A risk of serious anaphylatic reactions to asthma biologics: a pharmacovigilance study based on a global real-world database.

Asthma is a chronic inflammatory condition that affects the lung airways. Chronic use of oral glucocorticoids in patients with severe asthma is associated with several adverse events (AEs). Biologics (omalizumab, benralizumab, mepolizumab, reslizumab, and dupilumab) have been developed as alternative therapies for the treatment of asthma. In this study, we aimed to evaluate the risk of anaphylactic reactions associated with these five biologics based on a large global database. We utilized individual case reports from the Uppsala Monitoring Center from January 1968 to December 29, 2019. A disproportionality analysis was performed over all drugs and monoclonal antibodies. Anaphylactic reactions were defined according to the "anaphylactic reaction" of the standardized MedDRA queries. Contrary to dupilumab, omalizumab, benralizumab, and mepolizumab demonstrated positive signals related to anaphylactic reactions over all drugs and monoclonal antibodies. Reslizumab, which represented only 315 cases of all AEs, requires more reports to determine its association with anaphylactic reactions. More anaphylactic reactions have been identified than are known, and most cases (96.2%) are reported to be serious. Our findings indicate that omalizumab, benralizumab, and mepolizumab for asthma treatment are associated with a high risk of anaphylactic reactions; thus, more careful monitoring in the post-administration period is recommended.

Secreted phosphoprotein 1 regulates natural compound 3',4',5,7-tetrahydroxyflavone to inhibit mast cell-mediated allergic inflammation.

BACKGROUND: Mast cells (MCs) are important effector cells in anaphylaxis and anaphylactic disease. 3',4',5,7-tetrahydroxyflavone (THF) presents in many medicinal plants and exerts a variety of pharmacological effects. In this study, we evaluated the effect of THF on C48/80-induced anaphylaxis and the mechanisms underlying its effects, including the role of secreted phosphoprotein 1 (SPP1), which has not been reported to IgE-independent MC activation. RESULTS: THF inhibited C48/80-induced Ca2+ flow and degranulation via the PLCγ/PKC/IP3 pathway in vitro. RNA-seq showed that THF inhibited the expression of SPP1 and downstream molecules. SPP1 is involved in pseudo-anaphylaxis reactions. Silencing SPP1 affects the phosphorylation of AKT and P38. THF suppressed C48/80-induced paw edema, hypothermia and serum histamine, and chemokines release in vivo. CONCLUSIONS: Our results validated SPP1 is involved in IgE-independent MC activation anaphylactoid reactions. THF inhibited C48/80-mediated anaphylactoid reactions both in vivo and in vitro, suppressed calcium mobilization and inhibited SPP1-related pathways.

A Patient with Known Allergy to Local Anesthesia Presenting for a Dental Restoration.

Dentists should be equipped to treat an allergic reaction in a dental office, and in this scenario, the potential allergic reaction is noted after administration of a common local anesthetic lidocaine with epinephrine. The allergic reaction quickly escalates to a full-blown anaphylaxis, and the management of such an episode is detailed in this article.

An unexpected allergic skin reaction to peppermint oil capsules.

Peppermint oil capsules are prescribed to manage abdominal colic and distension, a common complaint in postcaesarean section patients. Arachis (peanut) oil is contained within one frequently prescribed peppermint formulation: Colpermin. This ingredient is contraindicated in patients with peanut and soya allergy; however, this is not stated in the side effects or contraindications section of the British National Formulary, or present on the medication packaging. A postpartum woman in her early 30s had an unexpected allergic reaction to the capsules, in the form of a generalised body rash, fortunately with no anaphylactic features. The patient reported the same reaction to soya in the past. After review of the patient's clinical and medication history, Colpermin capsules were thought to be responsible for the patient's symptoms. This case highlights the necessity for clearer documentation in prescribing formularies and on medication packaging to ensure patient safety.

5-Hydroxymethylfurfural multimers induce pseudo-allergic reaction through FcεRI at high doses.

Under acidic and high temperature conditions, 5-hydroxymethylfurfural (5-HMF) converted from sugar further produces dimers (Compound II) and trimers (Compound III). The polymers were less reported, and sensitization effect of them was reported in this study. Compounds II and III induced the local and systemic anaphylaxis effect in passive cutaneous anaphylaxis mice model and activated RBL-2H3 cell inducing [Ca2+ ] mobilization, resulting in the release of ß-hexosaminidase and histamine in vitro. The gene knockdown assay figured out that Compounds II and III induced degranulation through FcεRI. Further, Compounds II and III had a certain affinity with FcεRI by cell membrane chromatography and may combine on the "proline sandwich" structure indicated by molecular docking. All above suggested Compounds II and III can induce pseudo-allergic reaction through FcεRI in vivo and in vitro. Our work provides basic research to prove that the newly discovered 5-HMF transformants, Compounds II and III, induce pseudo-allergic reaction in vitro and in vivo through FcεRI, which is different pathway from 5-HMF. In foods with high sugar content, the sensitization of Compounds II and III needs more attention. In high-sugar foods and medicines, especially traditional Chinese medicine injections, the content of transformants needs to be detected.

Adverse Events Associated with the Clinical Use of Bee Venom: A Review.

Bee venom is used to treat various diseases but can cause a tickling sensation and anaphylaxis during clinical treatment. Adverse events (AEs) associated with bee venom may vary depending on the dosage, method, route of administration, and the country, region, and user. We summarized the AEs of bee venom used in various ways, such as by the injection of extracts, venom immunotherapy (VIT), live bee stings, or external preparations. We conducted a search in eight databases up to 28 February 2022. It took one month to set the topic and about 2 weeks to set the search terms and the search formula. We conducted a search in advance on 21 February to see if there were omissions in the search terms and whether the search formula was correct. There were no restrictions on the language or bee venom method used and diseases treated. However, natural stings that were not used for treatment were excluded. A total of 105 studies were selected, of which 67, 26, 8, and 4 were on the injection of extracts, VIT, live bee stings, and external preparation, respectively. Sixty-three studies accurately described AEs, while 42 did not report AEs. Thirty-five randomized controlled trials (RCTs) were evaluated for the risk of bias, and most of the studies had low significance. A large-scale clinical RCT that evaluates results based on objective criteria is needed. Strict criteria are needed for the reporting of AEs associated with bee venom.

Incidence Rate of Bee Venom Acupuncture Related Anaphylaxis: A Systematic Review.

BACKGROUND: Bee venom acupuncture (BVA) is an effective treatment method for various diseases. Bee venom, however, can cause adverse effects, even rarely including life-threatening anaphylaxis, so safety-related evidence is required. In this study, we systematically estimated the incidence rate of anaphylaxis in response to BVA. METHODS: We searched eight databases (MEDLINE (Pubmed), EMBASE, Cochrane Central Register of Controlled, KISS, KMBASE, Koreamed, OASIS, and NDSL) and systematically reviewed the articles that met the inclusion/exclusion criteria. RESULTS: Among 225 potentially relevant articles, 49 were selected for this study. The overall incidence rate of anaphylaxis in response to BVA was 0.045% (95% CI 0.028-0.062). Women (0.083%, 95% CI 0.010-0.157) showed a higher incidence rate than men (0.019%, 95% CI -0.018 to 0.055), while the incidence for patients who had a skin test conducted (0.041%, 95% CI 0.011-0.072) was not significantly different compared to that obtained for patients for which there was no information about a skin test (0.047%, 95% CI 0.026-0.067). The publication year affected the incidence rate: it was highest before 1999 (1.099%, 95% CI -1.043 to 3.241), lower between 2000 and 2009 (0.049%, 95% CI 0.025-0.073), and lowest between 2010 and 2021 (0.037% 95% CI 0.014-0.060). CONCLUSIONS: In this study, we provide reference data about risk size and factors of BVA-related anaphylaxis, which is essentially required for BVA application in clinics.

Threshold for Anaphylactoid Reaction to Polysorbate 80 in Canines.

Polysorbate 80 (PS80) functions as a dispersing agent or solubilizer in many pharmaceuticals, and as a stabilizer in biopharmaceuticals. Topical or parenteral administration of low doses of PS80 in biopharmaceuticals has been associated with mild allergic reactions, including local injection site reactions in humans. High doses of PS80, such as levels found in traditional Chinese herbal parenteral medicines, have been linked to systemic effects consistent with anaphylactoid-type reactions, which are characterized by the direct release of histamine from mast cells (degranulation). Nonclinical safety assessments of PS80 in vivo have mainly focused on canine model systems, a species established to be particularly sensitive to PS80. However, there is conflicting data about the dose and route of administration of PS80 required to elicit an anaphylactoid-type reaction in this model system. Therefore, studies using multiple dosing regimens in anesthetized and conscious dogs including a combination of cardiovascular data, clinical signs, and biomarkers of mast cell degranulation were conducted. An intravenous (IV) bolus of 1 mg/kg PS80 (0.25% w/v) elicited a positive anaphylactoid reaction including increased heart rate, hypotension, and clinical signs associated with anaphylactoid reactions (e.g., reddened muzzle). However, a full reaction was not observed with a subcutaneous (SC) injection of PS80 (0.25% w/v) up to 20 mg/kg and IV bolus or IV infusions up to 0.5 mg/kg. These data establish a threshold dose for eliciting an anaphylactoid reaction in canine which varies depending on the route of administration as well as the rate of PS80 infusion.

[«Criminal¼ local anesthesia in dentistry: a deliberate risk or a game without rules?] / «Kriminal'naya¼ mestnaya anesteziya v stomatologii: osoznannyi risk ili igra bez pravil?

The effectiveness and safety of drug treatment are the main criteria for its success. Local anesthetics, used in all medical fields, in some cases can cause a wide variety of undesirable side reactions, but in recent years, such manifestations that have arisen in Russian clinical practice tend to qualify as anaphylactic shock. This article presents the types of adverse reactions and global statistics of anaphylaxis to local anesthetics, as well as analyzes the possible reasons for the erroneous diagnosis of fatal outcomes of anaphylaxis. The purpose of the review was to clarify information about reliable markers of clinical and postmortem anaphylaxis, providing unambiguousness and objectivity of forensic medical examination. Attention is focused on the specific postmortem signs of immediate allergic reactions and the sequence of professional interpretation of all the circumstances associated with a fatal adverse reaction against the background of the use of local anesthetics.

Anaphylaxis caused by artisanal honey in a child: a case report.

BACKGROUND: Honey is a rare cause of food allergy, especially in children, but it can cause severe systemic allergic reactions. In the pediatric age group, only a few cases have been reported in the literature. Honey allergy may be caused by pollen content or bee-derived proteins. A role for Compositae has been suggested among pollen allergens. Allergology workup of a patient with suspected honey allergy is not well defined. Here we describe a rare case of anaphylaxis in a 5-year-old boy, sensitized to Compositae pollen (ragweed and mugwort), after the ingestion of artisanal honey. CASE PRESENTATION: The Slavic patient was referred to our hospital emergency department for generalized urticaria and breathing impairment. All the symptoms occurred approximately 30 minutes after the ingestion of a meal containing salmon and artisanal honey. The allergology workup revealed that a skin prick-by-prick test with the implicated artisanal honey was positive, while a variety of different commercial honey and salmon products yielded negative results. Skin prick test and serum-specific immunoglobulin E (IgE) results were also positive for Compositae pollen (ragweed and mugwort). Patients sensitized to weed pollens who ingest bee products may experience an immediate allergic reaction because of the cross-reaction between weed pollens and Compositae bee product pollen. In this case, primary sensitization may be due to airborne Compositae pollen. Commercial honey is heavily processed due to pasteurization and filtration, which removes most of the pollen. These observations highlight the role of Compositae pollen in the observed allergic reaction and suggest that the different pollen content in the artisanal honey relative to commercial honey was responsible for the allergic reaction in our patient. CONCLUSIONS: This is the first reported pediatric case of honey-induced anaphylaxis in a child under 6 years of age sensitized to Compositae pollen. Pediatricians should be aware of the potential risk of severe allergic reactions upon ingestion of honey and bee products, especially in patients sensitized to weed pollens. To diagnose honey allergy, obtaining a proper clinical history is essential. In addition, skin prick-by-prick tests are helpful, and may represent a simple method to screen for honey allergy in patients sensitized to Compositae pollen, in light of the potential risk.

Identification of Cleaved Haptoglobin in the Serum of Bee Venom-Hypersensitive Patients.

Background: Bee venom has been used as a therapeutic compound for various human diseases in oriental medicine; however, it can induce anaphylaxis in hypersensitive patients during treatment. Anaphylaxis is an acute allergic reaction that occurs after allergen exposure. IgE is released from immune-related cells such as mast cells and basophils during anaphylaxis. Various inflammatory mediators are also released into the bloodstream during the acute response. Objectives: We aimed to identify specific proteins from bee venom-hypersensitive patients. Methods: We analyzed the blood serum of control and bee venom-hypersensitive patients using two-dimensional (2D) electrophoresis. Results: An interesting protein spot with a molecular size of 10 kDa was identified at an isoelectric point (p.I.) of 5.5. Spots detected both before and after sweet bee venom therapy were not proteins induced by sweet bee venom. The 10 kDa protein was identified as the cleaved form of haptoglobin through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Statistical analysis indicated that the presence of the spot was highly significant in the bee venom-hypersensitive group. Conclusion: The findings suggest that cleaved haptoglobin may be a significant diagnostic protein for anaphylaxis. In addition, a high incidence of bee venom hypersensitivity may be associated with the haptoglobin genotype.

Oleanolic acid protects against mast cell-mediated allergic responses by suppressing Akt/NF-κB and STAT1 activation.

BACKGROUND: Oleanolic acid (OA) is an active compound found in a variety of medicinal herbs and plants. Though OA has been widely attributed with a variety of biological activities, studies focused on its anti-allergic inflammation properties are insufficient. PURPOSE: Given the rapid increase in allergic diseases and the lack of fundamental treatment options, this study aimed to find a safe and effective therapy for allergic disorders. METHODS: We evaluated the inhibitory effect of OA on allergic inflammatory response and the possible mechanisms underlying the effect using phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cell (HMC)-1, and a mouse model of compound 48/80-induced anaphylactic shock. RESULTS: OA suppressed pro-inflammatory cytokine expressions in PMACI-induced HMC-1 cells by inhibiting activation of the Akt, p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription (STAT) 1 signaling pathways. Moreover, OA showed a protective effect against compound 48/80-induced anaphylactic shock through inhibition of histamine release and immunoglobulin E level via regulation of NF-κB and STAT1 activation. CONCLUSION: The results showed that OA suppressed mast cell-mediated allergic response by transcriptional regulation. We suggest that OA has potential effect against allergic inflammatory disorders, including anaphylaxis, and might be a useful therapeutic agent for allergic disease.

Liquid Chromatography Tandem Mass Spectrometry Based Label-Free Quantification Method for Assessment of Allergen-Induced Anaphylactoid Reactions.

Mast cells are essential in mediating inflammatory processes. When activated, mast cells can rapidly release characteristic granules and various mediators into the interstitium. Tryptase (TPS) and ß-hexosaminidase (HEXB) are typical protease mediators stored in granules and released upon activation. They have been recognized as important biomarkers of anaphylaxis, and the released level is associated with the severity of allergic reactions. In this study, a sensitive, accurate, and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneously quantifying the two biomarkers was developed and validated in LAD2 cell culture supernatant, and P14R was used as internal standard. Good linearity was observed in the range of 50-2500 ng/mL for TPS and 10-2000 ng/mL for HEXB both with R2 > 0.99. The matrix effect and recovery were both within acceptable limits. We quantified TPS and HEXB released from Laboratory of Allergic Disease 2 (LAD2) mast cells treated with several potential allergens, and the results demonstrate that the method can be used to investigate TPS and HEXB levels in LAD2 mast cell model during allergy research. We anticipate our approach to be a robust and sensitive assessment method for more biomarkers with similar kinetics characteristics and to be a major tool of allergic drug assessment or antiallergic drug development in research.

Inhibitory function of Shikonin on MRGPRX2-mediated pseudo-allergic reactions induced by the secretagogue.

BACKGROUND: Mast cells (MCs) are crucial effectors in allergic disorders by secreting inflammatory mediators. The Mas-related G-protein-coupled receptor X2 (Mrgprx2) was shown to have a key role in IgE-independent allergic reactions. Therefore, potential drug candidates that directly target Mrgprx2 could be used to treat pseudo-allergic diseases. Shikonin, an active ingredient derived from Lithospermum erythrorhizon Sieb. et Zucc has been used for its anti-inflammatory properties since ancient China. PURPOSE: To investigate the inhibitory effects of Shikonin on IgE-independent allergy both in vitro and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of Shikonin was evaluated in PCA and systemic anaphylaxis models, Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of PLCγ-PKC-IP3 signaling pathway. The analytical method of surface plasmon resonance was employed to study the interaction between Shikonin and potential target protein Mrgprx2. RESULTS: Shikonin can suppress compound 48/80 (C48/80)-induced PCA, active systemic anaphylaxis, and MCs degranulation in mice in a dose-dependent manner. In addition, Shikonin reduced C48/80-induced calcium flux and suppressed LAD2 cell degranulation via PLCγ-PKC-IP3 signaling pathway. Moreover, Shikonin was found to inhibit C48/80-induced Mrgprx2 expression in HEK cells, displaying specific interactions with the Mrgprx2 protein. CONCLUSION: Shikonin could be a potential antagonist of Mrgprx2, thereby inhibiting pseudo-allergic reactions through Ca2+ mobilization.

Xanthone suppresses allergic contact dermatitis in vitro and in vivo.

Xanthone is a phenolic compound found in a few higher plant families; it has a variety of biological activities, including antioxidant, anti-inflammatory, and anticancer properties. However, the molecular and cellular mechanisms underlying the activity of xanthone in allergic contact dermatitis (ACD) remain to be explored. Therefore, this study aimed to investigate the regulatory effects of xanthone in ACD in human keratinocytes (HaCaT cell), and human mast cell line (HMC-1 cell) in vitro and in an experimental murine model. The results demonstrated that treatment with xanthone reduced the production of pro-inflammatory cytokines and chemokines including interleukin (IL)-1ß, IL-6, IL-8, and expression of chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated HaCaT cells. Xanthone also suppressed the production of pro-inflammatory cytokines, chemokines, and allergic mediators in phorbol myristate acetate/A23187 calcium ionophore (PMACI)-stimulated HMC-1 cells. Xanthone significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) and activation of caspase-1 signaling pathway in vitro model. Additionally, xanthone administration alleviated 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis like-skin lesion by reducing the serum levels of immunoglobulin E (IgE), histamine, and pro-inflammatory cytokines and suppressing MAPKs phosphorylation. Xanthone administration also inhibited mortality due to compound 48/80-induced anaphylactic shock and suppressed the passive cutaneous anaphylaxis (PCA) reaction mediated by IgE. Collectively, these results suggest that xanthone has a potential for use in the treatment of allergic inflammatory diseases.

MrgX2 is a promiscuous receptor for basic peptides causing mast cell pseudo-allergic and anaphylactoid reactions.

Activation of MrgX2, an orphan G protein-coupled receptor expressed on mast cells, leads to degranulation and histamine release. Human MrgX2 binds promiscuously to structurally diverse peptides and small molecules that tend to have basic properties (basic secretagogues), resulting in acute histamine-like adverse drug reactions of injected therapeutic agents. We set out to identify MrgX2 orthologues from other mammalian species used in nonclinical stages of drug development. Previously, the only known orthologue of human MrgX2 was from mouse, encoded by Mrgprb2. MrgX2 genes of rat, dog (beagle), minipig, pig, and Rhesus and cynomolgus monkey were identified by bioinformatic approaches and verified by their ability to mediate calcium mobilization in transfected cells in response to the classical MrgX2 agonist, compound 48/80. The peptide GSK3212448 is an inhibitor of the PRC2 epigenetic regulator that caused profound anaphylactoid reactions upon intravenous infusion to rat. We showed GSK3212448 to be a potent MrgX2 agonist particularly at rat MrgX2. We screened sets of drug-like molecules and peptides to confirm the highly promiscuous nature of MrgX2. Approximately 20% of drug-like molecules activated MrgX2 (pEC50 ranging from 4.5 to 6), with the principle determinant being basicity. All peptides tested of net charge +3 or greater exhibited agonist activity, including the cell penetrating peptides polyarginine (acetyl-Arg9-amide) and TAT (49-60), a fragment of HIV-1 TAT protein. Finally, we showed that the glycopeptide antibiotic vancomycin, which is associated with clinical pseudo-allergic reactions known as red man syndrome, is an agonist of MrgX2.