Detecting epinephrine auto-injector shortages in Finland 2016-2022: Log-data analysis of online information seeking.

INTRODUCTION: Medicine shortages prevail as a worldwide problem causing life-threatening situations for adults and children. Epinephrine auto-injectors are used for serious allergic reactions called anaphylaxis, and alternative auto-injectors are not always available in pharmacies. Healthcare professionals in Finland use the dedicated internet source, Physician's Database (PD), when seeking medical information in practice, while Health Library (HL) provides health information for citizens (S1 Data). The objectives were to assess whether (1) professionals' searches for epinephrine auto-injectors and (2) citizens' anaphylaxis article openings relate to epinephrine shortages in Finland. METHODS: Monthly log data on epinephrine auto-injectors (EpiPen®, Jext®, Emerade®) from PD and on openings of anaphylaxis articles from HL were collected during 2016-2022. Professionals' searches of seven auto-injectors and citizens' openings of four anaphylaxis articles were compared to information on epinephrine shortages reported by Finnish Medicines Agency. Professionals' auto-injector prescriptions provided by Social Insurance Institution were also assessed. RESULTS: Total searches in EpiPen® (N = 111,740), Jext® (N = 25,631), and Emerade® (N = 18,329) could be analyzed during 2016-2022. EpiPen® only could visually show seasonal patterns during summertime, peaking vigorously in the summer of 2018 when the major EpiPen® shortage appeared worldwide. Anaphylaxis articles equaled 2,030,855 openings altogether. Openings of one anaphylaxis article ("Bites and Stings") peaked during summertime, while another article ("Anaphylactic Reaction") peaked only once (three-fold increase) at the end of 2020 when COVID-19 vaccinations started, and auto-injector prescriptions were lowest. Fifty EpiPen®, one Jext®, and twelve Emerade® shortages were reported. Almost a two-fold increase in peaks of auto-injector prescriptions was found during summertime. CONCLUSION: This study shows that (1) epinephrine shortages related to professionals' searching for auto-injectors, and (2) citizens' information seeking on anaphylaxis related to summertime and shortages with lesser prescriptions. Therefore, the dedicated internet databases aimed at professionals and citizens could be used as additional information sources to detect anaphylactic reactions and auto-injector shortages.

A retrospective audit of adult and paediatric anaphylaxis management from two Australian metropolitan mixed emergency departments.

BACKGROUND: Anaphylaxis is a potentially life-threatening allergic reaction, with presentations to emergency departments (EDs) increasing across Australia. Understanding the features of those presenting with anaphylaxis and aspects related to its optimal clinical management across the admission, treatment and discharge settings is needed to minimise its impact. We aimed to evaluate the nature and management of presentations related to anaphylaxis across two Australian EDs. METHODS: Retrospective audit of paediatric and adult patients presenting to a community or tertiary level ED with anaphylaxis from 1 May 2018 to 30 April 2019. Data extracted from medical records included demographic characteristics, causative agents, clinical features, treatments administered across community, ambulance or ED settings, as well as post-discharge care arrangements including provision of Adrenaline Auto-Injector (AAI) and Allergy/Anaphylaxis Action Plan (AAP). RESULTS: A total of 369 (107 paediatric and 262 adult) ED presentations were identified. A total of 94 (36%) adult and 46 (43%) paediatric patients received pre-hospital adrenaline, with a further 91 (35%) adult and 29 (27%) paediatric patients receiving a dose of adrenaline in the ED. The most commonly administered treatment in ED were corticosteroids, given to 157 (60%) adult and 55 (51%) paediatric patients. Among those requiring an AAI for discharge, 123/210 (59%) adult and 57/91 (63%) of paediatric patients left hospital with an AAI. In contrast, among those requiring an allergy/anaphylaxis action plan (AAP) on discharge, 61/206 (30%) adult and 30/90 (33%) of paediatric patients left hospital with one. Factors associated with an increased likelihood of receiving AAI on discharge in paediatric and adult patients included receipt of any adrenaline, receipt of two or more doses of adrenaline, and longer duration of hospital stay. Adults presenting within business hours were more likely to be discharged with AAI, but no such difference was observed for paediatric patients. Similar findings were evident for provision of AAP on discharge. CONCLUSION: These findings demonstrate the need to improve assessment and treatment in the ED. In particular, the observed large variability in provision of AAI and AAP on discharge presents opportunities to explore strategies to improve awareness and provision of these critical components of post-discharge care.

Revisiting dexamethasone use in the pediatric emergency department.

PURPOSE OF REVIEW: Dexamethasone is an essential treatment for common pediatric inflammatory, airway, and respiratory conditions. We aim to provide up-to-date recommendations for treatment of anaphylaxis, croup, coronavirus disease, multisystem inflammatory syndrome in children, and asthma with dexamethasone for use in the pediatric emergency department. RECENT FINDINGS: Literature largely continues to support the use of dexamethasone in most of the above conditions, however, recommendations for dosing and duration are evolving. SUMMARY: The findings discussed in this review will enable pediatric emergency medicine providers to use dexamethasone effectively as treatment of common pediatric conditions and minimize the occurrence of side-effects caused by gratuitous corticosteroid use.

[TWO CASES OF LARYNGEAL EDEMA CAUSED BY SUBLINGUAL ALLERGEN IMMUNOTHERAPY].

Sublingual immunotherapy is a widely used treatment, and serious adverse reactions such as anaphylaxis are rare. We report two cases of laryngeal edema as adverse reactions to sublingual immunotherapy, which could be continued due to a change in the administration method. Case 1 presents a 15-year-old male suspected to have had anaphylaxis due to the dust at the age of 6 years. He started treatment with Miticure® and developed laryngeal edema 30 minutes after taking the 10000JAU dose on the 10th day. laryngeal edema was treated with intravenous infusion. Case 2 presents a 48-year-old woman. She started treatment with Cidacure® and developed respiratory distress and laryngeal edema 1 hour after taking the 5000JAU dose on the 5th day. she had resolved mildly without therapeutic intervention. In both cases, the patients were switched to sublingual spitting, resumed with the initial dose cautiously, and were able to continue. Sublingual immunotherapy is a safe treatment, but sudden adverse reactions may occur. Laryngeal symptoms may be treated by changing to the sublingual spitting method, but laryngeal findings should be examined, and the dosage should be carefully increased.

NButGT Reinforces the Beneficial Effects of Epinephrine on Cardiac Mitochondrial Respiration, Lactatemia and Cardiac Output in Experimental Anaphylactic Shock.

Anaphylactic shock (AS) is the most severe form of acute systemic hypersensitivity reaction. Although epinephrine can restore patients' hemodynamics, it might also be harmful, supporting the need for adjuvant treatment. We therefore investigated whether NButGT, enhancing O-GlcNAcylation and showing beneficial effects in acute heart failure might improve AS therapy. Ovalbumin-sensitized rats were randomly allocated to six groups: control (CON), shock (AS), shock treated with NButGT alone before (AS+pre-Nbut) or after (AS+post-Nbut) AS onset, shock treated with epinephrine alone (AS+EPI) and shock group treated with combination of epinephrine and NButGT (AS+EPI+preNBut). Induction of shock was performed with an intravenous (IV) ovalbumin. Cardiac protein and cycling enzymes O-GlcNAcylation levels, mean arterial pressure (MAP), heart rate, cardiac output (CO), left ventricle shortening fraction (LVSF), mitochondrial respiration, and lactatemia were evaluated using Western blotting experiments, invasive arterial monitoring, echocardiography, mitochondrial oximetry and arterial blood samples. AS decreased MAP (-77%, p < 0.001), CO (-90%, p < 0.001) and LVSF (-30%, p < 0.05). Epinephrine improved these parameters and, in particular, rats did not die in 15 min. But, cardiac mitochondrial respiration remained impaired (complexes I + II -29%, p < 0.05 and II -40%, p < 0.001) with hyperlactatemia. NButGT pretreatment (AS+pre-Nbut) efficiently increased cardiac O-GlcNAcylation level as compared to the AS+post-Nbut group. Compared to epinephrine alone, the adjunction of NButGT significantly improved CO, LVSF and mitochondrial respiration. MAP was not significantly increased but lactatemia decreased more markedly. Pretreatment with NButGT increases O-GlcNAcylation of cardiac proteins and has an additive effect on epinephrine, improving cardiac output and mitochondrial respiration and decreasing blood lactate levels. This new therapy might be useful when the risk of AS cannot be avoided.

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.

Allergy to Gibberellin-regulated proteins in an adolescent: A case of orange-induced anaphylaxis mediated by cofactors / Alergia a proteínas reguladas por giberelinas en un adolescente: un caso de anafilaxia inducida por naranja mediada por cofactores

This report is a case of anaphylaxis in an adolescent due to allergy to gibberellin-regulated proteins mediated by cofactors, in probable relation to a pollen/food allergy syndrome. It should also emphasizes the importance of obtaining a faithful clinical history, especially when it comes to adolescent patients as they tend to initiate toxic habits.(AU)

El pediatra de Atención Primaria y la anafilaxia / The primary care pediatrician and anaphylaxis

La anafilaxia es una reacción alérgica grave de instauración rápida y potencialmente mortal. El diagnóstico de anafilaxia es clínico y debe realizarse de manera precoz. Aparece en las 2 primeras horas tras exposición al alérgeno, en los primeros 30 minutos en alergia alimentaria y más precozmente con medicamentos intravenosos o picaduras de himenópteros. Los síntomas cutáneos suelen ser los primeros en manifestarse y están presentes en la mayoría de los casos, más de un 80%. Pueden ser leves o transitorios e incluso no estar presentes en un 18% de los casos. Si se afecta el sistema cardiocirculatorio estaríamos ante un shock anafiláctico. La causa más frecuente en Pediatría son los alimentos. Existen cofactores cuya presencia aumenta la probabilidad de anafilaxia; los más importantes son: el ejercicio, los fármacos, la fiebre y el estrés. El tratamiento de elección es la adrenalina intramuscular. Tanto los padres como los niños deben saber identificar los signos y/o síntomas del inicio de la anafilaxia para instaurar el tratamiento pautado en el plan de acción escrito.

Anaphylaxis is a severe, rapid and potentially fatal allergic reaction. The diagnosis of anaphylaxis is clinical and must be early. It appears in the first 2 hours after exposure to the allergen, in the first 30 minutes in food allergy and earlier with intravenous drugs or hymenoptera stings. Cutaneous symptoms are generally the first to appear and are present in most cases, more than 80%. They may be mild or transitory, or absent in 18% of cases. If the cardio-circulatory system is affected, an anaphylactic shock occurs. The most frequent cause in pediatrics is nutrition. There are several cofactors whose presence increases the likelihood of anaphylaxis; the most important are: exercise, medication, fever and stress. The treatment of choice is intramuscular adrenaline. Parents and children should be able to identify the signs and/or symptoms of anaphylaxis in order to implement the treatment prescribed in the written action plan. (AU)

Risk of Anaphylaxis Among New Users of GLP-1 Receptor Agonists: A Cohort Study.

OBJECTIVE: To assess risk of anaphylaxis among patients with type 2 diabetes mellitus who are initiating therapy with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), with a focus on those starting lixisenatide therapy. RESEARCH DESIGN AND METHODS: A cohort study was conducted in three large, U.S. claims databases (2017-2021). Adult (aged ≥18 years) new users of a GLP-1 RA who had type 2 diabetes mellitus and ≥6 months enrollment in the database before GLP-1 RA initiation (start of follow-up) were included. GLP-1 RAs evaluated were lixisenatide, an insulin glargine/lixisenatide fixed-ratio combination (FRC), exenatide, liraglutide or insulin degludec/liraglutide FRC, dulaglutide, and semaglutide (injectable and oral). The first anaphylaxis event during follow-up was identified using a validated algorithm. Incidence rates (IRs) and 95% CIs were calculated within each medication cohort. The unadjusted IR ratio (IRR) comparing anaphylaxis rates in the lixisenatide cohort with all other GLP-1 RAs combined was analyzed post hoc. RESULTS: There were 696,089 new users with 456,612 person-years of exposure to GLP-1 RAs. Baseline demographics, comorbidities, and use of other prescription medications in the 6 months before the index date were similar across medication cohorts. IRs (95% CIs) per 10,000 person-years were 1.0 (0.0-5.6) for lixisenatide, 6.0 (3.6-9.4) for exenatide, 5.1 (3.7-7.0) for liraglutide, 3.9 (3.1-4.8) for dulaglutide, and 3.6 (2.6-4.9) for semaglutide. The IRR (95% CI) for the anaphylaxis rate for the lixisenatide cohort compared with the pooled other GLP-1 RA cohort was 0.24 (0.01-1.35). CONCLUSIONS: Anaphylaxis is rare with GLP-1 RAs. Lixisenatide is unlikely to confer higher risk of anaphylaxis than other GLP-1 RAs.

Mast Cell-Targeting Therapies in Mast Cell Activation Syndromes.

PURPOSE OF REVIEW: Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS). RECENT FINDINGS: Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

Butyrate, Valerate, and Niacin Ameliorate Anaphylaxis by Suppressing IgE-Dependent Mast Cell Activation: Roles of GPR109A, PGE2, and Epigenetic Regulation.

Short-chain fatty acids (SCFAs) are produced by the intestinal microbiota during the fermentation of dietary fibers as secondary metabolites. Several recent studies reported that SCFAs modulate the development and function of immune-related cells. However, the molecular mechanisms by which SCFAs regulate mast cells (MCs) remain unclear. In the current study, we analyzed the function and gene expression of mouse MCs in the presence of SCFAs in vitro and in vivo. We found that the oral administration of valerate or butyrate ameliorated passive systemic anaphylaxis and passive cutaneous anaphylaxis in mice. The majority of SCFAs, particularly propionate, butyrate, valerate, and isovalerate, suppressed the IgE-mediated degranulation of bone marrow-derived MCs, which were eliminated by the Gi protein inhibitor pertussis toxin and by the knockdown of Gpr109a. A treatment with the HDAC inhibitor trichostatin A also suppressed IgE-mediated MC activation and reduced the surface expression level of FcεRI on MCs. Acetylsalicylic acid and indomethacin attenuated the suppressive effects of SCFAs on degranulation. The degranulation degree was significantly reduced by PGE2 but not by PGD2. Furthermore, SCFAs enhanced PGE2 release from stimulated MCs. The SCFA-mediated amelioration of anaphylaxis was exacerbated by COX inhibitors and an EP3 antagonist, but not by an EP4 antagonist. The administration of niacin, a ligand of GPR109A, alleviated the symptoms of passive cutaneous anaphylaxis, which was inhibited by cyclooxygenase inhibitors and the EP3 antagonist. We conclude that SCFAs suppress IgE-mediated activation of MCs in vivo and in vitro involving GPR109A, PGE2, and epigenetic regulation.

Screening of Prospective Antiallergic Compound as FcεRI Inhibitors and Its Antiallergic Efficacy Through Immunoinformatics Approaches.

The occurrence of allergy, a type I hypersensitivity reaction, is rising exponentially all over the world. Sometimes, allergy proves to be fatal for atopic patients, due to the occurrence of anaphylaxis. This study is aimed to find an anti-allergic agent that can inhibit the binding of IgE to Human High Affinity IgE Receptor (FCεRI), thereby preventing the degranulation of mast cells. A considerable number of potential anti-allergic compounds were assessed for their inhibitory strength through ADMET studies. AUTODOCK was used for estimating the binding energy between anti-allergic compounds and FCεRI, along with the interacting amino acids. The docked pose showing favorable binding energy was subjected to molecular dynamics simulation study. Marrubiin, a diterpenoid lactone from Lamiaceae, and epicatechin-3-gallate appears to be effective in blocking the Human High Affinity IgE Receptor (FCεRI). This in-silico study proposes the use of marrubiin and epicatechin-3-gallate, in the downregulation of allergic responses. Due to the better inhibition constant, future direction of this study is to analyze the safety and efficacy of marrubiin in anti-allergic activities through in-vivo clinical human trials.

Cannabidiol Inhibits IgE-Mediated Mast Cell Degranulation and Anaphylaxis in Mice.

SCOPE: Cannabidiol (CBD), the most abundant non-psychoactive constituent of the plant Cannabis sativa, is known to possess immune modulatory properties. This study investigates the effects of CBD on mast cell degranulation in human and mouse primary mast cells and passive cutaneous anaphylaxis in mice. METHODS AND RESULTS: Mouse bone marrow-derived mast cells and human cord-blood derived mast cells are generated. CBD suppressed antigen-stimulated mast cell degranulation in a concentration-dependent manner. Mechanistically, CBD inhibited both the phosphorylation of FcεRI downstream signaling molecules and calcium mobilization in mast cells, while exerting no effect on FcεRI expression and IgE binding to FcεRI. These suppressive effects are preserved in the mast cells that are depleted of type 1 (CB1) and type 2 (CB2) cannabinoid receptors, as well as in the presence of CB1 agonist, CB2 agonist, CB1 inverse agonist, and CB2 inverse agonist. CBD also inhibited the development of mast cells in a long-term culture. The intraperitoneal administration of CBD suppressed passive cutaneous anaphylaxis in mice as evidenced by a reduction in ear swelling and decrease in the number of degranulated mast cells. CONCLUSION: Based on these results, the administration of CBD is a new therapeutic intervention in mast cell-associated anaphylactic diseases.

Adrenaline autoinjectors for Australian out-of-hospital anaphylaxis: where to from here?

Intramuscular adrenaline autoinjectors are accepted as first-line treatment for out-of-hospital anaphylaxis but face ongoing issues of patient nonadherence related to drug expiry, availability, correct administration, and public recognition of the disease. Adrenaline is associated with possible harms in patients with defined comorbidities but is still considered preferable. Further research and policy is required to facilitate the effective treatment of anaphylaxis.

Factors Associated With Epinephrine Use in the Treatment of Anaphylaxis in Infants and Toddlers.

BACKGROUND: Undertreatment of anaphylaxis with epinephrine continues to be an unmet need and is a particular challenge among infants and toddlers. OBJECTIVE: To address this gap by identifying barriers and solutions to appropriate and timely administration of epinephrine. METHODS: We conducted a national online survey among primary caregivers of children who experienced a severe food-induced allergic reaction when younger than 36 months. Outcomes of interest included epinephrine use in community and health care settings to treat probable anaphylaxis. RESULTS: Of 264 probable anaphylaxis cases, 39% of infants (aged <12 months) and 61% of toddlers (aged 12-35 months) received epinephrine at any time during the child's most severe allergic reaction (P = .001). A previous diagnosis of a food allergy was reported in 62% of cases where epinephrine was used compared with 26% of cases where epinephrine was not used (P < .001). In children with a previous diagnosis of a food allergy, epinephrine was used in 89% of those who were prescribed an anaphylaxis action plan compared with 50% of those without a plan (P = .001). The adjusted odds ratio for the association between having an anaphylaxis action plan and epinephrine use in cases of probable anaphylaxis was 5.39 (95% confidence interval, 2.18-13.30). CONCLUSIONS: Epinephrine use at any time (including in health care settings) during probable anaphylaxis is more likely in infants and toddlers with a previously diagnosed food allergy than those without diagnosis. The provision of an anaphylaxis action plan is also associated with increased epinephrine use during probable anaphylaxis in this population.

Variation in the Guidelines for the Acute Management of Anaphylaxis in Pediatric Patients: An International Narrative Review.

OBJECTIVES: Evidence-based guidelines have been created and disseminated by multiple organizations to standardize the care of pediatric patients with anaphylaxis. Differences across these guidelines can cause confusion and potentially errors in clinical practice leading to patient harm. The aim of this study was to describe and identify patterns of variation in the current guidelines. METHODS: A narrative review with 3 major components was designed. First, a narrative review of current, peer-reviewed, guidelines published by national and international allergy and immunology, pediatric, and emergency medicine organizations was performed. That was followed by a gray literature review of guidelines by resuscitation councils and national health organizations. The third component focused on the translation of these guidelines at local and institutional levels by reviewing clinical pathways published by academic institutions. RESULTS: With regard to the fixed epinephrine autoinjector dosing, 50% (6 of 12) of the reviewed guidelines offered weight-based and 41.7% (5 of 12) age-based dosing recommendations. Furthermore, different weight cutoffs for the 0.15- and 0.3-mg autoinjectors were identified among guidelines. Variation was identified in the description of intramuscular epinephrine concentration ("1:1000," "1 mg/mL," or both), the recommended concentration for intravenous administration ("1:10,000" or "1:1000"), or the rate of infusion or titration. Eight of the 12 guidelines (66.7%) recommend a dose in milligrams, and 33.3% (4 of 12) in micrograms. Five of 12 (41.7%) used both milliliters and milligrams or micrograms. CONCLUSIONS: Notable variation in the current guidelines for the acute management of anaphylaxis in the pediatric population was identified. Flagging this variability could help inform a consensus-based approach toward harmonization of guidelines, which in turn could streamline the management of anaphylaxis in pediatric patients across the United States, Canada, Ireland, the United Kingdom, Europe, Australia, and New Zealand, and hopefully prevent errors and mitigate patient harm.