Management of Refractory Anaphylaxis: An Overview of Current Guidelines.

In this review, we compare different refractory anaphylaxis (RA) management guidelines focusing on cardiovascular involvement and best practice recommendations, discuss postulated pathogenic mechanisms underlining RA and highlight knowledge gaps and research priorities. There is a paucity of data supporting existing management guidelines. Therapeutic recommendations include the need for the timely administration of appropriate doses of aggressive fluid resuscitation and intravenous (IV) adrenaline in RA. The preferred second-line vasopressor (noradrenaline, vasopressin, metaraminol and dopamine) is unknown. Most guidelines recommend IV glucagon for patients on beta-blockers, despite a lack of evidence. The use of methylene blue or extracorporeal life support (ECLS) is also suggested as rescue therapy. Despite recent advances in understanding the pathogenesis of anaphylaxis, the factors that lead to a lack of response to the initial adrenaline and thus RA are unclear. Genetic factors, such as deficiency in platelet activating factor-acetyl hydrolase or hereditary alpha-tryptasaemia, mastocytosis may modulate reaction severity or response to treatment. Further research into the underlying pathophysiology of RA may help define potential new therapeutic approaches and reduce the morbidity and mortality of anaphylaxis.

Updated grading system for systemic allergic reactions: Joint Statement of the World Allergy Organization Anaphylaxis Committee and Allergen Immunotherapy Committee.

There is a lack of consensus over the description and severity assignment of allergic adverse reactions to immunotherapy, although there seems to be a consensus at least in terms of using the World Allergy Organization (WAO) grading systems to describe local adverse events for Sublingual Immunotherapy (SLIT) and Systemic Allergic Reactions (SARs) to Subcutaneous Immunotherapy (SCIT) amongst the major national/regional allergy societies. In this manuscript, we propose a modification of the previous WAO Grading system for SARs, which aligns with the newly-proposed Consortium for Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions in Food Allergy (version 3.0). We hope this can facilitate a unified grading system appropriate to SARs due to allergen immunotherapy, independent of allergen and route of administration, and across clinical and research practice.

Anaphylaxis mortality in the perioperative setting: Epidemiology, elicitors, risk factors and knowledge gaps.

Perioperative anaphylaxis (PA) is a severe condition that can be fatal, but data on PA mortality are scarce. The aim of this article is to review the epidemiology, elicitors and risk factors for PA mortality and identify knowledge gaps and areas for improvement regarding the management of severe PA. PA affects about 100 cases per million procedures. Mortality is rare, estimated at 3 to 5 cases per million procedures, but the PA mortality rate is higher than for other anaphylaxis aetiologies, at 1.4% to 4.8%. However, the data are incomplete. Published data mention neuromuscular blocking agents and antibiotics, mainly penicillin and cefazolin, as the main causes of fatal PA. Reported risk factors for fatal PA vary in different countries. Most frequently occurring comorbidities are obesity, male gender, cardiovascular diseases and ongoing treatment with beta-blockers. However, there are no clues about how these factors interact and the impact of individual risk factors. The pathophysiology of fatal PA is still not completely known. Genetic factors such as deficiency in PAF-acetyl hydrolase and hereditary alpha-tryptasemia, have been reported as modulators of severe anaphylaxis and possible targets for specific treatments. Our review underlines unmet needs in the field of fatal PA. Although we confirmed the need for timely administration of an adequate dose of adrenaline and the proper infusion of fluids, there is no evidence-based data on the proper dose of intravenous titrated adrenaline and which clinical manifestations would flag the need for fluid therapy. There are no large clinical studies supporting the administration of alternative vasopressors, such as glucagon and methylene blue. Further research on pathophysiological mechanisms of PA and its severity may address these issues and help clinicians to define new therapeutic approaches.

Adrenaline auto injectors pharmacokinetic/pharmacodynamic studies and potential consequences for clinical practice.

BACKGROUND: Anaphylaxis is a sudden multisystem allergic reaction which may result in a fatal outcome if not treated promptly. Guidelines worldwide suggest intramuscular adrenaline as the first-line treatment for anaphylaxis outside a perioperative reaction. Adrenaline autoinjectors (AAIs) are widely used self-administrable devices, especially in community settings. Different commercial AAIs have been authorized to be marketed in Europe. For an AAI to be efficacious, a rapid adrenaline delivery in patients, including those who are overweight or obese, resulting in an optimal cardiovascular (CV) response, is a key feature. AAIs are designed to achieve this requirement, which is reflected in their differing functional properties such as primary container selection, drug delivery mechanism (cartridge-or syringe-based), needle length, needle gauge, and adrenaline dose (150 µg, 300 µg, or 500 µg). However, the differences in functional properties across these devices may play a critical role in achieving these requirements as well as the differences in ergonomics in the handling of these devices. THE PURPOSE OF THIS REVIEW: Considering the dynamic pharmacokinetic/pharmacodynamic (PK/PD) profiles of different AAIs marketed in Europe and their effect on adrenaline delivery, the expert panel, also serving as author for this paper have carried out a detailed analysis of the PK/PD profiles of four AAIs, namely, Anapen, Emerade, EpiPen, and Jext, to delineate the adrenaline delivery and their subsequent physiological effects on the backdrop of device characteristics, dose strength, and the skin-to-muscle distances of the participants.

Epidemiology of anaphylaxis: is the trend still going up?

PURPOSE OF REVIEW: To understand the current global scale of anaphylaxis and identify possible strategies to increase the accuracy of epidemiological data. RECENT FINDINGS: Anaphylaxis mortality and morbidity statistics may gain new perspectives with the global implementation of the ICD-11. Improving the quality of epidemiological data related to anaphylaxis should clarify some areas of uncertainty about risk factors, leading to better targeting of strategies to protect those patients at risk, and support decision-making to facilitate health care planning and implementation of public health measures to prevent anaphylaxis. SUMMARY: The true rate of anaphylaxis is unknown due to a number of factors, such as misdiagnosis, miscoding and undernotification. Moreover, there is lack of information about anaphylaxis epidemiology in many countries. Difficulties on collecting accurate and comparable data should be acknowledged and anaphylaxis data can vary widely. Currently, most robust data are derived from hospitalization datasets and national mortality databases. Anaphylaxis accounts for up to 0.26% of overall hospital admissions. It is suggested that the number of hospital admissions for anaphylaxis is increasing in many countries, both with respect to all-causes of anaphylaxis and by trigger, but the mortality rate remains low. However, there are still great challenges in capturing quality anaphylaxis mortality and morbidity statistics. Better understanding of anaphylaxis trends should clarify some areas of uncertainty about risk factors and prospect effective prevention strategies. As the knowledge derived from populations is key information for more realistic decision-making, the construction of the new section addressed to anaphylaxis in the ICD-11 will allow the collection of more accurate epidemiological data to support high quality management of patients, and to better facilitate health care planning to implement public health measures, reduce the morbidity and mortality attributable to anaphylaxis.

Determining clinical predictors to identify non-specific abdominal pain and the added value of laboratory examinations: A prospective derivation study in a paediatric emergency department.

AIM: To develop a model to discriminate non-specific abdominal pain (NSAP) from organic pain in the paediatric emergency department (PED) and evaluate the added value of laboratory markers. METHODS: Prospective cohort study in an urban French PED including all patients aged ≥4 years with abdominal pain between November 2020 and May 2021. The outcome was the discrimination between NSAP (patients coded to have only "pain" or "constipation") and organic pain (all other diagnoses) using stepwise backward multivariate logistic regression method with bootstrap resampling. RESULTS: The study enrolled 246 patients. Overall, 163 patients (66.2%) had NSAP. Four variables associated with organic pain: pain in the epigastric region (OR 0.48 [0.23-0.99]), worsening pain (0.57 [0.32-0.99]), pain migration (0.42 [0.17-0.99]) and vomiting (0.47 [0.26-0.84]) were integrated in a clinical model. To discriminate NSAP with a probability of 65%, model sensitivity was 71.8% (64.9-78.7), specificity was 53.0% (42.3-63.7), and the Net Benefit (NB) was 15.4%. White Blood Count and C-reactive protein results improved discriminative capacity of the model (AUC 0.708 [0.643-0.773] vs. 0.654 [0.585-0.723], p = 0.01) with a supplementary NB of 12%. Patient follow-up showed 95% diagnostic accuracy. CONCLUSION: This study reveals a four-clinical predictor model with a NB of 15% in predicting NSAP. Validation studies are necessary.

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.

Oral immunotherapy for food allergy: Translation from studies to clinical practice?

Oral immunotherapy (OIT) is now recognized as an alternative active treatment to strict food avoidance in certain patients with IgE-mediated food allergy. Studies have confirmed the efficacy of OIT to desensitize children with allergy to cow's milk, eggs, and peanuts. The benefits, risks, and constraints of OIT are becoming increasingly well understood. However, there is no consensual criteria to select patients to whom OIT could be proposed, and many issues remain to address including the definitions of desensitization and long-term efficacy, the assessment of patient's experience in real life, the optimization of buildup and maintenance protocols, and the utility of multiple food OIT. The recent authorization by medical agency concerning the first medicine for peanut OIT is a step forward towards higher standardization in the practice of OIT. This article summarizes in comprehensive narrative format data on efficacy, tolerance, impact on quality of life and adverse effects of OIT and discuss elements to consider in clinical practice before starting OIT.

Fatal and near-fatal anaphylaxis: The Allergy-Vigilance® Network data (2002-2020).

BACKGROUND: Having a better understanding of the risk factors of severe anaphylaxis is a crucial challenge for physicians. METHODS: To retrospectively analyse fatal/near-fatal anaphylaxis cases recorded by the Allergy-Vigilance® Network (2002-2020) and evaluate the characteristics associated with survival, age and allergens. RESULTS: Among the 3510 anaphylaxis cases documented in the network, 70 (2%) patients (males: 57%; mean age: 35.4 y) presented grade 4 (Ring-Messmer) anaphylaxis and 25 died (19 food-related); 33% had a history of asthma. The main allergens were food (60%; peanut, 20%; milks, 11%) involved in 25/26 cases in children and in 17/44 (39%) cases in adults. Non-food anaphylaxis was related to drugs/latex (24%; neuromuscular blocking agents, 10%; betalactamins, 6%), Hymenoptera (16%). Three food-related cases (one death) occurred during oral food challenge in children. Patients with a food allergy were younger (22.2 years vs. 55 years, p < .001), had more likely a history of asthma (50% vs. 7%; p < .001), a pre-existing allergy (62% vs. 18%; p < .001) compared with other allergies. A cofactor was identified in 35 cases (50%) but predominantly in adults as opposed to children (64% vs. 27%; p = .01). The patients who died were younger (25.6 vs. 40.8 years; p = .01) than the survivors and mostly presented bronchospasm (56% vs. 29%; p = .05). Gaps in the prevention and management of anaphylaxis were noted in 15 cases (21%). CONCLUSIONS: Severe food anaphylaxis has specific features compared with other causes such as young age, asthma history and exercise. Food is also involved in severe anaphylaxis in adults that should not be underestimated.

Physician's experience on managing asthma in adolescents: results of the International AMADO (Asthma Management in ADOlescents) survey.

BACKGROUND: Worldwide prevalence of asthma seems to be increasing in adolescents, but limited data is available regarding the management of asthma in this age group. OBJECTIVE: Therefore, we conducted an international survey focused on physicians who manage asthma in order to understand how Asthma Management in ADOlescents (AMADO) is currently performed. METHODS: The AMADO survey is a web-based global survey of physician's attitudes towards the management of asthma in adolescents, circulated for 17 weeks. The survey had an anonymous and voluntary standard. The questionnaire consisted in 27 questions covering the training background of respondents, difficulties in diagnosis, and in management of asthma in adolescents. RESULTS: Two hundred forty-four responses were received from 46 countries, from all continents. Most (65%) of participants indicated allergy as being their main specialty. The majority of participants (62%) had more than 5 years of clinical practice, but 62% have no formal training in management of adolescents with asthma. Most of participants (96%) indicated having at least one case of asthma in adolescents per month. 60% of respondents mentioned that the asthmatic adolescents only had the consultation due to the family imposition. All respondents mentioned having difficulties in the management of asthma in adolescents due to patient poor adherence. Overall, 44% of participants have no specific health care resources for adolescents in their departments. Main suggestions from the participants were: optimization of time and personalized communication to these cohort, and standardization of multidisciplinary actions to improve adherence to asthma control treatment. CONCLUSION: Management of asthma in adolescents is still a challenge in clinical practice. The results from this survey helped us to identify the key issues to improve clinical outcomes in the future. This survey is the first step of the international AMADO initiative, which intends to optimize diagnosis and control of asthma and prevent avoidable deaths.

The global burden of illness of peanut allergy: A comprehensive literature review.

Peanut allergy (PA) currently affects approximately 2% of the general population of Western nations and may be increasing in prevalence. Patients with PA and their families/caregivers bear a considerable burden of self-management to avoid accidental peanut exposure and to administer emergency medication (adrenaline) if needed. Compared with other food allergies, PA is associated with higher rates of accidental exposure, severe reactions and potentially fatal anaphylaxis. Approximately 7%-14% of patients with PA experience accidental peanut exposure annually, and one-third to one-half may experience anaphylaxis, although fatalities are rare. These risks impose considerably high healthcare utilization and economic costs for patients with PA and restrictions on daily activities. Measures to accommodate patients with PA are often inadequate, with inconsistent standards for food labelling and inadequate safety policies in public establishments such as restaurants and schools. Children with PA are often bullied, resulting in sadness, humiliation and anxiety. These factors cumulatively contribute to significantly reduced health-related quality of life for patients with PA and families/caregivers. Such factors also provide essential context for risk/benefit assessments of new PA therapies. This narrative review comprehensively assessed the various factors comprising the burden of PA.

A Proposal from the Montpellier World Health Organization Collaborating Centre for Better Management and Prevention of Anaphylaxis.

Since the first description of anaphylaxis in 1902, its clinical importance as an emergency condition has been recognized worldwide. Anaphylaxis is a severe, potentially life-threatening systemic hypersensitivity reaction characterized by rapid onset and the potential to endanger life through respiratory or circulatory compromise. It is usually, although not always, associated with skin and mucosal changes. Although the academic/scientific communities have advocated to promote greater awareness and protocols for the management of anaphylaxis based on best evidence, there are few efforts documenting feedback as to the success of these efforts. In this article, we review the key unmet needs related to the diagnosis and management of anaphylaxis, and propose a public health initiative for prevention measures and a timetable action plan that intends to strengthen the collaboration among health professionals and especially primary care physicians dealing with anaphylaxis, which can encourage enhanced quality of care of patients with anaphylaxis. More than calling for a harmonized action for the best management of anaphylaxis to prevent undue morbidity and mortality, the Montpellier World Health Organization Collaborating Centre here proposes an action plan as a baseline for a global initiative against anaphylaxis. We strongly believe that these collaborative efforts are a strong public health and societal priority that is consistent with the overarching goals of providing optimal care of allergic patients and best practices of allergology.

Allergy to Peanuts imPacting Emotions And Life (APPEAL): the impact of peanut allergy on children, adolescents, adults and caregivers in France.

BACKGROUND: Peanut allergy (PA) has increased in developed countries and can have a dramatic effect on quality of life but data surrounding this is limited in France. Allergy to Peanuts imPacting Emotions And Life study (APPEAL) investigated the experience and impact of living with PA in France. METHODS: Respondents affected by PA directly (children aged 8-12 years, teenagers aged 13-17 years, or adults aged ≥ 18 years) or indirectly (caregiver) completed either an online questionnaire (APPEAL-1, N = 198), or provided in-depth interviews (APPEAL-2, N = 32). Quantitative data was evaluated using descriptive statistics. Qualitative data was analysed thematically, using MAXQDA software. RESULTS: Of 198 responders in APPEAL-1, 88% stated that PA affects their daily activities, and 74% felt isolated as a result of living with PA. Feelings of worry about exposure to peanuts on social occasions where food is involved was reported by 91%. A total of 44% reported some restrictions in their job options, 85% in socializing. Psychological impact of PA included responders feeling emotions of frustration (89%), uncertainty (87%), and stress (93%) and 93% reporting encountering instances of feeling different due to their PA. Main factors that drove PA impact included social activities and relationships; whereas main coping strategies to avoid peanuts included monitoring, communication and planning. CONCLUSION: The analysis of French respondents from the APPEAL study demonstrates the impact and burden of PA on allergic children, teenagers, adults and their caregivers, and highlights the unmet need to be addressed.