IL-6 levels has been shown to be a useful biomarker along with negative skin testing. We can conclude that after a HSR and an appropriate allergy diagnosis of CRR, nivolumab can be safely reintroduced by desensitization without reducing the target dose or the appropriate dilution concentration.

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.