Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

Overview of Allergy and Anaphylaxis.

Allergic reactions and anaphylaxis occur on a severity continuum from mild and self-limited to potentially life-threatening or fatal reactions. Anaphylaxis is typically a multiorgan phenomenon involving a broad range of effector cells and mediators. Emergency department visits for anaphylaxis are increasing, especially among children. There is a broad differential diagnosis for anaphylaxis, and the diagnosis of anaphylaxis can be aided by the use of the National Institutes of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network clinical diagnostic criteria. Risk factors for severe anaphylaxis include older age, delayed epinephrine administration, and cardiopulmonary comorbidities.

Updated guidance regarding the risk of allergic reactions to COVID-19 vaccines and recommended evaluation and management: A GRADE assessment and international consensus approach.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.

Refractory Anaphylaxis: A New Entity for Severe Anaphylaxis.

Anaphylaxis reactions lie on a spectrum of severity, ranging from relatively mild lower respiratory involvement (depending on the definition of anaphylaxis used) to more severe reactions that are refractory to initial treatment with epinephrine and may rarely cause death. A variety of grading scales exist to characterize severe reactions, but there is a lack of consensus about the optimal approach to define severity. More recently, a new entity called refractory anaphylaxis (RA) has emerged in the literature, characterized by the persistence of anaphylaxis despite initial epinephrine treatment. However, slightly different definitions have been proposed to date. In this Rostrum, we review these definitions as well as data relating to epidemiology, elicitors, risk factors, and management of RA. We propose a need to align the different definitions for RA, to improve epidemiological surveillance, advance our understanding of the pathophysiology of RA, and optimize management strategies to reduce morbidity and mortality.

How to define severity: A review of allergic reaction severity scoring systems.

Numerous scoring systems have been developed to improve and standardize the diagnosis and management of acute allergic reactions and anaphylaxis; however, considerable variability exists among these systems. This review article discusses existing severity scoring systems and identifies specific knowledge gaps that remain. Future research is needed to resolve the limitations of existing grading systems, including attempting to link reaction severity with treatment advice and conducting validation studies in different clinical settings, patient populations, and geographies to promote grading system application and dissemination in both clinical care and research.

Trends and Variation in Pediatric Anaphylaxis Care From 2016 to 2022.

BACKGROUND: Variation in the use of treatments and hospitalization for anaphylaxis would suggest a lack of consensus in therapeutic approach. OBJECTIVE: To evaluate trends and practice variation in the emergency department (ED) care of children with anaphylaxis in a large US cohort. METHODS: We conducted a 48-site retrospective cohort study using the Pediatric Health Information System from January 2016 through September 2022. Children younger than 18 years with a primary diagnosis of anaphylaxis were included. Care trends were assessed using negative binomial regression modeling. Rates of medication use, hospitalizations, and revisits were reported as medians with interquartile ranges (IQRs). RESULTS: There were 42,909 ED visits for anaphylaxis, with a 4.2% per-year increase in visit incidence (95% CI, 1.8-6.7) during the study period. The median hospitalization rate was 3.5% (IQR, 2.2-6.0), and the 3-day ED revisit rate was 0.6% (IQR, 0.4-0.9). The hospital-level median use of therapies included intramuscular epinephrine (55.3%; IQR, 50.1-59.9), systemic steroids (73.8%; IQR, 63.9-81.4), antihistamines (59.9%; IQR, 53.5-65.5), H2-receptor antagonists (56.8%; IQR, 42.3-66.2), bronchodilators (15.1%; IQR, 12.5-17.0), inhaled epinephrine (1.1%; IQR, 0.6-1.9), and fluid boluses (19.8%; IQR, 11.3-29.3). Severe reactions requiring intensive care unit admission (1.5%; IQR, 0.8-2.2), vasopressors (0.3%; IQR, 0.0-0.6), and intubation (0.2%; IQR, 0.0-0.3) were rare. CONCLUSIONS: ED visits for anaphylaxis increased during the study period, but hospitalization rates were low. Substantial variation exists between EDs regarding the use of anaphylaxis therapies, supporting the need for future research to evaluate the efficacy of these medications.

Who Needs Epinephrine? Anaphylaxis, Autoinjectors, and Parachutes.

International guidelines stipulate that intramuscular (IM) epinephrine (adrenaline) is the first-line treatment for anaphylaxis, with an established good safety profile. The availability of epinephrine autoinjectors (EAI) has greatly facilitated the lay administration of IM epinephrine in community settings. However, key areas of uncertainty remain around epinephrine usage. These include variations in prescribing EAI, what symptoms should prompt epinephrine administration, whether emergency medical services (EMS) need to be contacted after administration, and whether epinephrine administered via EAI reduces mortality from anaphylaxis or improves quality of life measures. We provide a balanced commentary on these issues. There is increasing recognition that a poor response to epinephrine, particularly after 2 doses, is a useful marker of severity and the need for urgent escalation. It is likely that patients who respond to a single epinephrine dose do not require EMS activation or emergency department transfer, but data are needed to demonstrate the safety of this approach. Lastly, patients at risk of anaphylaxis must be counseled against over-reliance on EAI alone.

Reducing Pediatric Emergency Department Prescription Errors.

BACKGROUND: Prescription errors are a significant cause of iatrogenic harm in the health care system. Pediatric emergency department (ED) patients are particularly vulnerable to error. We sought to decrease prescription errors in an academic pediatric ED by 20% over a 24-month period by implementing identified national best practice guidelines. METHODS: From 2017 to 2019, a multidisciplinary, fellow-driven quality improvement (QI) project was conducted using the Model for Improvement. Four key drivers were identified including simplifying the electronic order entry into prescription folders, improving knowledge of dosing by indication, increasing error feedback to prescribers, and creating awareness of common prescription pitfalls. Four interventions were subsequently implemented. Outcome measures included prescription errors per 1000 prescriptions written for all medications and top 10 error-prone antibiotics. Process measures included provider awareness and use of prescription folders; the balancing measure was provider satisfaction. Differences in outcome measures were assessed by statistical process control methodology. Process and balancing measures were analyzed using 1-way analysis of variance and χ2 testing. RESULTS: Before our interventions, 8.6 errors per 1000 prescriptions written were identified, with 62% of errors from the top 10 most error-prone antibiotics. After interventions, error rate per 1000 prescriptions decreased from 8.6 to 4.5 overall and from 20.1 to 8.8 for top 10 error-prone antibiotics. Provider awareness of prescription folders was significantly increased. CONCLUSION: QI efforts to implement previously defined best practices, including simplifying and standardizing computerized provider order entry (CPOE), significantly reduced prescription errors. Synergistic effect of educational and technological efforts likely contributed to the measured improvement.

Overview of Allergy and Anaphylaxis.

Allergic reactions and anaphylaxis occur on a severity continuum from mild and self-limited to potentially life-threatening or fatal reactions. Anaphylaxis is typically a multiorgan phenomenon involving a broad range of effector cells and mediators. Emergency department visits for anaphylaxis are increasing, especially among children. There is a broad differential diagnosis for anaphylaxis, and the diagnosis of anaphylaxis can be aided by the use of the National Institutes of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network clinical diagnostic criteria. Risk factors for severe anaphylaxis include older age, delayed epinephrine administration, and cardiopulmonary comorbidities.

Anaphylaxis: Data Gaps and Research Needs.

There are significant anaphylaxis data and knowledge gaps that result in suboptimal patient care and outcomes. To address these gaps there is need for collaborative, multidisciplinary research networks to strategically design practice changing research specific to the following anaphylaxis themes: Population Science, Basic and Translational Sciences, Acute Management, and Long-Term Management. Top priorities are to refine anaphylaxis diagnostic criteria, identify accurate diagnostic and predictive anaphylaxis biomarkers, standardize postanaphylaxis care (observation periods, hospitalization criteria), and determine immunotherapy best practices. Addressing these gaps will result in improved, optimal care and clinical outcomes for patients with or at risk of anaphylaxis.

Anaphylaxis knowledge gaps and future research priorities: A consensus report.

BACKGROUND: Despite a better understanding of the epidemiology, pathogenesis, and management of patients with anaphylaxis, there remain knowledge gaps. Enumerating and prioritizing these gaps would allow limited scientific resources to be directed more effectively. OBJECTIVE: We sought to systematically describe and appraise anaphylaxis knowledge gaps and future research priorities based on their potential impact and feasibility. METHODS: We convened a 25-member multidisciplinary panel of anaphylaxis experts. Panelists formulated knowledge gaps/research priority statements in an anonymous electronic survey. Four anaphylaxis themed writing groups were formed to refine statements: (1) Population Science, (2) Basic and Translational Sciences, (3) Emergency Department Care/Acute Management, and (4) Long-Term Management Strategies and Prevention. Revised statements were incorporated into an anonymous electronic survey, and panelists were asked to rate the impact and feasibility of addressing statements on a continuous 0 to 100 scale. RESULTS: The panel generated 98 statements across the 4 anaphylaxis themes: Population Science (29), Basic and Translational Sciences (27), Emergency Department Care/Acute Management (24), and Long-Term Management Strategies and Prevention (18). Median scores for impact and feasibility ranged from 50.0 to 95.0 and from 40.0 to 90.0, respectively. Key statements based on median rating for impact/feasibility included the need to refine anaphylaxis diagnostic criteria, identify reliable diagnostic, predictive, and prognostic anaphylaxis bioassays, develop clinical prediction models to standardize postanaphylaxis observation periods and hospitalization criteria, and determine immunotherapy best practices. CONCLUSIONS: We identified and systematically appraised anaphylaxis knowledge gaps and future research priorities. This study reinforces the need to harmonize scientific pursuits to optimize the outcomes of patients with and at risk of anaphylaxis.

The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Severity grading system for acute allergic reactions: A multidisciplinary Delphi study.

BACKGROUND: There is no widely adopted severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions, thus limiting the ability to optimize and standardize management practices and advance research. OBJECTIVE: The aim of this study was to develop a severity grading system for acute allergic reactions for use in clinical care and research. METHODS: From May to September 2020, we convened a 21-member multidisciplinary panel of allergy and emergency care experts; 9 members formed a writing group to critically appraise and assess the strengths and limitations of prior severity grading systems and develop the structure and content for an optimal severity grading system. The entire study panel then revised the grading system and sought consensus by utilizing Delphi methodology. RESULTS: The writing group recommended that an optimal grading system encompass the severity of acute allergic reactions on a continuum from mild allergic reactions to anaphylactic shock. Additionally, the severity grading system must be able to discriminate between clinically important differences in reaction severity to be relevant in research while also being intuitive and straightforward to apply in clinical care. Consensus was reached for all elements of the proposed severity grading system. CONCLUSION: We developed a consensus severity grading system for acute allergic reactions, including anaphylactic and nonanaphylactic reactions. Successful international validation, refinement, dissemination, and application of the grading system will improve communication among providers and patients about the severity of allergic reactions and will help advance future research.

PEMCRC anaphylaxis study protocol: a multicentre cohort study to derive and validate clinical decision models for the emergency department management of children with anaphylaxis.

INTRODUCTION: There remain significant knowledge gaps about the management and outcomes of children with anaphylaxis. These gaps have led to practice variation regarding decisions to hospitalise children and length of observation periods following treatment with epinephrine. The objectives of this multicentre study are to (1) determine the prevalence of and risk factors for severe, persistent, refractory and biphasic anaphylaxis, as well as persistent and biphasic non-anaphylactic reactions; (2) derive and validate prediction models for emergency department (ED) discharge; and (3) determine data-driven lengths of ED and inpatient observation prior to discharge to home based on initial reaction severity. METHODS AND ANALYSIS: The study is being conducted through the Pediatric Emergency Medicine Collaborative Research Committee (PEMCRC). Children 6 months to less than 18 years of age presenting to 30 participating EDs for anaphylaxis from October 2015 to December 2019 will be eligible. The primary outcomes for each objective are (1) severe, persistent, refractory or biphasic anaphylaxis, as well as persistent or biphasic non-anaphylactic reactions; (2) safe ED discharge, defined as no receipt of acute anaphylaxis medications or hypotension beyond 4 hours from first administered dose of epinephrine; and (3) time from first to last administered dose of epinephrine and vasopressor cessation. Analyses for each objective include (1) descriptive statistics to estimate prevalence and generalised estimating equations that will be used to investigate risk factors for anaphylaxis outcomes, (2) least absolute shrinkage and selection operator regression and binary recursive partitioning to derive and validate prediction models of children who may be candidates for safe ED discharge, and (3) Kaplan-Meier analyses to assess timing from first to last epinephrine doses and vasopressor cessation based on initial reaction severity. ETHICS AND DISSEMINATION: All sites will obtain institutional review board approval; results will be published in peer-reviewed journals and disseminated via traditional and social media, blogs and online education platforms.

Persistent, refractory, and biphasic anaphylaxis: A multidisciplinary Delphi study.

BACKGROUND: The use of inconsistent definitions for anaphylaxis outcomes limits our understanding of the natural history and epidemiology of anaphylaxis, hindering clinical practice and research efforts. OBJECTIVE: Our aim was to develop consensus definitions for clinically relevant anaphylaxis outcomes by utilizing a multidisciplinary group of clinical and research experts in anaphylaxis. METHODS: Using Delphi methodology, we developed agenda topics and drafted questions to review during monthly conference calls. Through online surveys, a 19-member panel consisting of experts in allergy and/or immunology and emergency medicine rated their level of agreement with the appropriateness of statements on a scale of 1 to 9. A median value of 1.0 to 3.4 was considered inappropriate, a median value of 3.5 to 6.9 was considered uncertain, and a median value of 7.0 to 9.0 was considered appropriate. A disagreement index was then calculated, with values less than 1.0 categorized as "consensus reached." If consensus was not reached after the initial survey, subsequent surveys incorporating the aggregate de-identified responses from prior surveys were sent to panel members. This process was repeated until consensus was reached or 4 survey rounds had been completed, after which the question was categorized as "no consensus reached." RESULTS: The panel developed outcome definitions for persistent, refractory, and biphasic anaphylaxis, as well as for persistent and biphasic nonanaphylactic reactions. There was also consensus among panel members regarding the need to develop an anaphylaxis severity grading system. CONCLUSION: Dissemination and application of these definitions in clinical care and research will help standardize the terminology used to describe anaphylaxis outcomes and serve as the foundation for future research, including research aimed at development of an anaphylaxis severity grading system.

Are Children with a History of Asthma More Likely to Have Severe Anaphylactic Reactions? A Retrospective Cohort Study.

OBJECTIVE: To assess whether a history of asthma was associated with anaphylaxis severity in children hospitalized for anaphylaxis. STUDY DESIGN: Retrospective cohort study of children ≤21 years old hospitalized for anaphylaxis from 2009 to 2016. The primary outcome was severe anaphylactic reactions defined by examination findings (stridor, respiratory distress, or hypotension) or administered therapies (≥2 dose of intramuscular epinephrine, continuous albuterol, vasopressors, or positive pressure ventilation). Multivariable analyses were used to assess whether a history of asthma was associated with severe anaphylactic reactions, adjusting for patient age, allergen, and history of atopic dermatitis or anaphylaxis. RESULTS: Among 603 children hospitalized for anaphylaxis, 231 (38.3%) had a history of asthma. Children with a history of asthma were older (median age, 6.6 years [IQR, 3.6-12.1] vs 4.0 years [IQR, 1.6-9.3]), more likely to have a history of anaphylaxis (38.1% vs 18.0%), and have food as the inciting allergen (68.0% vs 52.2%). Children with a history of asthma were not more likely to have severe anaphylactic reactions (OR, 0.97; 95% CI, 0.67-1.39). CONCLUSIONS: Children hospitalized for anaphylaxis with a history of asthma were not more likely to have severe anaphylactic reactions compared with children without asthma. This study supports managing children with anaphylaxis based on the severity of symptomatology, and, if validated, clinicians should not consider asthma comorbidity as a stand-alone criterion for hospitalization.