Vaccines and allergy: Back to the right places.

Hypersensitivity reactions represent one of the most common causes of hesitancy for adherence to national vaccination programs. The majority of hypersensitivity reactions after vaccination are mild, and anaphylaxis is reported to be rare, although it remains challenging to estimate the frequency attributed to each single vaccine, either because of the lower number of administered doses of less common vaccines, or the administration of simultaneous vaccine in most of the vaccination programs. Although literature remains scattered, international consensus guides clinicians in identifying patients who might need the administration of vaccines in protected environments due to demonstrated hypersensitivity to vaccine components or adjuvants. Here we provide the current guidance on hypersensitivity reactions to vaccines and on vaccination of children with allergy disorders.

Hymenoptera venom allergy in children and adolescents.

PURPOSE OF REVIEW: This review will identify and summarize the published existing data pertaining specifically to Hymenoptera venom allergy in children and adolescents, highlighting the major studies currently available on venom immunotherapy (VIT) and its prognosis in children. RECENT FINDINGS: The current review covers the incidence and prevalence of Hymenoptera venom allergy (HVA) in children, factors influencing occurrence and severity of reactions (age, sex, comorbidities, etc.), indications to perform diagnostic tests and start VIT in children, different existing VIT protocols and their safety and efficacy. SUMMARY: Hymenoptera venom allergy is the second most common cause of anaphylaxis in children and it considerably affects quality of life. Cutaneous reactions are the most prevalent clinical presentation in children who usually have a more favourable prognosis than adult patients. However, studies on HVA in children and adolescents are still limited. Currently VIT is the only treatment able to modify the natural history of HVA in adults as well as in children, and to protect patients from systemic reactions after subsequent stings.

A retrospective comparison of IgE-mediated cow's milk protein allergy management strategies in pediatric cohorts.

BACKGROUND: Complete avoidance of milk is the usual management for IgE-mediated cow's milk protein allergy (CMPA). A baked milk ladder is a method of dietary advancement therapy in IgE-mediated CMPA in Ireland, while in Spain, avoidance of milk awaiting natural tolerance acquisition through an oral food challenge (OFC) is employed. The aim of this study was to evaluate the use of dietary advancement therapy using a milk ladder compared with complete avoidance of milk for managing IgE-mediated CMPA. METHODS: This is a retrospective chart review of 371 pediatric patients from the population who have been treated for IgE-mediated CMPA between 2011 and 2020, with the milk ladder (Ireland) or complete avoidance followed by an OFC (Spain). The main outcome was the introduction of cow's milk. RESULTS: Milk ladder patients were 3.67 times more likely to succeed in comparison with milk avoidance (p < .001). Anaphylaxis during the treatment period occurred in 34 patients in the milk avoidance groups, while three patients in the milk ladder group experienced anaphylaxis due to accidental exposure to milk (p < .001). Failure to complete treatment was associated with a higher skin prick test in the milk avoidance group and a raised specific IgE in the milk ladder group. CONCLUSION: This is the first study that compares outcomes of dietary advancement therapy to complete avoidance for CMPA management, demonstrating that cow's milk can be successfully and safely reintroduced using dietary advancement therapy using a milk ladder.

Efficacy and safety of hymenoptera venom immunotherapy.

Background: Being stung by Hymenoptera species can cause life-threatening anaphylaxis. Although venom immunotherapy (VIT) seems to be the most effective treatment, its long-term efficacy, and risk factors for adverse events remain unclear. Objective: The objective was to investigate the long-term efficacy of VIT and evaluate adverse events and risk factors related to this. Method: Patients who received VIT in a tertiary-care adult allergy clinic between January 2005 and July 2022 were included. Patients' data were compared with those of individuals who had been diagnosed with bee and/or wasp venom allergy during the same period but had not received VIT and experienced field re-stings. Results: The study included 105 patients with venom allergy, of whom 68 received VIT and 37 did not receive VIT. Twenty-three patients (34%) completed 5 years of VIT, and the overall mean ± standard deviation VIT duration was 46.9 ± 20.9 months. Re-stings occurred in 5 of 23 patients who completed 5 years of VIT, and none of them developed a systemic reaction. Eighteen patients (40%) experienced re-stings after prematurely discontinuing VIT, of whom eight (44%) developed a systemic reaction. In the control group of patients who did not receive VIT, 26 patients (70.3%) experienced re-stings, and all had systemic reactions (100%), with no change in their median Mueller scores. There was a significant difference in the median Mueller score change between the patients who received VIT and the controls who did not (p = 0.016). A total of 13 patients (19%) experienced adverse events while receiving VIT, which were systemic reactions in nine honeybee VIT. The use of ß-blockers was determined as the most important risk factor (odds ratio 15.9 [95% confidence interval, 1.2-208.8]; p = 0.035). Conclusion: It was confirmed that VIT was effective in both reducing the incidence and the severity of re-sting reactions. These effects were more pronounced in the patients who completed 5 years of VIT.

Evidence-based data support strategies for the prevention of Hymenoptera venom anaphylaxis.

PURPOSE OF REVIEW: This review aims to identify phenotypes at-risk of Hymenoptera venom-induced anaphylaxis (HVA), focusing on different perspectives (epidemiological, clinical, and therapeutic) in order to adapt future preventive strategies. RECENT FINDINGS: HVA remains one of the leading causes of anaphylaxis, with a broad pattern of symptoms. Although most cases occur outside healthcare settings, data indicate a high emergency admission rate due to insect stings. Mortality is often underestimated because of the lack of witnesses and difficulties in recognizing the signs and the culprit. Targeting risk factors could be a clue to improve these statistics and the prognosis of the disease.Potential risk factors for severe HVA in the European population are basal serum tryptase (BST) above 8 µg, mast cell disorders, the absence of skin symptoms, and cardiovascular conditions requiring the use of beta blockers and ACE inhibitors. Identifying these criteria, mainly based on clinical patterns, helps to develop personalized strategies for management and prevention. SUMMARY: With a personalized medicine approach, phenotypes must be characterized to adapt to the management of patients suffering from Hymenoptera venom anaphylaxis (HVA), including venom immunotherapy (VIT). In this systematic review, all articles mentioned systemic reactions with heterogeneous severity degrees. Half of those reported grade III-IV systemic reactions (Ring and Messmer). HVA clinical patterns could be worsened by one Hymenoptera sting, a patient's history with mast cell disorders, or cardiovascular diseases. VIT failure was attributed to bee venom extract and monotherapy in two-thirds of publications. Findings stress the difficulty of having uniform epidemiological data on HVA and the lack of financial support in some world regions to support appropriate management of these conditions. Although observing a heterogeneity of data, we were able to identify potential risk factors, in particular for the severe cases. We believe our work will support allergists and health professionals to implement improved personalized management of patients suffering from severe HVA.

Soluble antigen arrays provide increased efficacy and safety over free peptides for tolerogenic immunotherapy.

Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA used (hydrolysable (hSAgA) and non-hydrolysable 'click' SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Over time, the peptides induced an IgE-independent anaphylactic reaction, the incidence of which was significantly delayed when peptides were in SAgA form rather than in free form. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Immunologic anaphylaxis occurred in NOD mice in a dose-dependent manner but not in C57BL/6 or BALB/c mice; however, its incidence did not correlate with the level of anti-peptide antibodies. We provide evidence that SAgAs significantly improve the efficacy of peptides to induce tolerance and prevent autoimmune diabetes while at the same time reducing their anaphylactogenic potential.

Characterization of the potential allergenicity of enzymatically hydrolyzed casein in Balb/c mouse model.

Bovine casein is a major allergen present in cow milk to induce anaphylaxis. In this study, the potential allergenicity of enzymatically hydrolyzed casein (HC) was evaluated based on in vitro and in vivo. The results showed that Alcalase and Protamex treatment (AT, PT) reduced the potential allergenicity of CN, with the greatest reductions of 68.25% and 50.75%, respectively. In addition, in vivo results showed that HC effectively alleviated allergic response symptoms of Balb/c mice; a significant tendency toward decreased serum IgG1 and mast cell tryptase levels was observed, accompanied by a decrease of Th2-associated IL-4, IL-5, and IL-13 and an increase of IFN-γ levels in spleen. Moreover, the inflammation of the lung, jejunum, and ileum was remarkably ameliorated. The findings indicated that HC induced a shift toward Th1 response and maintained the Th1/Th2 immune balance. Importantly, our results provide the basis for the production of hypoallergenic dairy products.

Primary, secondary and tertiary prevention of food allergy: current practices and future directions / Prevención primaria, secundaria y terciaria de la alergia alimentaria: prácticas actuales y direcciones futuras

The incidence of food allergies has risen around the globe, and experts have been exploring methods of preventing such allergies in young children to ease the burden of disease and reduce the morbidity and mortality caused by anaphylaxis to food allergens. Such preventative measures can be categorised as primary, secondary and tertiary prevention, which are discussed in detail in this review. Primary prevention is defined as the prevention of becoming sensitised towards specific allergens. The evidence suggests that avoiding common allergenic foods during pregnancy and breastfeeding is not protective against food allergies, and guidelines recommend weaning from 4 to 6 months of age, with recent studies supporting the early introduction of peanuts at 4 months to prevent peanut allergy. Secondary prevention targets patients who are already sensitised and aims to halt the progression of sensitisation, with evidence for high rates of success and safety in trials of early introduction to milk and peanuts using oral immunotherapy in sensitised infants. Tertiary allergy prevention focuses on reducing the risk of a patient having anaphylaxis, with oral immunotherapy being the most common method of promoting tolerance in allergic children. Several studies have demonstrated successful reintroduction for milk, egg and peanut; however, no such guidelines are recommended for other foods. Finally, dietary advancement therapy in the form of milk and egg ladders has been employed as a method of primary, secondary and tertiary prevention of allergies, particularly in Ireland, the UK and Canada.(AU)

Primary, secondary and tertiary prevention of food allergy: current practices and future directions.

The incidence of food allergies has risen around the globe, and experts have been exploring methods of preventing such allergies in young children to ease the burden of disease and reduce the morbidity and mortality caused by anaphylaxis to food allergens. Such preventative measures can be categorised as primary, secondary and tertiary prevention, which are discussed in detail in this review. Primary prevention is defined as the prevention of becoming sensitised towards specific allergens. The evidence suggests that avoiding common allergenic foods during pregnancy and breastfeeding is not protective against food allergies, and guidelines recommend weaning from 4 to 6 months of age, with recent studies supporting the early introduction of peanuts at 4 months to prevent peanut allergy. Secondary prevention targets patients who are already sensitised and aims to halt the progression of sensitisation, with evidence for high rates of success and safety in trials of early introduction to milk and peanuts using oral immunotherapy in sensitised infants. Tertiary allergy prevention focuses on reducing the risk of a patient having anaphylaxis, with oral immunotherapy being the most common method of promoting tolerance in allergic children. Several studies have demonstrated successful reintroduction for milk, egg and peanut; however, no such guidelines are recommended for other foods. Finally, dietary advancement therapy in the form of milk and egg ladders has been employed as a method of primary, secondary and tertiary prevention of allergies, particularly in Ireland, the UK and Canada.

Free PEG Suppresses Anaphylaxis to PEGylated Nanomedicine in Swine.

Covalent conjugation of poly(ethylene glycol) (PEG) is frequently employed to enhance the pharmacokinetics and biodistribution of various protein and nanoparticle therapeutics. Unfortunately, some PEGylated drugs can induce elevated levels of antibodies that can bind PEG, i.e., anti-PEG antibodies (APA), in some patients. APA in turn can reduce the efficacy and increase the risks of allergic reactions, including anaphylaxis. There is currently no intervention available in the clinic that specifically mitigates allergic reactions to PEGylated drugs without the use of broad immunosuppression. We previously showed that infusion of high molecular weight free PEG could safely and effectively suppress the induction of APA in mice and restore prolonged circulation of various PEGylated therapeutics. Here, we explored the effectiveness of free PEG as a prophylaxis against anaphylaxis induced by PEG-specific allergic reactions in swine. Injection of PEG-liposomes (PL) resulted in anaphylactoid shock (pseudoanaphylaxis) within 1-3 min in both naïve and PL-sensitized swine. In contrast, repeated injection of free PEG alone did not result in allergic reactions, and injection of free PEG effectively suppressed allergic reactions to PL, including in previously PL-sensitized swine. These results strongly support the further investigation of free PEG for reducing APA and allergic responses to PEGylated therapeutics.

Prevention of Anaphylaxis Episodes in Idiopathic Anaphylaxis by Omalizumab.

INTRODUCTION: In 15-35 percent of patients with anaphylaxis, the triggering allergen cannot be found; therefore, a diagnosis of idiopathic anaphylaxis (IA) is made. We report on the outcomes in patients with IA treated with omalizumab. METHODS: We included consequent omalizumab-treated IA adult patients treated with omalizumab 300 mg every 4 weeks. RESULTS: Out of 7 patients, 6 were female, median age 40 years with the frequency of anaphylaxis episodes from 3 in 2 years to 5 in 4 months. Baseline tryptase ranged from 1.71 to 12.0 µg/L. An increase in tryptase during anaphylaxis was documented in 6 patients. Activating KIT p.D816V variant was detected in 2 patients. One patient also had hereditary alpha-tryptasemia (HαT). The duration of omalizumab treatment was 0.5-7.5 years. None of the patients have experienced an anaphylactic reaction since the start of treatment. Mild systemic reactions were reported in 6 patients (86%). The presence of underlying cMCD had no impact on the treatment outcome. CONCLUSION: All patients in our study had complete responses to omalizumab. The presence of KIT p.D816V and HαT did not influence the response to omalizumab treatment.

Polyethylene glycol and immunology: aspects of allergic reactions and their mechanisms, as well as ways to prevent them in clinical practice.

In modern medical practice, where polyethylene glycol is widely used as a component of various drugs, such as vaccines, chemotherapy drugs, and antibiotics, including vaccines, the issue of allergic reactions to this substance is becoming increasingly important. The purpose of this study is to review and systematise data on various aspects of allergic reactions to polyethylene glycol with the aim of better understanding their pathogenesis, clinical manifestations, diagnostic methods, and possible treatment approaches. The study analysed literature data in modern databases, such as MEDLINE, PubMed, and Scopus, on allergic reactions to polyethylene glycol, using the keywords: "PEG", "polyethylene glycol", "allergy", "side effect". The main aspects of allergy to this substance were highlighted, including mechanisms of development, diagnostic methods, and possible treatment strategies. The analysis found that allergic reactions to polyethylene glycol can manifest in a variety of ways, including anaphylaxis and systemic reactions. A possible role for the immune response has been identified, including the production of IgE and IgM antibodies, complement activation, and accelerated clearance in response to polyethylene glycol, in blood plasma. Data are also provided on how to diagnose an increased risk of an allergic reaction in patients who have previously received drugs with this type of drug transporter and in patients receiving high molecular weight types of polyethylene glycol. The results of this review contribute to a better understanding of allergic reactions to polyethylene glycol and provide information for the development of more effective diagnostic and treatment methods.

Prevention of allergic reactions during oxaliplatin desensitization through inhibition of Bruton tyrosine kinase.

BACKGROUND: Acute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Breakthrough symptoms, including anaphylaxis, can still occur during RDD. OBJECTIVE: Our aim was to evaluate whether pretreatment with acalabrutinib, a Bruton tyrosine kinase inhibitor, can prevent anaphylaxis during RDD in a patient sensitized to oxaliplatin. METHODS: A 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his fifth cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib before and during RDD were reviewed, and the patient elected to proceed. RESULTS: With acalabrutinib taken before and during the RDD, the patient was able to tolerate oxaliplatin RDD without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient's positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% vs 0.98%) before the RDD but did protect against basopenia (0.74% vs 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% vs 2.38%) or polyclonal anti-human IgE antibody (0.08% vs 44.2%). CONCLUSIONS: Five doses of acalabrutinib, 100 mg, orally twice daily starting during the evening 2 days before and continuing through RDD allowed a sensitized patient to receive oxaliplatin successfully and safely.

Management of food allergy based on oral food challenge.

PURPOSE OF REVIEW: Food allergy is a growing health problem that affects both patients and society in multiple ways. Despite the emergence of novel diagnostic tools, such as component-resolved diagnostics (CRD) and basophil activation tests (BAT), oral food challenge (OFC) still plays an indispensable role in the management of food allergies. This review aimed to highlight the indications and safety concerns of conducting an OFC and to provide insights into post-OFC management based on recent findings. RECENT FINDINGS: Standardized OFC protocols have regional diversification, especially in Japan and Western countries. Recent studies suggested that the interval between doses should be at least more than an hour. Furthermore, applying a stepwise method tailored to the patient's specific immunoglobulin E level and history of anaphylaxis seems to mitigate these risks. Recent surveys have shown that, following a positive OFC, options other than strict avoidance are also selected. SUMMARY: OFC serves diverse purposes, yet the risks it carries warrant caution. The stepwise protocol appears promising for its safety. Subthreshold consumption following OFC shows potential; however, further research on its efficacy and safety is required. Management following OFC should be tailored and well discussed between clinicians and patients.

Sustained silencing peanut allergy by xanthopurpurin is associated with suppression of peripheral and bone marrow IgE-producing B cell.

Introduction: Peanut allergy is an immunoglobulin E (IgE) mediated food allergy. Rubia cordifolia L. (R. cordifolia), a Chinese herbal medicine, protects against peanut-induced anaphylaxis by suppressing IgE production in vivo. This study aims to identify IgE-inhibitory compounds from the water extract of R. cordifolia and investigate the underlying mechanisms using in vitro and in vivo models. Methods: Compounds were isolated from R. cordifolia water extract and their bioactivity on IgE production was assessed using a human myeloma U266 cell line. The purified active compound, xanthopurpurin (XPP), was identified by LC-MS and NMR. Peanut-allergic C3H/HeJ mice were orally administered with or without XPP at 200µg or 400µg per mouse per day for 4 weeks. Serum peanut-specific IgE levels, symptom scores, body temperatures, and plasma histamine levels were measured at challenge. Cytokines in splenocyte cultures were determined by ELISA, and IgE + B cells were analyzed by flow cytometry. Acute and sub-chronic toxicity were evaluated. IL-4 promoter DNA methylation, RNA-Seq, and qPCR analysis were performed to determine the regulatory mechanisms of XPP. Results: XPP significantly and dose-dependently suppressed the IgE production in U266 cells. XPP significantly reduced peanut-specific IgE (>80%, p <0.01), and plasma histamine levels and protected the mice against peanut-allergic reactions in both early and late treatment experiments (p < 0.05, n=9). XPP showed a strong protective effect even 5 weeks after discontinuing the treatment. XPP significantly reduced the IL-4 level without affecting IgG or IgA and IFN-γ production. Flow cytometry data showed that XPP reduced peripheral and bone marrow IgE + B cells compared to the untreated group. XPP increased IL-4 promoter methylation. RNA-Seq and RT-PCR experiments revealed that XPP regulated the gene expression of CCND1, DUSP4, SDC1, ETS1, PTPRC, and IL6R, which are related to plasma cell IgE production. All safety testing results were in the normal range. Conclusions: XPP successfully protected peanut-allergic mice against peanut anaphylaxis by suppressing IgE production. XPP suppresses murine IgE-producing B cell numbers and inhibits IgE production and associated genes in human plasma cells. XPP may be a potential therapy for IgE-mediated food allergy.

Sesame seed allergy.

ABSTRACT: In the US, sesame was recognized as the ninth major food allergen in 2021, underscoring the importance of updated allergen labeling to facilitate effective prevention plans and anaphylaxis response. This article discusses the prevalence of sesame seed allergy among children in the US and outlines strategies for nurses to understand the assessment, treatment, and education of patients regarding this allergen.

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.