Update on iron supplementation in patients with cancer-related anemia.

INTRODUCTION: Numerous clinical trials affirm the efficacy and safety of IV iron to treat cancer-related anemia (CRA). Nonetheless, evaluation and treatment of CRA remains suboptimal. AREAS COVERED: This review summarizes CRA therapy with a focus on iron deficiency and its treatment. The literature search was conducted using the National Library of Medicine (PubMed) database from 2004 to 2024. Topics reviewed include CRA pathophysiology, laboratory diagnosis of iron deficiency, a summary of clinical trial results using IV iron to treat CRA, and safety aspects. EXPERT OPINION: Despite overwhelming positive efficacy and safety data, IV iron remains underutilized to treat CRA. This is likely due to persistent (unfounded) concerns about IV iron safety and lack of physician awareness of newer clinical trial data. This leads to poor patient quality of life and patient exposure to anemia treatments that have greater safety risks than IV iron. Solutions to this problem include increased educational efforts and considering alternative treatment models in which other providers separately manage CRA. The recent availability of new oral iron therapy products that are effective in treating anemia of inflammation has the potential to dramatically simplify the treatment of CRA.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

Three new discovery effector proteins from Candidatus Liberibacter asiaticus psy62 inhibit plant defense through interaction with AtCAT3 and AtGAPA.

KEY MESSAGE: We identify three SDEs that inhibiting host defence from Candidatus Liberibacter asiaticus psy62, which is an important supplement to the pathogenesis of HLB. Candidatus Liberibacter asiaticus (CLas) is the main pathogen of citrus Huanglongbing (HLB). 38 new possible sec-dependent effectors (SDEs) of CLas psy62 were predicted by updated predictor SignalP 5.0, which 12 new SDEs were found using alkaline phosphate assay. Among them, SDE4310, SDE4435 and SDE4955 inhibited hypersensitivity reactions (HR) in Arabidopsis thaliana (Arabidopsis, At) and Nicotiana benthamiana leaves induced by pathogens, which lead to a decrease in cell death and reactive oxygen species (ROS) accumulation. And the expression levels of SDE4310, SDE4435, and SDE4955 genes elevated significantly in mild symptom citrus leaves. When SDE4310, SDE4435 and SDE4955 were overexpressed in Arabidopsis, HR pathway key genes pathogenesis-related 2 (PR2), PR5, nonexpressor of pathogenesis-related 1 (NPR1) and isochorismate synthase 1 (ICS1) expression significantly decreased and the growth of pathogen was greatly increased relative to control with Pst DC3000/AvrRps4 treatment. Our findings also indicated that SDE4310, SDE4435 and SDE4955 interacted with AtCAT3 (catalase 3) and AtGAPA (glyceraldehyde-3-phosphate dehydrogenase A). In conclusion, our results suggest that SDE4310, SDE4435 and SDE4955 are CLas psy62 effector proteins that may have redundant functions. They inhibit ROS burst and cell death by interacting with AtCAT3 and AtGAPA to negatively regulate host defense.

Involvement of autologous myeloid dendritic cells in the evaluation of immediate hypersensitivity reactions to betalactams.

BACKGROUND: Amoxicillin (AX) and clavulanic acid (CLV) are the betalactam antibiotics (BLs) most used to treat bacterial infections, although they can trigger immediate hypersensitivity reactions (IDHRs). The maturation analysis of monocyte-derived dendritic cells (moDCs) and their capacity to induce proliferative response of lymphocytes are useful to test the sensitisation to a drug, although without optimal sensitivity. Nevertheless, this can be improved using directly isolated DCs such as myeloid DCs (mDCs). METHODS: mDCs and moDCs were obtained from 28 allergic patients (AP), 14 to AX, 14 to CLV and from 10 healthy controls (HC). The expression of CCR7, CD40, CD80, CD83, and CD86 was analysed after stimulation with both BLs. We measured the capacity of these pre-primed DCs to induce drug-specific activation of different lymphocyte subpopulations, CD3+, CD4+, CD8+, CD4+Th1, and CD4+Th2, by flow cytometry. RESULTS: Higher expression of CCR7, CD40, CD80, CD83, and CD86 was observed on mDCs compared to moDCs from AP after stimulating with the culprit BL. Similarly, mDCs induced higher proliferative response, mainly of CD4+Th2 cells, compared to moDCs, reaching up to 67% of positive results with AX, whereas of only 25% with CLV. CONCLUSIONS: mDCs from selective AP efficiently recognise the culprit drug which trigger the IDHR. mDCs also trigger proliferation of lymphocytes, mainly those with a Th2 cytokine pattern, although these responses depend on the nature of the drug, mimicking the patient's reaction.

High-dose oxaliplatin induces severe hypersensitivity reactions and high recurrence rates during rechallenge in patients treated with hepatic arterial infusion chemotherapy.

AIM: To analyze the risk factors for oxaliplatin (OXA)-induced severe hypersensitivity reactions and identify the recurrence rate of the reactions after an OXA rechallenge in patients treated with hepatic arterial infusion chemotherapy (HAIC). METHODS: Among the 2251 patients treated with HAIC (OXA), 84 patients with gastrointestinal cancer who displayed hypersensitivity reactions between May 2013 and May 2022 were included in this study. Among the 84 patients, 23 (27.4%) developed severe anaphylactic reactions (grade III/IV), and 61 (72.6%) developed grade I/II reactions. We explored the risk factors for severe OXA-induced hypersensitivity reactions. Twenty-seven patients with grade I/II reactions underwent retreatment (HAIC with OXA), and the recurrence rate of the hypersensitivity reactions was determined. A multivariate logistic regression model was used to analyze the risk factors for OXA-induced hypersensitivity reaction. RESULTS: In the study, multivariate analysis indicated that the dose of OXA (odds ratio [OR] 3.077, 95 % confidence interval [CI] 1.106-8.558, p = 0.031) was an independent risk factor for OXA-induced severe hypersensitivity reactions. Twenty-seven patients with non-severe hypersensitivity reactions underwent retreatment HAIC with OXA and 14 (51.9 %) experienced HSR recurrence, including 2 (7.4 %) who experienced hypersensitivity shock. CONCLUSIONS: The administration of OXA doses is a risk factor for OXA-induced severe hypersensitivity reactions in patients treated with HAIC (OXA). Rechallenging HAIC with OXA appears to be associated with a higher recurrence rate of the HSR.

"Antibiotic hypersensitivity reactions in Cystic Fibrosis: A thorough inspection on a stumbling block in patient care".

One hurdle in the management of CF, a disease characterized by progressive endobronchial infection, is the presence of hypersensitivity reactions to antimicrobials due to prolonged and repetitive treatment courses. The aim of this review is to compile existing data and provide insight to medical professionals on a long-debated topic for optimum patient care. Clinical studies were inducted from the last 15 years and filtered based on their relativity to drug hypersensitivity reactions (DHRs), antibiotics and CF. After completing the selection process, 10 clinical studies were thoroughly examined. The most frequent antibiotic group related to DHRs were beta-lactams. Frequency of the most common overall type of reaction (immediate or nonimmediate) differed among clinical studies. Although severe reactions seem rare comparatively, they do occur during and even after completion of treatment regimens. The prevalence of true drug allergies should be confirmed using a variety of tests available, however, should not be confused with overall DHR rates. Genetic mutations, gender and lifetime antibiotic dose were not related with an increased risk for DHR development. On the contrary, the most important factor according to most studies was the cumulative antimicrobial dose in a given period of time, especially when delivered parenterally. DHRs are an indisputable problem in the management of CF patients. Understanding possible risk factors and increased awareness is vital in both hospital and outpatient settings as early detection can decrease the severity of the reactions.

Perioperative Management Conundrum for a Case With Multiple Commonly Used Drug Hypersensitivity.

Perioperative hypersensitivity reactions vary from mild to potentially fatal anaphylaxis, resulting in significant morbidity and mortality. Most of the perioperative hypersensitivity and allergic reactions are attributed to antibiotics, antiseptic solutions, latex, and opioids. In the current thrust for opioid-free anesthesia, owing to its multiple advantages, paracetamol and nonsteroidal antiinflammatory agents play a significant role in multi-modal pain and inflammatory response management. Nearly nine out of ten individuals experience postoperative pain, one-third experience postoperative nausea and vomiting, and one-fourth experience fever, irrespective of surgery and type of anesthesia, often as an inflammatory response. While perioperative hypersensitivity reactions are common, a patient allergic to multiple commonly used drugs for the treatment of pain, fever, acid-peptic disorder, and nausea and vomiting is scarce. Such cases pose a great challenge in perioperative management. A 14-year-old male child with a traumatic foot drop planned for tibialis posterior tendon transfer developed an allergic reaction with mild fever following an injection of Ranitidine and Ondansetron in the preoperative area. Surgery was deferred and was investigated for allergy profile testing for commonly used drugs, which showed high IgE levels and moderate to severe hypersensitivity for diclofenac and paracetamol. The patient was operated on after one month under spinal anesthesia, avoiding ranitidine, ondansetron, diclofenac, and paracetamol. The following morning, he developed a high-grade fever (102.3° F), which did not resolve with conservative measures. Hypersensitivity and allergic reactions to NSAIDs are reported in the literature. While there are multiple drugs available as NSAIDs, cross-sensitivity or allergy to other drugs within the same group, and even chemically related groups, is also another possibility that needs to be considered while managing such patients. Mefenamic acid controlled the fever, and the child was discharged home after 48 hours of observation. However, the case posed a great perioperative management dilemma; the present report intends to highlight and discuss it.

Impact of institutional interventions on the rate of paclitaxel hypersensitivity reactions.

PURPOSE: Paclitaxel is associated with hypersensitivity reactions (HSRs). Intravenous premedication regimens have been devised to decrease the incidence and severity of HSRs. At our institution oral histamine 1 receptor antagonists (H1RA) and histamine 2 receptor antagonists (H2RA) were adopted as standard. Standardizations were implemented for consistent premedication use in all disease states. The purpose of this retrospective study was to compare the incidence and severity of HSRs before and after standardization. METHODS: Patients who received paclitaxel from 20 April 2018 to 8 December 2020 having an HSR were included in analysis. An infusion was flagged for review if a rescue medication was administered after the start of the paclitaxel infusion. The incidences of all HSR prior to and post-standardization were compared. A subgroup analysis of patients receiving paclitaxel for the first and second time was performed. RESULTS: There were 3499infusions in the pre-standardization group and 1159infusions in the post-standardization group. After review, 100 HSRs pre-standardization and 38 HSRs post-standardization were confirmed reactions. The rate of overall HSRs was 2.9% in the pre-standardization group and 3.3% in the post-standardization group (p = 0.48). HSRs, during the first and second doses of paclitaxel, occurred in 10.2% of the pre-standardization and 8.5% of the post-standardization group (p = 0.55). CONCLUSIONS: This retrospective interventional study demonstrated that same-day intravenous dexamethasone, oral H1RA, and oral H2RA are safe premedication regimens for paclitaxel. No change in the severity of reactions was seen. Overall, better adherence to premedication administration was seen post-standardization.

Rapid drug desensitization to taxanes: a descriptive study from Turkey.

AIM: To present the characteristics of drug hypersensitivity reactions (DHRs) among taxane recipients with non-small cell lung carcinoma (NSCLC), and to describe the results of rapid drug desensitization (RDD). METHODS: A retrospective cross-sectional study included 45 patients who were treated with taxane for NSCLC and were found to be hypersensitive to taxane. All patients were administered the standard 3-bag, 12-step RDD protocol following the development of DHR. RDD success was evaluated separately for each cycle, and successful RDD was defined as the completion of the cycle with application of 12 steps of the desensitization protocol and the absence of early and/or late reactions afterwards. RESULTS: Among 45 patients hypersensitive to taxane 43 (95.6%) successfully received taxane cycles with desensitization. Failed RDD occurred in only 2 (4.4%) patients. The total number of desensitization cycles was 183, of which 181 (98.9%) were successful. The mean age of patients with successful desensitization was 59.42 ± 10.48 years and 37 (86.0%) of them were male. CONCLUSION: RDD is a reliable procedure that enables effective administration and completion of first-line taxane treatments in taxane-sensitive patients.

Interleukin-6 as a biomarker of hypersensitivity reactions in chemotherapeutics and monoclonal antibodies.

BACKGROUND: In recent years, a new type of immediate hypersensitivity reaction known as cytokine release began to emerge, and within this phenotype of reactions, interleukin-6 is the most frequently associated with the presence during drug administration. Chemotherapeutic agents (QT) and monoclonal antibodies. OBJECTIVE: Determine interleukin-6 levels in hypersensitivity reactions to QT and monoclonal antibodies. METHODS: Observational and prospective study that was carried out from March 1, 2021 to March 1, 2022 in a university hospital in northeastern Mexico. Symptoms, severity, interleukin-6 levels, and skin tests of hypersensitivity reaction were evaluated at QT and monoclonal antibodies. RESULTS: A total of 41 patients with oncological disease were included, the most frequent being ovarian cancer. Symptoms as initial hypersensitivity reaction were neuromuscular in taxanes and cutaneous in Platinums.41.5% presented elevation of interleukin-6, and it was found more frequently in presence of metastases. Positive skin tests were found more frequently in the carboplatin and doxorubicin groups. The most frequently presented phenotype was type I in paclitaxel, carboplatin, and doxorubicin, and mixed-reaction (type I and cytokine release) in oxaliplatin. CONCLUSION: With the increasing prevalence of hypersensitivity reactions to biologic and antineoplastic therapies, interleukin-6 should be recognized as a biomarker in immediate hypersensitivity reactions to QT and monoclonal antibodies.

Hypersensitivity Reactions Following Onabotulinum Toxin A Touch-up Injection Possibly Associated with Covid-19 Infection.

As one of the most common cosmetic procedures, botulinum toxin A (BTX-A) injections are basically safe. The typical allergic reactions include erythema, edema, pruritus, and wheal, which generally occur at the initial injection. Herein, we reported two cases of hypersensitivity reactions following cosmetic BTX-A touch-up injection. Type I allergic reactions provoked by re-exposure to the excipients such as gelatin may play a role in the event. In addition, this condition may be associated with the preceding Covid-19 infection, even with complete symptoms remission and negative tests results. Noteworthily, one case developed anaphylactic symptoms resembling purpuric drug eruption (PDE). These cases may serve as a significant complement to the botulinum toxin treatment safety profiles. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Hypersensitivity Reactions to Taxanes: A Comprehensive and Systematic Review of the Efficacy and Safety of Desensitization.

Taxanes in the treatment of cancer are associated with a significant incidence of hypersensitivity reactions, which may preclude their use in patients in need of first line therapy. Drug desensitization induces transient immunological tolerance and has allowed the reintroduction of taxanes in highly allergic patients. Increase the knowledge of hypersensitivity reactions (HSR) during the administration of taxanes. A systematic review regarding the safety and efficacy of rapid drug desensitization (RDD) for taxanes HSR. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was registered in PROSPERO(CRD42021242324) and a comprehensive search was conducted in Medline, Embase, Web of Science and Scopus databases. 25 studies encompassing 10 countries were identified and 976 patients with initial HSR to paclitaxel (n = 707) and docetaxel (n = 284), that underwent a total of 2,396 desensitizations. The most common symptoms were cutaneous (74.6%) with paclitaxel and respiratory (72.6%) with docetaxel. Severe initial hypersensitivity reactions including anaphylaxis occurred in 39.6% and 13% of paclitaxel and docetaxel cases respectively and during the first (87.4%) or second exposure (81.5%). Patients tolerated well RDD and breakthrough reactions (BTR) occurred in 32.2% of paclitaxel-treated patients and in 20.6% of docetaxel treated patients. Premedications included corticosteroids, antihistamines and leukotriene receptor antagonists. The most commonly used protocol was the BWH 3 bags 12 steps, all protocols showed a success rate between 95-100%, with no reported deaths. RDD is a safe and effective procedure in patients with HSR to taxanes and protocols should be standardized for wide range implementation.

Hypersensitivity reactions to anticancer chemotherapy and monoclonal antibodies: Safety and efficacy of desensitization.

BACKGROUND: Hypersensitivity reactions to anticancer chemotherapy and monoclonal antibodies may lead to discontinuation of first-line treatment options. Identification of these reactions can provide specific diagnosis and treatment by rapid drug desensitizations. OBJECTIVE: To determine the hypersensitivity reactions involved in anticancer chemotherapy and monoclonal antibodies, and the safety and efficacy of rapid drug desensitization. METHODS: We conducted an observational study of hypersensitivity reaction presented after the administration of anticancer chemotherapy and monoclonal antibodies in Mexico. We documented the symptoms of initial reaction and their severity, and the results of skin tests. We also report our experience of the administration of 12-step (mild-moderate reactions) and 16-step (severe reactions) desensitization protocols in these patients. RESULTS: Overall, 93 patients received 336 rapid drug desensitization; 105 to taxanes, 115 to platinum drugs, 101 to monoclonal antibodies, and 15 other anticancer chemotherapy. Hypersensitivity reaction to taxanes occurred in the first or second administration, platinum drugs after the sixth cycle, and rituximab in the first cycle. The most common symptom in carboplatin was urticaria, paclitaxel back pain, oxaliplatin and docetaxel dyspnea, and in the monoclonal antibodies cardiovascular symptoms. Skin tests were positive in 75% of the carboplatin group, and only 16.7% in docetaxel. There was a rapid drug desensitization success rate of 99.4% and 85.7% did not present any related hypersensitivity reaction. CONCLUSION: The diagnosis of hypersensitivity reaction to anticancer chemotherapy and monoclonal antibodies offers a panorama in the management of oncological diseases. Our standardized desensitization protocol is safe and effective and can be reproduced in other centers to treat patients who need to maintain first-line treatment.

Delayed hypersensitivity reactions to iodinated contrast media: A diagnostic approach by skin tests.

BACKGROUND: Adverse drug reactions to iodinated contrast media (ICM) have risen due to their increasing use in x-ray-based imaging modalities. Delayed hypersensitivity reactions are mainly caused by nonionic monomeric compounds and represent an issue impacting the diagnostic-therapeutic pathways of cancer, cardiology and surgery patients. OBJECTIVES: To prospectively evaluate the usefulness of skin tests in delayed hypersensitivity reactions to ICM and to evaluate the tolerability of iobitridol, a monomeric nonionic low osmolality compound, as a possible safe alternative. METHODS: Patients with delayed hypersensitivity reactions to ICM referred to us from 2020 to 2022 were prospectively enrolled in the study. All patients underwent patch test and, if negative, intradermal test with the culprit ICM and iobitridol as alternative. RESULTS: A total of 37 patients (females 24, 64.9%) were enrolled in the study. Iodixanol and iomeprol were the most frequently involved ICM (48.5% and 35.2%, respectively); 62.2% of patients presented maculopapular eruption, while 37.8% reported delayed urticaria-like rash. Skin tests resulted positive to the culprit ICM in 19 patients (51.4%), 16 to patch test and 3 to intradermal test. Skin tests with iobitridol, tested as alternative, resulted positive in 3/19 patients (15.8%). All 16 patients with negative results to iobitridol were administered this ICM and tolerated it. CONCLUSIONS: In at least half of patients, delayed-type hypersensitivity was demonstrated by skin tests, particularly by patch test. This diagnostic approach resulted simple, cost-effective and safe, not only to confirm the culprit ICM but also to identify iobitridol as feasible alternative.

Is ranitidine necessary as premedication for regimens containing paclitaxel? A non-inferiority study.

BACKGROUND: Histamine type-2-receptor antagonist drugs (H2-antagonists) have been used as standard treatment to prevent hypersensitivity reactions (HRs) in paclitaxel-containing regimens, however, their use has been strongly questioned. Ranitidine has been the most widely used H2-antagonist. Therefore, especially after its withdrawal from the market, the objective of this study is to determine the impact of its elimination from premedication on HR incidence. METHODS: A cohort, multicenter, observational, prospective, and non-inferiority study, including paclitaxel-naïve cancer patients, designed to determine the incidence of HRs of any grade associated with paclitaxel administration and analyze non-inferiority against the incidence estimated in the literature (20%), with 5% as the maximum difference (Δ). Patients with a solid neoplasm of any type/stage, who initiated treatment with paclitaxel without H2-antagonists in the premedication regimen were enrolled. RESULTS: A total of 441 patients were included, of whom 50 presented 54 HRs of any grade. The cumulative incidence was 11.3% (95%CI 8.5-14.7), thus fulfilling the hypothesis of non-inferiority. Of the overall HRs detected, 15 were grade ≥ 3 with a cumulative incidence of 3.4% (95%CI 1.9-5.5). CONCLUSIONS: This study demonstrates that the elimination of ranitidine from paclitaxel premedication schedules is non-inferior in the development of HRs of any grade compared to the administration of H2-antagonists.

Role of anti-polyethylene glycol (PEG) antibodies in the allergic reactions to PEG-containing Covid-19 vaccines: Evidence for immunogenicity of PEG.

A small fraction of recipients who receive polyethylene-glycol (PEG)-containing COVID-19 mRNA-LNP vaccines (Comirnaty and Spikevax) develop hypersensitivity reactions (HSRs) or anaphylaxis. A causal role of anti-PEG antibodies (Abs) has been proposed, but not yet been proven in humans.We used ELISA for serial measurements of SARS-CoV-2 neutralizing Ab (anti-S) and anti-PEG IgG/IgM Ab levels before and after the first and subsequent booster vaccinations with mRNA-LNP vaccines in a total of 291 blood donors. The HSRs in 15 subjects were graded and correlated with anti-PEG IgG/IgM, just as the anti-S and anti-PEG Ab levels with each other. The impacts of gender, allergy, mastocytosis and use of cosmetics were also analyzed. Serial testing of two or more plasma samples showed substantial individual variation of anti-S Ab levels after repeated vaccinations, just as the levels of anti-PEG IgG and IgM, which were over baseline in 98-99 % of unvaccinated individuals. About 3-4 % of subjects in the strongly left-skewed distribution had 15-45-fold higher values than the median, referred to as anti-PEG Ab supercarriers. Both vaccines caused significant rises of anti-PEG IgG/IgM with >10-fold rises in about âˆ¼10 % of Comirnaty, and all Spikevax recipients. The anti-PEG IgG and/or IgM levels in the 15 vaccine reactors (3 anaphylaxis) were significantly higher compared to nonreactors. Serial testing of plasma showed significant correlation between the booster injection-induced rises of anti-S and anti-PEG IgGs, suggesting coupled anti-S and anti-PEG immunogenicity.Conclusions: The small percentage of people who have extremelevels of anti-PEG Ab in their blood may be at increased risk for HSRs/anaphylaxis to PEGylated vaccines and other PEGylated injectables. This risk might be further increased by the anti-PEG immunogenicity of these vaccines. Screening for anti-PEG Ab "supercarriers" may help predicting reactors and thus preventing these adverse phenomena.

Anaphylatoxin Complement 5a in Pfizer BNT162b2-Induced Immediate-Type Vaccine Hypersensitivity Reactions.

The underlying immunological mechanisms of immediate-type hypersensitivity reactions (HSR) to COVID-19 vaccines are poorly understood. We investigate the mechanisms of immediate-type hypersensitivity reactions to the Pfizer BNT162b2 vaccine and the response of antibodies to the polyethylene glycol (PEG)ylated lipid nanoparticle after two doses of vaccination. Sixty-seven participants, median age 35 and 77.3% females who tolerated two doses of the BNT162b2 vaccine (non-reactors), were subjected to various blood-sampling time points. A separate group of vaccine reactors (10 anaphylaxis and 37 anonymised tryptase samples) were recruited for blood sampling. Immunoglobulin (Ig)G, IgM and IgE antibodies to the BNT162b2 vaccine, biomarkers associated with allergic reaction, including tryptase for anaphylaxis, complement 5a(C5a), intercellular adhesion molecule 1 (ICAM-1) for endothelial activation and Interleukin (IL)-4, IL-10, IL-33, tumour necrosis factor (TNF) and monocyte chemoattractant protein (MCP-1), were measured. Basophil activation test (BAT) was performed in BNT162b2-induced anaphylaxis patients by flow cytometry. The majority of patients with immediate-type BNT162b2 vaccine HSR demonstrated raised C5a and Th2-related cytokines but normal tryptase levels during the acute reaction, together with significantly higher levels of IgM antibodies to the BNT162b2 vaccine (IgM 67.2 (median) vs. 23.9 AU/mL, p < 0.001) and ICAM-1 when compared to non-reactor controls. No detectable IgE antibodies to the BNT162b2 vaccine were found in these patients. The basophil activation tests by flow cytometry to the Pfizer vaccine, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG) and PEG-2000 were negative in four anaphylaxis patients. Acute hypersensitivity reactions post BNT162b2 vaccination suggest pseudo-allergic reactions via the activation of anaphylatoxins C5a and are independent of IgE-mechanisms. Vaccine reactors have significantly higher levels of anti-BNT162b2 IgM although its precise role remains unclear.

Relevance of the diagnosis of hypersensitivity reactions to antineoplastic and biological agents: experience with drug provocation test.

Summary: Background. Evidence regarding drug provocation test (DPT) with chemotherapeutic agents is scarce. The aim of our study is to describe the experience of DPT in patients with a history of hypersensitivity reactions (HSRs) to antineoplastic and biological agents. Methods. This was an eight-year retrospective, observational, descriptive study of patients with a history of HSRs to chemotherapy who were submitted to DPT. Anamnesis, skin tests (ST) and DPT were analyzed. Patients with a negative DPT were submitted to at least one regular supervised administration (RSA). Patients with positive DPT or HSR during RSA were offered rapid drug desensitization (RDD). Results. A total of 54 patients were submitted to DPT. The most common suspected drugs were platins (n = 36), followed by taxanes (n = 11). Most initial reactions were classified as grade II (n = 39) according to Brown's grading system. ST with platinum (n = 35), taxanes (n = 10) and biological agents (n = 4) were negative, except for one intradermal test with paclitaxel, which was positive. A total of 64 DPTs were performed. Eleven percent of all DPTs were positive (platins (n = 6), doxorubicin (n = 1)). Of the 57 RSA with the culprit drugs, 2 were positive (platins). The diagnosis of hypersensitivity was confirmed by DPT/RSA in 9 patients. All patients with positive DPT/RSA presented HSRs of equal or less severity than the initial one. Conclusions. DPT followed by RSA allowed to exclude HSRs in 45 patients (55 culprit drugs). DPT before desensitization prevents non-hypersensitivity patients from undergoing RDD. In our study DPT was safe, all reactions were managed by an allergist.

Differentiating between Laryngopharyngeal Dysesthesia and Hypersensitivity Reactions to Oxaliplatin and Addressing Dyspnea: 2 Case Reports.

Oxaliplatin is a key drug for colorectal cancer and causes peripheral neuropathy. Oxaliplatin-induced laryngopharyngeal dysesthesia is an acute peripheral neuropathy similar to a hypersensitivity reaction. Hypersensitivity reactions to oxaliplatin do not require immediate discontinuation, but re-challenge and desensitization therapy can be very burdensome for patients. We encountered 2 cases in which laryngopharyngeal dysesthesia could be differentiated from hypersensitivity reactions to oxaliplatin, and treatment could continue. The first case was that of a 58-year-old woman who developed dyspnea during the first course of combination therapy with capecitabine and oxaliplatin as the primary treatment for advanced rectal cancer. After laryngopharyngeal dysesthesia was differentiated from hypersensitivity reaction based on these typical symptoms, she was considered to have grade 3 (Common Terminology Criteria for Adverse Events [CTCAE] ver. 5) laryngopharyngeal dysesthesia. The second course of oxaliplatin was extended from 2 to 4 h, but symptoms recurred. The third course was performed with a reduced dose of oxaliplatin from 130 mg/m2 to 100 mg/m2, and the patient could complete the treatment without symptom recurrence. The second case involved a 76-year-old woman who developed grade 3 laryngopharyngeal dysesthesia during the first course of combination therapy with capecitabine and oxaliplatin as the primary treatment for localized colon cancer. Based on the experience of the first case, we reduced the oxaliplatin dose from 130 mg/m2 to 100 mg/m2 for the second course, and the patient completed the treatment without symptoms. This dose reduction was effective for grade 3 laryngopharyngeal dysesthesia caused by oxaliplatin without reducing therapeutic efficacy.