Changing the history of anaphylaxis mortality statistics through the World Health Organization's International Classification of Diseases-11.

We review the history of the classification and coding changes for anaphylaxis and provide current and perspective information in the field. In 2012, an analysis of Brazilian data demonstrated undernotification of anaphylaxis-related deaths because of the difficulties of coding using the International Classification of Diseases, 10th Revision. This work triggered strategic international actions supported by the Joint Allergy Academies and the International Classification of Diseases World Health Organization (WHO) leadership to update the classification of allergic disorders for the International Classification of Diseases, 11th Revision (ICD-11), which resulted in construction of the pioneer "Allergic and hypersensitivity conditions" chapter. The usability of the new framework has been tested by evaluating the same data published in 2012 from the ICD-11 perspective. Coding accuracy was much improved, reaching 95% for definite anaphylaxis. As the results were provided to the WHO Mortality Reference Group, coding rules have been changed, allowing anaphylaxis to be recorded as an underlying cause of death in official mortality statistics. The mandatory use of ICD-11 from January 2022 for documenting cause of death could have 2 immediate consequences: (1) the reported number of anaphylaxis-related deaths might increase because of more appropriate coding and (2) the cross-sectional and longitudinal mortality data generated might ultimately lead to a better understanding of anaphylaxis epidemiology and improved health policies directed at reducing anaphylaxis-related mortality.

Guiding Principles for the Recognition, Diagnosis, and Management of Infants with Anaphylaxis: An Expert Panel Consensus.

Infant anaphylaxis is an emerging risk, with food allergy the most common cause. Although the presentation of anaphylaxis involves the same systems as in older children and adults, there are real-world challenges to identifying symptoms of an allergic emergency in nonverbal children, as well as implementing optimal treatment. Recognition of anaphylaxis in infants can be challenging because allergic symptoms and certain normal infant behaviors may overlap. Intramuscular epinephrine is the treatment of choice for infants, as it is for older children and adults, and an epinephrine autoinjector approved by the Food and Drug Administration is now available for infants weighing between 7.5 and 15 kg. A panel of experts sought to develop guiding principles for the recognition, diagnosis, and management of anaphylaxis in infants, and provide a framework for the development of new guidelines and future research. Accordingly, anaphylaxis emergency action planning for infants was addressed by the panel. In considering formation of future infant anaphylaxis guidelines, health care providers should be aware of the needs to improve the recognition, diagnosis, and management of infants with anaphylaxis. Future research should identify and validate clinical criteria for the diagnosis of anaphylaxis in infants, as well as risk factors for the most severe reactions.

Critical view of anaphylaxis epidemiology: open questions and new perspectives.

In contrast to the majority of allergic or hypersensitivity conditions, worldwide anaphylaxis epidemiological data remain sparse with low accuracy, which hampers comparable morbidity statistics. Data can differ widely depending on a number of variables. In the current document we reviewed the forms on which anaphylaxis has been defined and classified; and how it can affect epidemiological data. With regards to the methods used to capture morbidity statistics, we observed the impact of the anaphylaxis coding utilizing the World Health Organization's International Classification of Diseases. As an outcome and depending on the anaphylaxis definition, we extracted the cumulative incidence, which may not reflect the real number of new cases. The new ICD-11 anaphylaxis subsection developments and critical view of morbidity statistics data are discussed in order to reach new perspectives on anaphylaxis epidemiology.

Adherence with epinephrine autoinjector prescriptions in primary care.

BACKGROUND: The aim of this study was to estimate primary adherence for epinephrine autoinjector (EA) prescriptions in primary care practices in Manitoba, Canada. METHODS: A retrospective analysis of electronic medical record and administrative data was performed to determine primary adherence, defined as dispensation of a new EA prescription within 90 days of the date the prescription was written. Multivariable logistic regression models were used to test predictors of filling an EA prescription. RESULTS: Of 1212 EA prescriptions written between 2012 and 2014, only 69.9% (N = 847) were filled. An increased number of prescriptions for non-EA mediations was associated with an increased odds ratio of not filling an EA prescription. INTERPRETATION: This is the first study in Canada to examine adherence for EA prescriptions. The non-adherence rate identified is higher than rates previously reported in the literature, and indicates that many EA prescriptions for adults seen in primary care may never be filled. It also suggests that prescriptions of EAs for all patients at risk of anaphylaxis in community settings should consistently be accompanied by concise information about the importance of having the EA prescription filled and having the EA readily available.

Epinephrine for First-aid Management of Anaphylaxis.

Anaphylaxis is a severe, generalized allergic or hypersensitivity reaction that is rapid in onset and may cause death. Epinephrine (adrenaline) can be life-saving when administered as rapidly as possible once anaphylaxis is recognized. This clinical report from the American Academy of Pediatrics is an update of the 2007 clinical report on this topic. It provides information to help clinicians identify patients at risk of anaphylaxis and new information about epinephrine and epinephrine autoinjectors (EAs). The report also highlights the importance of patient and family education about the recognition and management of anaphylaxis in the community. Key points emphasized include the following: (1) validated clinical criteria are available to facilitate prompt diagnosis of anaphylaxis; (2) prompt intramuscular epinephrine injection in the mid-outer thigh reduces hospitalizations, morbidity, and mortality; (3) prescribing EAs facilitates timely epinephrine injection in community settings for patients with a history of anaphylaxis and, if specific circumstances warrant, for some high-risk patients who have not previously experienced anaphylaxis; (4) prescribing epinephrine for infants and young children weighing <15 kg, especially those who weigh 7.5 kg and under, currently presents a dilemma, because the lowest dose available in EAs, 0.15 mg, is a high dose for many infants and some young children; (5) effective management of anaphylaxis in the community requires a comprehensive approach involving children, families, preschools, schools, camps, and sports organizations; and (6) prevention of anaphylaxis recurrences involves confirmation of the trigger, discussion of specific allergen avoidance, allergen immunotherapy (eg, with stinging insect venom, if relevant), and a written, personalized anaphylaxis emergency action plan; and (7) the management of anaphylaxis also involves education of children and supervising adults about anaphylaxis recognition and first-aid treatment.

Fatal anaphylaxis registries data support changes in the who anaphylaxis mortality coding rules.

Anaphylaxis is defined as a severe life-threatening generalized or systemic hypersensitivity reaction. The difficulty of coding anaphylaxis fatalities under the World Health Organization (WHO) International Classification of Diseases (ICD) system is recognized as an important reason for under-notification of anaphylaxis deaths. On current death certificates, a limited number of ICD codes are valid as underlying causes of death, and death certificates do not include the word anaphylaxis per se. In this review, we provide evidences supporting the need for changes in WHO mortality coding rules and call for addition of anaphylaxis as an underlying cause of death on international death certificates. This publication will be included in support of a formal request to the WHO as a formal request for this move taking the 11th ICD revision.

rAed a 4: A New 67-kDa Aedes aegypti Mosquito Salivary Allergen for the Diagnosis of Mosquito Allergy.

BACKGROUND: Accurate diagnosis of mosquito allergy has been hampered by the laborious task of obtaining mosquito salivary allergens. We have previously studied 3 recombinant (r) Aedes aegypti mosquito salivary allergens: rAed a 1, rAed a 2 and rAed a 3. Here, we report the expression, purification, identification and evaluation of rAed a 4, a 67-kDa α-glucosidase. METHODS: rAed a 4 was expressed using a baculovirus/insect cell system, purified by a combination of anion- and cation-exchange chromatography, and identified by immunoblotting. A. aegypti saliva extract was prepared in our laboratory. An indirect enzyme-linked immunosorbent assay (ELISA) was developed to measure rAed a 4-specific immunoglobulin E (IgE) and IgG antibodies in sera from 13 individuals with a positive mosquito-bite test from a laboratory-reared mosquito. Sera from 18 individuals with a negative bite test served as controls. RESULTS: Purified rAed a 4 bound to the IgE in mosquito-allergic sera, as detected by ELISA and immunoblotting. The binding of rAed a 4 to IgE could be inhibited in a dose-dependent manner by the addition of an A. aegypti extract. Mosquito-allergic individuals had significantly higher mean levels of rAed a 4-specific IgE and IgG than controls. Using the mean of the controls ± 2 SD as a cut-off level, 46% of the 13 allergic individuals had a positive IgE, while none of the controls was positive (p < 0.001). CONCLUSIONS: Aed a 4 is a major allergen in mosquito saliva. Its recombinant form has the hydrolase function and can be used for the diagnosis of mosquito allergy.

Epinephrine doses delivered from auto-injectors stored at excessively high temperatures.

CONTEXT: Prompt injection of epinephrine (adrenaline) from epinephrine auto-injectors (EAIs) is the primary treatment for anaphylaxis in out-of-hospital settings. Storage of EAIs at room temperature (25 °C) is advised; however, storage at excessively high temperatures sometimes occurs. To our knowledge, there are no previous publications on the doses of epinephrine ejected from EAIs after storage at such temperatures. OBJECTIVE: We examined the epinephrine doses delivered from activated EAIs stored constantly or cyclically at 70 °C. METHODS: Twenty-five in-date EAIs were stored constantly or cyclically at 70 °C (excessive heat) or 25 °C (controls) for 5 d or 10 d. EAIs were activated and the epinephrine doses in the ejected solutions were measured using HPLC-UV. The enantiomeric purity of epinephrine was also measured by HPLC-UV. RESULTS: Control EAIs ejected a volume of 0.300 ± 0.006 mL containing 103.7 ± 3.3% of labeled dose (LD). After 5 d or 10 d of constant storage at 70 °C and activation at 70 °C, EAIs ejected a volume of 0.367 ± 0.008 mL containing 96.8 ± 3.8% LD and 0.373 ± 0.007 mL containing 77.7 ± 3.3% LD, respectively. After 5 d of cyclic storage at 70 °C and cooling to 25 °C before activation, EAIs ejected a volume of 0.311 ± 0.008 mL containing 87.2 ± 1.9% LD. Under the experimental conditions of this study, the resultant chromatographic peaks of epinephrine solutions from all EAIs represented only the pure l-enantiomer of epinephrine. CONCLUSION: EAIs should be stored under recommended conditions of the manufacturer. EAIs stored at excessively high temperatures cannot be used to treat humans while still hot, and when cooled, cannot be relied on to deliver the labeled epinephrine dose in anaphylaxis.

2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.

The World Allergy Organization (WAO) Guidelines for the assessment and management of anaphylaxis provide a unique global perspective on this increasingly common, potentially life-threatening disease. Recommendations made in the original WAO Anaphylaxis Guidelines remain clinically valid and relevant, and are a widely accessed and frequently cited resource. In this 2015 update of the evidence supporting recommendations in the Guidelines, new information based on anaphylaxis publications from January 2014 through mid- 2015 is summarized. Advances in epidemiology, diagnosis, and management in healthcare and community settings are highlighted. Additionally, new information about patient factors that increase the risk of severe and/or fatal anaphylaxis and patient co-factors that amplify anaphylactic episodes is presented and new information about anaphylaxis triggers and confirmation of triggers to facilitate specific trigger avoidance and immunomodulation is reviewed. The update includes tables summarizing important advances in anaphylaxis research.

Sublingual Diffusion of Epinephrine Microcrystals from Rapidly Disintegrating Tablets for the Potential First-Aid Treatment of Anaphylaxis: In Vitro and Ex Vivo Study.

For the first-aid treatment of anaphylaxis, epinephrine (Epi) 0.3 mg intramuscular (IM) injection in the thigh is the drug of choice. Epi auto-injectors are widely recommended for anaphylaxis treatment in community settings but not necessarily carried or used as prescribed when anaphylaxis occurs. We therefore developed rapidly disintegrating sublingual tablets (RDSTs) as an alternative noninvasive dosage form. Our objective in this study was to evaluate the effect of reducing Epi particle size on its in vitro and ex vivo diffusion, with the goal of enhancing Epi sublingual absorption from Epi RDSTs. Epi particle size was reduced by top-bottom technique using a microfluidizer for one pass at 30,000 Psi. The micronized Epi crystals (Epi-MC) were characterized using Zetasizer, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Epi RDSTs were formulated and manufactured using our previously developed method. In vitro and ex vivo diffusion of Epi 10, 20, and 40 mg RDSTs and Epi-MC 10 and 20 mg RDSTs (n = 4) were evaluated using Franz cells. Epi 10 mg solution was used as a control. Mean (±standard deviation (SD)) Epi particle size was successfully reduced from 131.8 ± 10.5 to 2.5 ± 0.4 µm. Cumulative Epi diffused and influx from 40 mg Epi RDSTs and 20 mg Epi-MC RDSTs were not significantly different from each other in vitro and ex vivo (p > 0.05). Also, Epi permeability from 20 mg Epi-MC RDSTs was significantly higher than from the rest (p < 0.05). Epi-MC RDSTs improved Epi diffusion twofold and might have the potential to reduce the Epi dose needed in RDSTs by 50%.

Insights and advances in chronic urticaria: a Canadian perspective.

In the past few years there have been significant advances which have changed the face of chronic urticaria. In this review, we aim to update physicians about clinically relevant advances in the classification, diagnosis and management of chronic urticaria that have occurred in recent years. These include clarification of the terminology used to describe and classify urticaria. We also detail the development and validation of instruments to assess urticaria and understand the impairment on quality-of-life and the morbidity caused by this disease. Additionally, the approach to management of chronic urticaria now focuses on evidence-based use of non-impairing, non-sedating H1-antihistamines given initially in standard doses and if this is not effective, in up to 4-fold doses. For urticaria refractory to H1-antihistamines, omalizumab treatment has emerged as an effective, safe option.

Adrenaline (epinephrine) microcrystal sublingual tablet formulation: enhanced absorption in a preclinical model.

OBJECTIVES: For anaphylaxis treatment in community settings, adrenaline (epinephrine) administration using an auto-injector in the thigh is universally recommended. Despite this, many people at risk of anaphylaxis in community settings do not carry their prescribed auto-injectors consistently and hesitate to use them when anaphylaxis occurs.The objective of this research was to study the effect of a substantial reduction in adrenaline (Epi) particle size to a few micrometres (Epi microcrystals (Epi-MC)) on enhancing adrenaline dissolution and increasing the rate and extent of sublingual absorption from a previously developed rapidly disintegrating sublingual tablet (RDST) formulation in a validated preclinical model. METHODS: The in-vivo absorption of Epi-MC 20 mg RDSTs and Epi 40 mg RDSTs was evaluated in rabbits. Epi 0.3 mg intramuscular (IM) injection in the thigh and placebo RDSTs were used as positive and negative controls, respectively. KEY FINDINGS: Epimean (standard deviation) area under the plasma concentration vs time curves up to 60 min and Cmax from Epi-MC 20 mg and Epi 40 mg RDSTs did not differ significantly (P > 0.05) from Epi 0.3 mg IM injection. After adrenaline, regardless of route of administration, pharmacokinetic parameters were significantly higher (P < 0.05) than after placebo RDSTs administration (reflecting endogenous adrenaline levels). CONCLUSION: Epi-MC RDSTs facilitated a twofold increase in Epi absorption and a 50% reduction in the sublingual dose. This novel sublingual tablet formulation is potentially useful for the first-aid treatment of anaphylaxis in community settings.

Anaphylaxis: Unique aspects of clinical diagnosis and management in infants (birth to age 2 years).

In this rostrum we aim to increase awareness of anaphylaxis in infancy in order to improve clinical diagnosis, management, and prevention of recurrences. Anaphylaxis is increasingly reported in this age group. Foods are the most common triggers. Presentation typically involves the skin (generalized urticaria), the respiratory tract (cough, wheeze, stridor, and dyspnea), and/or the gastrointestinal tract (persistent vomiting). Tryptase levels are seldom increased because of infant anaphylaxis, although baseline tryptase levels can be increased in the first few months of life, reflecting mast cell burden in the developing immune system. The differential diagnosis of infant anaphylaxis includes consideration of age-unique entities, such as food protein-induced enterocolitis syndrome with acute presentation. Epinephrine (adrenaline) treatment is underused in health care and community settings. No epinephrine autoinjectors contain an optimal dose for infants weighing 10 kg or less. After treatment of an anaphylactic episode, follow-up with a physician, preferably an allergy/immunology specialist, is important for confirmation of anaphylaxis triggers and prevention of recurrences through avoidance of confirmed specific triggers. Natural desensitization to milk and egg can occur. Future research should include validation of the clinical criteria for anaphylaxis diagnosis in infants, prospective longitudinal monitoring of baseline serum tryptase levels in healthy and atopic infants during the first year of life, studies of infant comorbidities and cofactors that increase the risk of severe anaphylaxis, development of autoinjectors containing a 0.1-mg epinephrine dose suitable for infants, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis recurrences.

Drug-device combination products in the twenty-first century: epinephrine auto-injector development using human factors engineering.

INTRODUCTION: The systematic application of human factors engineering (HFE) principles to the development of drug-device combination products, including epinephrine auto-injectors (EAIs), has the potential to improve the effectiveness and safety of drug administration. AREAS COVERED: A PubMed search was performed to assess the role of HFE in the development of drug-device combination products. The following keywords were used in different combinations: 'human factors engineering,' 'human factors,' 'medical products,' 'epinephrine/adrenaline auto-injector,' 'healthcare' and 'patient safety.' This review provides a summary of HFE principles and their application to the development of drug-device combination products as advised by the US FDA. It also describes the HFE process that was applied to the development of Auvi-Q, a novel EAI, highlighting specific steps that occurred during the product-development program. EXPERT OPINION: For drug-device combination products, device labeling and usability are critical and have the potential to impact clinical outcomes. Application of HFE principles to the development of drug-delivery devices has the potential to improve product quality and reliability, reduce risk and improve patient safety when applied early in the development process. Additional clinical and real-world studies will confirm whether the application of HFE has helped to develop an EAI that better meets the needs of patients at risk of anaphylaxis.