Relationship between Tryptase and Hypotension in Anaphylaxis during Anesthesia.

INTRODUCTION: Hypotension is a cardiovascular symptom that appears at the onset of anaphylaxis. It is considered an important factor as it affects the severity of anaphylaxis; however, its details remain to be elucidated. In this study, we investigated the characteristics of hypotension at the onset of anaphylaxis during anesthesia, along with the relationship between hypotension, tryptase and histamine. MATERIALS AND METHODS: The minimum systolic blood pressures of patients diagnosed with anaphylaxis using the clinical diagnostic criteria of the World Allergy Organization guidelines were extracted from electronic anesthesia records. We analyzed changes in tryptase and histamine that were measured after the onset of anaphylaxis. We analyzed the relationship of tryptase and histamine with the minimum systolic blood pressure and the severity of anaphylaxis. RESULTS: Of 55,996 patients, 25 were diagnosed with anaphylaxis during anesthesia (0.045%). Among these patients, the minimum systolic blood pressure was less than 90 mmHg. Furthermore, the minimum systolic blood pressure was inversely correlated with tryptase levels immediately to 1 hour, and 2 to 4 hours after the onset of anaphylaxis. The minimum systolic blood pressure was inversely correlated with the severity of anaphylaxis. The severity of anaphylaxis was positively correlated with tryptase levels immediately to 1 hour, and 2 to 4 hours after the onset of anaphylaxis. CONCLUSION: Hypotension tended to reflect the severity of anaphylaxis. Tryptase is an adjunct in the diagnosis of hypotension and may be a useful indicator of the severity of anaphylaxis. A larger-scale study is needed to validate these results.

Development and Evaluation of Modified Criteria for Infant and Toddler Anaphylaxis.

BACKGROUND: Current clinical criteria for identifying anaphylaxis do not account for unique aspects of infant anaphylaxis presentation and have not been validated in patients less than two years of age. This may contribute to under recognition and is thus an unmet need. OBJECTIVE: To demonstrate age-specific signs and symptoms that more accurately identify anaphylaxis in young children and to develop and compare modified criteria for "likely anaphylaxis" against the widely used 2006 National Institute of Allergy and Infectious Diseases / Food Allergy and Anaphylaxis Network criteria. METHODS: Retrospective chart review of 175 clinical encounters presenting with suspected allergic or anaphylactic reactions to a pediatric emergency department. Modified criteria for likely anaphylaxis were developed and evaluated against the NIAID/FAAN criteria. RESULTS: The study population included 33% infants (ages < 12 months), 39% toddlers (ages 12 months to < 36 months), and 29% children (ages ≥ 36 months). The NIAID/FAAN criteria captured 85% of all patient encounters in the study while the modified criteria captured 98% (p < 0.001). Compared to NIAID/FAAN criteria, modified criteria had 22.8% improved performance among infants (p < 0.001) and 10.3% improved performance among toddlers (p = 0.04). CONCLUSION: We developed modified anaphylaxis clinical criteria that incorporated symptoms specific to infants and young children. The modified criteria increased identification of anaphylaxis in infants and potentially toddlers. Future research is needed to validate our findings on a larger cohort.

IL-4-STAT6 axis amplifies histamine-induced vascular endothelial dysfunction and hypovolemic shock.

BACKGROUND: Mast cell (MC)-derived mediators induce vasodilatation and fluid extravasation, leading to cardiovascular failure in severe anaphylaxis. We have previously revealed a synergistic interaction between the cytokine IL-4 and the MC-derived mediator histamine in modulating vascular endothelial (VE) dysfunction and severe anaphylaxis. The mechanism by which IL-4 exacerbates histamine-induced VE dysfunction and severe anaphylaxis are unknown. OBJECTIVE: To identify the IL-4-induced molecular processes regulating the amplification of histamine-induced VE barrier dysfunction and the severity of IgE-mediated anaphylaxic reactions. METHODS: RNAseq, Western blot, Ca2+ imaging and barrier functional analyses on the vascular endothelial cell line (EA.hy926). Pharmacologic degraders (selective PROTAC (proteolysis-targeting chimera) and genetic (lentiviral shRNA) inhibitors were used to determine the roles of STAT3 and STAT6 in conjunction with in vivo model systems of histamine-induced hypovolemic shock. RESULTS: IL-4 enhancement of histamine-induced VE barrier dysfunction was associated with increased VE-Cadherin degradation, intracellular calcium flux, phospho-Src levels and required transcription and de novo protein synthesis. RNAseq analyses of IL-4 stimulated VE cells identified dysregulation of genes involved in cell proliferation, cell development, and cell growth and transcription factor motif analyses revealed a significant enrichment of differential expressed genes (DEGs) with putative STAT3 and STAT6 motif. IL-4 stimulation in EA.hy926 cells induced both STAT3Y705 and STAT3S727 phosphorylation. Genetic and pharmacologic ablation of VE STAT3 activity revealed a role for STAT3 in basal VE barrier function, however IL-4 enhancement and histamine-induced VE barrier dysfunction was predominantly STAT3-independent. In contrast, IL-4 enhancement and histamine-induced VE barrier dysfunction was STAT6-dependent. Consistent with this finding, pharmacologic knockdown of STAT6 abrogated IL-4-mediated amplification of histamine-induced hypovolemia. CONCLUSIONS: These studies unveil a novel role of the IL-4/ STAT6 signaling axis in the priming of VE cells predisposing to exacerbation of histamine-induced anaphylaxis.

Prediction of pediatric peanut oral food challenge outcomes using machine learning.

Background: Clinical testing, including food-specific skin and serum IgE level tests, provides limited accuracy to predict food allergy. Confirmatory oral food challenges (OFCs) are often required, but the associated risks, cost, and logistic difficulties comprise a barrier to proper diagnosis. Objective: We sought to utilize advanced machine learning methodologies to integrate clinical variables associated with peanut allergy to create a predictive model for OFCs to improve predictive performance over that of purely statistical methods. Methods: Machine learning was applied to the Learning Early about Peanut Allergy (LEAP) study of 463 peanut OFCs and associated clinical variables. Patient-wise cross-validation was used to create ensemble models that were evaluated on holdout test sets. These models were further evaluated by using 2 additional peanut allergy OFC cohorts: the IMPACT study cohort and a local University of Michigan cohort. Results: In the LEAP data set, the ensemble models achieved a maximum mean area under the curve of 0.997, with a sensitivity and specificity of 0.994 and 1.00, respectively. In the combined validation data sets, the top ensemble model achieved a maximum area under the curve of 0.871, with a sensitivity and specificity of 0.763 and 0.980, respectively. Conclusions: Machine learning models for predicting peanut OFC results have the potential to accurately predict OFC outcomes, potentially minimizing the need for OFCs while increasing confidence in food allergy diagnoses.

[EPIPEN INSTRUCTIONS FOR ANAPHYLAXIS PATIENTS DURING DISPENSING: FACTORS RELATED TO THE QUALITY OF PHARMACISTS' INSTRUCTIONS].

BACKGROUND AND AIM: We previously reported that pharmacists working in pharmacies don't have enough knowledge and enough experience teaching anaphylaxis (An) and EpiPen use. We administered a questionnaire survey to pharmacists with experience handling EpiPen prescriptions. We investigated the relationship between the questionnaire results and the factors in the pharmacists' background regarding the explanation and guidance to patients. RESULTS: The percentage of pharmacists working in pharmacies who provided guidance using visual information and demonstrations was insufficient. Moreover, this figure decreased after the second guidance session. Objective confirmation of patient understanding was also insufficient. The results indicated that self-examination and participation in drug information sessions were important background factors for pharmacists who provided detailed guidance to patients. DISCUSSION: For appropriate long-term management of their condition, An patients must master the EpiPen technique. Pharmacists' guidance plays a critical role in this regard. A support system should be established for proper instruction of pharmacy patients by improving pharmacists' self-education and other educational opportunities.

Oral mucosa effectively protects against peanut allergy in mice.

BACKGROUND: Oral consumption of peanut products early in life reduces the incidence of peanut allergy in children. However, little is known about whether exposure via the oral mucosa alone is sufficient, or if the gastrointestinal tract must be engaged to protect against peanut allergy. OBJECTIVE: We used a mouse model and examined the effects of peanut allergen administration only to the oral cavity on allergy development induced by environmental exposure. METHODS: Naïve BALB/c mice were administered peanut flour (PNF) sublingually, followed by epicutaneous exposure to PNF to mimic a human condition. The sublingual volume was adjusted to engage only the oral cavity and prevent it from reaching the esophagus or gastrointestinal tract. The efficacy was evaluated by examining the anaphylactic response, antibody titers, and T follicular helper (Tfh) cells. RESULTS: The mice exposed epicutaneously to PNF developed peanut allergy as demonstrated by increased plasma levels of peanut-specific IgE and the manifestation of acute systemic anaphylaxis upon intraperitoneal challenge with peanut extract. The development of peanut allergy was suppressed when mice had been given PNF sublingually before epicutaneous exposure. There were fewer Tfh cells in the skin-draining lymph nodes of mice that received sublingual PNF compared with PBS. Suppression of IgE production was observed with sublingual PNF at one-tenth of the intragastric PNF dose. DISCUSSION: Administration of peanut allergens only to the oral cavity effectively prevents the development of peanut allergy. The capacity of the oral mucosa to promote immunologic tolerance needs to be evaluated further to prevent food allergy.

Structural analysis of human IgE monoclonal antibody epitopes on dust mite allergen Der p 2.

BACKGROUND: Human IgE (hIgE) mAbs against major mite allergen Der p 2 developed using human hybridoma technology were used for IgE epitope mapping and analysis of epitopes associated with the hIgE repertoire. OBJECTIVE: We sought to elucidate the new hIgE mAb 4C8 epitope on Der p 2 and compare it to the hIgE mAb 2F10 epitope in the context of the allergenic structure of Der p 2. METHODS: X-ray crystallography was used to determine the epitope of anti-Der p 2 hIgE mAb 4C8. Epitope mutants created by targeted mutagenesis were analyzed by immunoassays and in vivo using a human high-affinity IgE receptor (FcεRIα)-transgenic mouse model of passive systemic anaphylaxis. RESULTS: The structure of recombinant Der p 2 with hIgE mAb 4C8 Fab was determined at 3.05 Å. The newly identified epitope region does not overlap with the hIgE mAb 2F10 epitope or the region recognized by 3 overlapping hIgE mAbs (1B8, 5D10, and 2G1). Compared with wild-type Der p 2, single or double 4C8 and 2F10 epitope mutants bound less IgE antibodies from allergic patients by as much as 93%. Human FcεRIα-transgenic mice sensitized by hIgE mAbs, which were susceptible to anaphylaxis when challenged with wild-type Der p 2, could no longer cross-link FcεRI to induce anaphylaxis when challenged with the epitope mutants. CONCLUSIONS: These data establish the structural basis of allergenicity of 2 hIgE mAb nonoverlapping epitopes on Der p 2, which appear to make important contributions to the hIgE repertoire against Der p 2 and provide molecular targets for future design of allergy therapeutics.

Impaired high-density lipoprotein function and endothelial barrier stability in severe anaphylaxis.

BACKGROUND: Growing evidence demonstrates the importance of high- and low-density lipoprotein cholesterol in certain immune and allergy-mediated diseases. OBJECTIVE: This study aimed to evaluate levels of high- and low-density lipoprotein cholesterol and apolipoproteins A1 and B in sera from a cohort of patients presenting with hypersensitivity reactions. We further assessed the function of high-density lipoprotein particles as well as their involvement in the molecular mechanisms of anaphylaxis. METHODS: Lipid profile determination was performed in paired (acute and baseline) serum samples from 153 patients. Thirty-eight experienced a non-anaphylactic reaction and 115 had an anaphylactic reaction (88 moderate and 27 severe). Lecithin cholesterol acyl transferase activity was assessed in patient sera, and we also evaluated macrophage cholesterol efflux in response to the serum samples. Last, the effect of anaphylactic-derived high-density lipoprotein (HDL) particles on the endothelial barrier was studied. Detailed methods are provided in the Methods section in this article's Online Repository available at www.jacionline.org. RESULTS: Serum samples from severe anaphylactic reactions show statistically significant low levels of HDL cholesterol, low-density lipoprotein cholesterol, and apolipoproteins A1 and B, which points to their possible role as biomarkers. Specifically, HDL particles play a protective role in cardiovascular diseases. Using functional human serum cell assays, we observed impaired capacity of apolipoprotein B-depleted serum to induce macrophage cholesterol efflux in severe anaphylactic reactions. In addition, purified HDL particles from human anaphylactic sera failed to stabilize and maintain the endothelial barrier. CONCLUSION: These results encourage further research on HDL functions in severe anaphylaxis, which may lead to new diagnostic and therapeutic strategies.

Balancing Benefits and Risks: A Literature Review on Hypersensitivity Reactions to Human G-CSF (Granulocyte Colony-Stimulating Factor).

Human granulocyte colony-stimulating factor (G-CSF) is a granulopoietic growth factor used in the treatment of neutropenia following chemotherapy, myeloablative treatment, or healthy donors preparing for allogeneic transplantation. Few hypersensitivity reactions (HRs) have been reported, and its true prevalence is unknown. We aimed to systematically characterize G-CSF-induced HRs while including a comprehensive list of adverse reactions. We reviewed articles published before January 2024 by searching in the PubMed, Embase, Cochrane Library, and Web of Science databases using a combination of the keywords listed, selected the ones needed, and extracted relevant data. The search resulted in 68 entries, 17 relevant to our study and 7 others found from manually searching bibliographic sources. A total of 40 cases of G-CSF-induced HR were described and classified as immediate (29) or delayed (11). Immediate ones were mostly caused by filgrastim (13 minimum), with at least 9 being grade 5 on the WAO anaphylaxis scale. Delayed reactions were mostly maculopapular exanthemas and allowed for the continuation of G-CSF. Reactions after first exposure frequently appeared and were present in at least 11 of the 40 cases. Only five desensitization protocols have been found concerning the topic at hand in the analyzed data. We believe this study brings to light the research interest in this topic that could benefit from further exploration, and propose regular updating to include the most recently published evidence.

Differences in the Course, Diagnosis, and Treatment of Food Allergies Depending on Age-Comparison of Children and Adults.

Food allergy (FA) has become a common global public health issue, with a growing prevalence in the modern world and a significant impact on the lives of patients, their families, and caregivers. It affects every area of life and is associated with elevated costs. Food allergy is an adverse immune reaction that occurs in response to a given food. The symptoms vary from mild to severe and can lead to anaphylaxis. This is why it is important to focus on the factors influencing the occurrence of food allergies, specific diagnostic methods, effective therapies, and especially prevention. Recently, many guidelines have emphasized the impact of introducing specific foods into a child's diet at an early age in order to prevent food allergies. Childhood allergies vary with age. In infants, the most common allergy is to cow's milk. Later in life, peanut allergy is more frequently diagnosed. Numerous common childhood allergies can be outgrown by adulthood. Adults can also develop new IgE-mediated FA. The gold standard for diagnosis is the oral provocation test. Skin prick tests, specific IgE measurements, and component-resolved diagnostic techniques are helpful in the diagnosis. Multiple different approaches are being tried as possible treatments, such as immunotherapy or monoclonal antibodies. This article focuses on the prevention and quality of life of allergic patients. This article aims to systematize the latest knowledge and highlight the differences between food allergies in pediatric and adult populations.

Assessment of potential adverse events following the 2022-2023 seasonal influenza vaccines among U.S. adults aged 65 years and older.

BACKGROUND: While safety of influenza vaccines is well-established, some studies have suggested potential associations between influenza vaccines and certain adverse events (AEs). This study examined the safety of the 2022-2023 influenza vaccines among U.S. adults ≥ 65 years. METHODS: A self-controlled case series compared incidence rates of anaphylaxis, encephalitis/encephalomyelitis, Guillain-Barré Syndrome (GBS), and transverse myelitis following 2022-2023 seasonal influenza vaccinations (i.e., any, high-dose or adjuvanted) in risk and control intervals among Medicare beneficiaries ≥ 65 years. We used conditional Poisson regression to estimate incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) adjusted for event-dependent observation time and seasonality. Analyses also accounted for uncertainty from outcome misclassification where feasible. For AEs with any statistically significant associations, we stratified results by concomitant vaccination status. RESULTS: Among 12.7 million vaccine recipients, we observed 76 anaphylaxis, 276 encephalitis/encephalomyelitis, 134 GBS and 75 transverse myelitis cases. Only rates of anaphylaxis were elevated in risk compared to control intervals. With all adjustments, an elevated, but non-statistically significant, anaphylaxis rate was observed following any (IRR: 2.40, 95% CI: 0.96-6.03), high-dose (IRR: 2.31, 95% CI: 0.67-7.91), and adjuvanted (IRR: 3.28, 95% CI: 0.71-15.08) influenza vaccination; anaphylaxis IRRs were 2.54 (95% CI: 0.49-13.05) and 1.64 (95% CI: 0.38-7.05) for persons with and without concomitant vaccination, respectively. CONCLUSIONS: Rates of encephalitis/encephalomyelitis, GBS, or transverse myelitis were not elevated following 2022-2023 seasonal influenza vaccinations among U.S. adults ≥ 65 years. There was an increased rate of anaphylaxis following influenza vaccination that may have been influenced by concomitant vaccination.

Epinephrine induced lactic acidosis during the management of anaphylactic shock: a case report.

In a case of contrast media-induced anaphylactic shock managed with epinephrine, a 57-year-old male developed lactic acidosis without cardiogenic shock or global hypoperfusion, highlighting epinephrine's potential to trigger lactic acidosis. Despite previous management of similar reactions with antihistamines and corticosteroids, this case required intensive care unit admission and emergency intervention, with lactate levels peaking alarmingly. The rapid resolution of acidosis following epinephrine discontinuation underscores the need for careful monitoring and the consideration of alternative vasopressor strategies in severe anaphylaxis, illustrating the complex relationship between epinephrine's metabolic effects and anaphylaxis-induced tissue hypoperfusion.

Anaphylaxis triggered by a hidden threat: A rare hydatid disease case report.

INTRODUCTION AND IMPORTANCE: Hydatid disease, caused by Echinococcus granulosus, is a zoonotic infection prevalent in specific regions, including Tunisia. Complications are rare but potentially life-threatening. This case report highlights the significance of early diagnosis and intervention in a unique case where anaphylaxis resulted from minor abdominal trauma in a 17-year-old male with an undiagnosed hydatid cyst. CASE REPORT: The patient arrived at the emergency department with syncope and hypotension after a classroom accident. Physical examination showed an urticarial rash and abdominal tenderness. Anaphylactic shock was diagnosed and promptly treated. A computed tomography scan confirmed a ruptured liver hydatid cyst. The patient received anthelmintic treatment and underwent conservative surgical management. Intraoperatively, a second anaphylactic shock occurred and was promptly treated. The post-operative course was uneventful, and histopathological analysis identified Echinococcus granulosus. CLINICAL DISCUSSION: This case emphasizes the importance of recognizing hydatid disease as a potential cause of anaphylaxis post-trauma, even in asymptomatic patients. Early diagnosis through imaging is crucial for prompt intervention. Surgical management should be considered, with conservative approaches favored in acute cases. Post-surgical albendazole treatment is essential to prevent recurrence. CONCLUSION: This report serves as a valuable reference for healthcare professionals, highlighting the need for heightened clinical suspicion in cases like this. It underscores the significance of considering hydatid cyst rupture in the differential diagnosis of anaphylaxis following blunt trauma. Awareness among pediatricians, emergency physicians, and primary care providers can lead to early diagnosis and better patient outcomes, preventing severe complications or fatalities associated with this rare condition.

Perioperative Anaphylaxis in Japanese Secondary Care Institutions: Incidence, Causes, and the Imperative for Improved Diagnostic Practices.

Background This research investigates the incidence, suspected causes, and diagnostic procedures for perioperative anaphylaxis (POA), a potentially severe complication, in secondary care hospitals across Japan. Methodology We surveyed Saiseikai hospitals and gathered data on surgical procedures, POA occurrences, potential triggers, and diagnostic methods. Results Among 70,523 surgeries, seven were associated with POA, resulting in an approximate incidence rate of 0.01%. Rocuronium was the most commonly suspected trigger, followed by sugammadex, latex, and angiography contrast agents. Despite the importance of skin tests as the most basic and crucial diagnostic method, they were conducted in only three instances. No in vitro tests for drug identification were conducted, and in four cases, the cause was determined merely based on the timing of drug administration, indicating significant diagnostic limitations. Conclusions The study underscores the critical situation in Japan regarding insufficient diagnostic practices and difficulties in identifying triggering drugs rather than the consistent prevalence of POA in secondary care facilities. The findings emphasize the need for improved diagnostic proficiency and more rigorous drug identification practices to ensure prompt and accurate POA diagnosis. It is essential to conduct further research and interventions to increase patient safety during the perioperative period in secondary care settings.

Improving clinical practice through patient registries in allergy and immunology.

Patient registries are a mechanism for collecting data on allergic and immunologic diseases that provide important information on epidemiology and outcomes that can ultimately improve patient care. Key criteria for establishing effective registries include the use of a clearly defined purpose, identifying the target population and ensuring consistent data collection. Registries in allergic diseases include those for diseases such as inborn errors of immunity, food allergy, asthma and anaphylaxis, pharmacological interventions in vulnerable populations, and adverse effects of pharmacologic interventions including hypersensitivity reactions to drugs and vaccines. Important insights gained from patient registries in our field include contributions in phenotype and outcomes in inborn errors of immunity, the risk for adverse reactions in food-allergic patients in multiple settings, the benefits and risk of biologic medications for asthma during pregnancy, vaccine safety, and the categorization and genetic determination of risk for severe cutaneous adverse reactions to medications. Impediments to the development of clinically meaningful patient registries include the lack of funding resources for registry establishment and the quality, quantity, and consistency of available data. Despite these drawbacks, high-quality and successful registries are invaluable in informing clinical practice and improving outcomes in patients with allergic and immunological diseases.

Evaluation of treatment and long-term management of anaphylaxis in pediatric departments of Greece: a 2-year nationwide survey.

BACKGROUND: Anaphylaxis proportions of incidence are increasing globally. However, limited data are available regarding anaphylaxis in the pediatric population of Greece. PURPOSE: The aim of the study was to evaluate management of anaphylaxis in Greek pediatric departments. METHODS: We performed a questionnaire-based study of children aged less than 16 years presenting with anaphylaxis in 10 national pediatric hospitals over a period of 2 years. Management of anaphylaxis was assessed prior to and after an informative intervention. RESULTS: In all, 127 cases of anaphylaxis were identified. Epinephrine was administered in almost half of all cases (51.2%), predominantly through intramuscular route (88.5%), while the majority of anaphylaxis patients were treated with antihistamines (92.9%) and corticosteroids (70.1%). Epinephrine was more likely administered by physicians if the elicitor was a drug (P < 0.003). Regarding long-term management, an epinephrine auto-injector was prescribed in 66.9% of patients. Follow-up information was available for most of the patients (92.9%), the majority of whom (76.3%) were referred to an allergist. More than half of these patients (63.6%) had a documented allergy follow-up, which identified a causative allergen in 53.3% of cases. No statistically significant differences were recorded prior to and after the intervention regarding management of anaphylaxis. CONCLUSIONS: This nationwide study highlighted the necessity of further improvement in terms of anaphylaxis treatment and secondary prevention measures. This presupposes appropriate education and training of healthcare professionals, thus contributing to proper and comprehensive care of the pediatric population.

Alpha-gal syndrome: when treatment of hypovolemic shock can lead to anaphylaxis.

Delayed anaphylaxis after ingestion of red meat because of galactose-alpha-1,3-galactose (alpha-gal) syndrome has increased in recent years. The mechanism involves an immunoglobulin E reaction to alpha-gal, a molecule found in mammalian meat, dairy products, medications and excipients containing mammalian-derived components, and tick salivary glycans. Sensitization occurs due to the bite of a lone star tick and the transmission of alpha-gal molecules into person's bloodstream. We describe a case of alpha-gal syndrome with severe food, drug, and perioperative allergy in which anaphylaxis with hypovolemic shock occurred immediately after an emergency surgical procedure, when a gelatin-containing drug was injected. This case study confirms that the clinical manifestations of alpha-gal syndrome could be different depending on the route of administration, with immediate reactions if an alpha-gal-containing drug is injected and delayed type allergic manifestations occurring several hours after oral intake. The purpose of this report is to highlight the importance of risk communication in case of exposure to medical products and surgical procedures of patients with alpha-gal syndrome and to encourage drug manufacturers to indicate clearly the origin of excipients in product literature.