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Keywords:

  • adolescents;
  • adults;
  • anaphylaxis;
  • children;
  • management

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

Anaphylaxis is a clinical emergency, and all healthcare professionals should be familiar with its recognition and acute and ongoing management. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Taskforce on Anaphylaxis. They aim to provide evidence-based recommendations for the recognition, risk factor assessment, and the management of patients who are at risk of, are experiencing, or have experienced anaphylaxis. While the primary audience is allergists, these guidelines are also relevant to all other healthcare professionals. The development of these guidelines has been underpinned by two systematic reviews of the literature, both on the epidemiology and on clinical management of anaphylaxis. Anaphylaxis is a potentially life-threatening condition whose clinical diagnosis is based on recognition of a constellation of presenting features. First-line treatment for anaphylaxis is intramuscular adrenaline. Useful second-line interventions may include removing the trigger where possible, calling for help, correct positioning of the patient, high-flow oxygen, intravenous fluids, inhaled short-acting bronchodilators, and nebulized adrenaline. Discharge arrangements should involve an assessment of the risk of further reactions, a management plan with an anaphylaxis emergency action plan, and, where appropriate, prescribing an adrenaline auto-injector. If an adrenaline auto-injector is prescribed, education on when and how to use the device should be provided. Specialist follow-up is essential to investigate possible triggers, to perform a comprehensive risk assessment, and to prevent future episodes by developing personalized risk reduction strategies including, where possible, commencing allergen immunotherapy. Training for the patient and all caregivers is essential. There are still many gaps in the evidence base for anaphylaxis.

Abbreviations
ACE inhibitor

angiotensin-converting enzyme inhibitor

AGREE II

Appraisal of Guidelines for Research & Evaluation

BP

blood pressure

EAACI

European Academy of Allergy and Clinical Immunology

ED

emergency departments

EIA

exercise-induced anaphylaxis

FDEIA

food-dependent, exercise-induced anaphylaxis

GRADE

Grading of Recommendations, Assessment, Development and Evaluation

ICD

International Classification of Diseases Codes

IgE

immunoglobulin E

NSAID

nonsteroidal anti-inflammatory drugs

PEF

peak expiratory flow

VIT

Hymenoptera venom immunotherapy

Anaphylaxis is a clinical emergency, and all healthcare professionals should be familiar with its management. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Anaphylaxis and are part of the EAACI Guidelines for Food Allergy and Anaphylaxis. The guidelines aim to provide evidence-based recommendations for the recognition, risk assessment, and management of patients who have experienced, are experiencing, or are at risk of experiencing anaphylaxis. The primary audience is allergists but they are also likely to be of relevance to all other healthcare professionals (e.g., doctors, nurses, and paramedics) in emergency departments (ED), hospital, and primary care. Development of the guidelines has been informed by two systematic reviews of the epidemiology and clinical management of anaphylaxis [1, 2] with weaker forms of evidence being used where there were insufficient data or where high-level evidence is practically or ethically unobtainable. These guidelines build on the previous EAACI Position Paper on Anaphylaxis in Childhood [3] and are complementary to other current anaphylaxis guidelines [4-6]. Distinctive features include a European focus and the placing of particular emphasis on the practical issues associated with long-term management.

Anaphylaxis is defined as a ‘severe, life-threatening systemic hypersensitivity reaction’ [7] (Box 1). This is characterized by being rapid in onset with potentially life-threatening airway, breathing, or circulatory problems; it is usually, but not always, associated with skin and mucosal changes [5]. These guidelines focus mainly on allergic anaphylaxis involving specific immunoglobulin E (IgE) but are also relevant to anaphylaxis involving other mechanisms.

Box 1.

Key terms

AnaphylaxisSevere, potentially life-threatening systemic hypersensitivity reaction [6, 7]. This is characterized by being rapid in onset with life-threatening airway, breathing, or circulatory problems and is usually, although not always, associated with skin and mucosal changes
Adrenaline (epinephrine)A drug with combined α- and β-agonist actions which result in (i) peripheral vasoconstriction, thereby reversing hypotension and mucosal edema; (ii) increased rate and force of cardiac contractions, thereby reversing hypotension; and (iii) reversal of bronchoconstriction and reduction in the release of inflammatory mediators
Adrenaline auto-injectorDevice designed to be used by a nonmedical person to give a predefined dose of intramuscular adrenaline
CofactorsPatient-related or external circumstances that are associated with more severe allergic reactions. They are also known as augmentation factors
Management plansLay summary of the clinical plan that patients should follow. It will have an emergency action plan with likely presenting symptoms and how to respond to each. It should also provide additional information such as avoidance advice if applicable and contact details for further advice from allergy clinic and patient support groups

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

These guidelines were produced using the Appraisal of Guidelines for Research & Evaluation (AGREE II) approach [8, 9], a structured approach to guideline production. This is designed to ensure appropriate representation of the full range of stakeholders, a careful search for and critical appraisal of the relevant literature, a systematic approach to the formulation and presentation of recommendations, and steps to ensure that the risk of bias is minimized at each step of the process. The process began in January 2012, ensuing over 18 months, with in detail discussion of the frame of guidelines for clinical practice, the main aims of the guidelines, the target conditions, agreeing the intended end-user for the recommendations, agreeing the intended end-user group, and ensuring adequate professional and lay representation in the guidelines development process. The process involved:

Clarifying the scope and purpose of the guidelines

The scope of these EAACI guidelines is multifaceted providing statements that assist clinicians in the management of anaphylaxis in daily practice; harmonizing the approach to this clinical emergency among stakeholders across Europe; and advocating for further research.

Ensuring appropriate stakeholder involvement

Participants in the Anaphylaxis Taskforce represented a range of 14 European countries, and disciplinary and clinical backgrounds, for example emergency physicians (A. B. Bellou), primary care (A. Sheikh), psychology (A. DunnGalvin), patient groups (F. Timmermans, L. Harada), and dietitians (B. J. Vlieg–Boerstra).

Systematic reviews of the evidence

The initial full range of questions that were considered important were rationalized through several rounds of iteration to agree to three key questions that were then pursued through two formal systematic reviews of the evidence [1, 2, 10, 11] (see Box 2).

Box 2.

Key questions addressed in the two supporting systematic reviews [1, 2]

  • What is the epidemiology (i.e., frequency, risk factors, and outcomes) of anaphylaxis and how do these vary by time, place, and person?
  • What is the effectiveness of interventions for the acute management of anaphylaxis?
  • What is the effectiveness of interventions for the long-term management of those at high risk of further episodes of anaphylaxis?

Formulating recommendations

We graded the strength and consistency of key findings from these systematic reviews to formulate evidence-linked recommendations for care [12] (Box 3). This involved formulating clear recommendations and making clear the strength of evidence underpinning each recommendation. Experts identified the resource implications of implementing the recommendations, barriers, and facilitators to the implementation of each recommendation, advice on approaches to implementing the recommendations and suggested audit criteria that can help with assessing organizational compliance with each recommendation (see Supporting Information Tables S1 and S2).

Box 3.

Assigning levels of evidence and recommendations [12]

Level of evidence
Level ISystematic reviews, meta-analysis, randomized controlled trials
Level IITwo groups, nonrandomized studies (e.g., cohort, case–control)
Level IIIOne group nonrandomized (e.g., before and after, pretest, and post-test)
Level IVDescriptive studies that include analysis of outcomes (single-subject design, case series)
Level VCase reports and expert opinion that include narrative literature, reviews, and consensus statements
Grades of recommendation
Grade AConsistent level I studies
Grade BConsistent level II or III studies or extrapolations from level I studies
Grade CLevel IV studies or extrapolations from level II or III studies
Grade DLevel V evidence or troublingly inconsistent or inconclusive studies at any level

Peer review and public comment

A draft of these guidelines was externally peer-reviewed by invited experts from a range of organizations, countries, and professional backgrounds. Additionally, the draft guidelines were made available on the EAACI Web site for a 3-week period in July 2013 to allow all stakeholders to comment. All feedback was considered by the Anaphylaxis Taskforce and, where appropriate, final revisions were made in light of the feedback received. We will be pleased to continue to receive feedback on these guidelines, which should be addressed to the corresponding author.

Identification of evidence gaps

The process of developing these guidelines has identified a number of evidence gaps and we plan in the future to formally prioritize these. We plan to draft outline research briefs that funders can use to commission research on these questions.

Editorial independence and managing conflict of interests

The production of these guidelines was funded and supported by EAACI. The funder did not have any influence on the guidelines production process, on its contents, or on the decision to publish. Taskforce members' conflict of interests were taken into account by the Taskforce Chair as recommendations were formulated.

Updating the guidelines

We plan to update these guidelines in 2017 unless there are important advances before then.

Epidemiology

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

A detailed description of the epidemiology of anaphylaxis can be found in the underpinning systematic review referred to above [1]. The exact incidence and prevalence of anaphylaxis in Europe is challenging to establish due to a number of factors. The current definition of anaphylaxis is complex and difficult to use in epidemiological studies [13]. Additionally, the World Health Organization's International Classification of Diseases codes (ICD-9 and current ICD-10) focus on anaphylactic shock and do not cover the full range of triggers, meaning that not all allergy cases are likely to be captured in routine data systems. ICD-11 is in development but still seems to miss major triggers [14]. Additionally, anaphylaxis has an acute and unexpected onset, may vary in severity, and may resolve spontaneously [15]. For all these reasons, underdiagnosis and under-reporting are likely to be common and as a result, epidemiological measures are likely to underestimate the true disease burden.

The results of 10 European studies suggest an incidence of 1.5–7.9 per 100 000 person-years [1] with studies from the UK showing an increase in admissions with anaphylaxis over the last two decades [1]. Based on three European population-based studies, prevalence is estimated at 0.3% (95% CI, 0.1–0.5) [1]. Overall, the case fatality rate for anaphylaxis is low, below 0.001% [1].

Key triggers include food, drugs, and stinging insects; in up to 20%, the elicitor is not identified. Their relative importance varies with age and geography studied. For ED presentations, drugs and foods are the most common elicitors of anaphylaxis, with age-related differences [1, 16]. Foods are the most frequent cause of anaphylaxis in children, with pollen allergy and asthma being important risk factors [1]. Drug- and Hymenoptera venom-triggered anaphylaxis are more common in adults than in children. Compared to males, adult females have a higher frequency of anaphylaxis [1] in general and specifically to plant foods and nonsteroidal anti-inflammatory drugs (NSAID) [1]. Drugs are the most frequent cause of anaphylaxis in hospitalized patients [1]. For anaphylaxis during anesthesia, neuromuscular blocking agents are the most frequent triggers in adult patients in most countries, with a higher incidence in females [1].

Clinical presentation and diagnosis

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

The clinical manifestations of anaphylaxis depend on the organ systems involved. Widely accepted criteria to help clinicians identify likely anaphylaxis [17, 18] (Box 4) emphasize the rapid onset of its multiple symptoms and signs. These criteria significantly improve the identification of anaphylaxis [19] and demonstrate excellent sensitivity (96.7%) and good specificity (82.4%) for the diagnosis of anaphylaxis in a retrospective ED study [20]. Symptoms and signs of anaphylaxis usually occur within 2 h of exposure to the allergen [21], usually within 30 min for food allergy and even faster with parenteral medication or insect stings. In a large case series of fatal anaphylaxis, the median time from symptoms to arrest has been reported as 30, 15, and 5 min for food, insect venom, and parenteral medication, respectively [22].

Among the symptoms of anaphylaxis, cutaneous manifestations occur in most cases [23, 24]. In a recent study describing a cohort of 2012 pediatric and adult patients with anaphylaxis, the skin was the most frequently affected organ (84%), followed by cardiovascular symptoms (72%) and respiratory symptoms (68%) [25]. Anaphylaxis, however, can develop in the absence of cutaneous manifestations. Respiratory or cardiovascular symptoms or signs are the potentially life-threatening features of anaphylaxis [26]. Respiratory symptoms occur more frequently in children, and cardiovascular symptoms predominate in adults [25-31]. Nausea and vomiting may also be associated with anaphylaxis [22] (Fig. 1).

image

Figure 1. Symptoms associated with anaphylaxis. GI, gastrointestinal.

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Biphasic anaphylactic reactions have been reported to develop in up to 20% of reactions [24, 32-34] although the evidence for this is of low quality. They usually occur within 4–12 of the first symptoms or signs and may be more severe. A delay in giving adrenaline (epinephrine), insufficient adrenaline, or failure to administer a glucocorticosteroid may increase the risk of biphasic reactions [33-37].

Anaphylaxis is a clinical diagnosis that builds on the criteria shown in Box 4. Retrospectively, the diagnosis may be supported if serum tryptase is elevated within a few hours after the reaction when compared with the patient's baseline levels; levels are often normal especially in food-triggered reactions in children [38]. Evidence of IgE sensitization on skin prick [39] or in vitro testing may also aid the diagnosis; provocation testing, ideally with any potential cofactors [40], may be required if diagnostic doubt remains [26]. Children may outgrow their food allergy, even if severe [41].

Box 4.

Clinical criteria for diagnosing anaphylaxis

Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:

  1. PEF, peak expiratory flow; BP, blood pressure.

  2. Reproduced from Sampson et al. [17] with permission (C).

  3. a

    Low systolic blood pressure for children is defined as <70 mmHg from 1 month to 1 year, less than (70 mmHg + [2 × age]) from 1 to 10 years and <90 mmHg from 11 to 17 years.

1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips?tongue?uvula AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (e.g., dyspnea, wheeze?bronchospasm, stridor, reduced PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
a. Involvement of the skin?mucosal tissue (e.g., generalized hives, itch-flush, swollen lips?tongue?uvula
b. Respiratory compromise (e.g., dyspnea, wheeze?bronchospasm, stridor, reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or >30% decrease in systolic BPa
b. Adults: systolic BP of <90 mmHg or >30% decrease from that person's baseline

The differential diagnosis of anaphylaxis includes medical diseases, which affect the organ systems most frequently involved in anaphylaxis (Box 5).

Box 5.

Differential diagnosis of anaphylaxis (D)

Skin or mucosal
chronic remittent or physical urticaria and angioedema
pollen food syndrome
Respiratory diseases
acute laryngotracheitis
tracheal or bronchial obstruction (e.g., foreign substances, vocal cord dysfunction)
status asthmaticus (without involvement of other organs)
Cardiovascular diseases
vasovagal syncope
pulmonary embolism
myocardial infarction
cardiac arrhythmias
hypertensive crisis
cardiogenic shock
Pharmacological or toxic reactions
ethanol
histamine, e.g. scombroid fish poisoning
opiates
Neuropsychiatric diseases
hyperventilation syndrome
anxiety and panic disorder
somatoform disorder (e.g., psychogenic dyspnea, vocal cord dysfunction)
dissociative disorder and conversion (e.g., globus hystericus)
epilepsy
cerebrovascular event
psychoses
artifact (factitious disorder)
Hoigné's syndrome
coma, e.g. metabolic, traumatic
Endocrinological diseases
hypoglycemia
thyrotoxic crisis
carcinoid syndrome
vasointestinal polypeptide tumors
pheochromocytoma

Adapted from Simons et al. [6] and Muraro et al. [3] with permission.

Factors increasing the risk of severe allergic reactions

Risk factors for anaphylaxis include individual patient-related factors and circumstances [25, 26, 42-46] (Box 6). We do not have precise data on the magnitude of risk associated with each.

Box 6.

Examples of risk factors and cofactors of anaphylaxis

Lifestyle factors
physical exertion
alcohol
Drugs
NSAID
ACE inhibitors
β-blockers
Patient-specific factors
adolescence, advanced age, and sex
infections
hormonal status
psychogenic stress
Pre-existing conditions
asthma and other IgE-dependent diseases
cardiovascular disease
mastocytosis and/or increased basal tryptase
Concomitant diseases

Co-existing asthma is a risk factor for anaphylaxis and fatal anaphylaxis, especially if severe and uncontrolled [47, 48]. Mast cell disorders, and probably underlying cardiovascular disease, are also associated with an increased risk of severe or fatal anaphylaxis [24, 49, 50].

Specific allergens

Patients with peanut and tree nut allergy are at an increased risk for a severe reaction [51]. In patients with insect venom allergy, increased severity has been reported for older age, pre-existing cardiovascular disease, mast cell disorder, including mastocytosis and mast cell activation syndrome [52, 53], elevated baseline serum tryptase concentrations, concomitant treatment with a beta-adrenergic blocker and/or angiotensin-converting enzyme (ACE) inhibitor, and a previous severe reaction [54-57].

Cofactors

Cofactors increase the risk of an allergic reaction occurring or its severity. They have been described in nearly 20% of young patients in a prospective registry study [28] (Box 6) and include exercise, fever, acute infection, premenstrual status, and emotional stress. NSAID and alcohol also seem to enhance some food-allergic reactions [40]. Exercise-induced anaphylaxis (EIA) and food-dependent, exercise-induced anaphylaxis (FDEIA) are more often seen in adults than in children. The association with exercise is crucial for the onset of symptoms or signs [58-60]. The range of triggering physical activities and intensities is broad. EIA is not fully reproducible so that same exercise may not always result in anaphylaxis in a given patient.

Emergency management of anaphylaxis

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

Patients with anaphylaxis require immediate assessment using an Airway, Breathing, Circulation, Disability and Exposure approach. Problems should be treated as they are found and a call put out for emergency services (Box 7). Deaths result from upper airway, lower respiratory, and/or cardiovascular compromise so emergency management must focus on these manifestations. We recommend first-line treatment with intramuscular adrenaline before instituting other interventions as adrenaline is still underutilized in anaphylaxis [61] although it is potentially lifesaving. Cardiopulmonary resuscitation should be immediately instituted if cardiorespiratory arrest occurs. An overview is presented in Fig. 2 and check list in Box 8.

image

Figure 2. Schematic illustration of the initial management of anaphylaxis.

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Box 7.

Emergency management: recommendations

RecommendationEvidence levelGradeKey references
First-line intervention: adrenaline
Adrenaline is potentially lifesaving and must therefore promptly be administered as the first-line treatment for the emergency management of anaphylaxisIVC [22, 45, 46, 63, 64]
Earlier administration of adrenaline should be considered on an individual basis when an allergic reaction is likely to develop into anaphylaxisVDExpert consensus
Adrenaline should be administered by intramuscular injection into the mid-outer thighIB [65, 66]
In patients requiring repeat doses of adrenaline, these should be administered at least 5 min apartVD[66], expert consensus
With inadequate response to two or more doses of intramuscular adrenaline, adrenaline may be administered as an infusion by appropriately experienced intensive care, emergency department, and critical care physicians, with appropriate cardiac monitoringIVD [64]
Second-line interventions
Trigger of the anaphylaxis episode should be removedVDExpert consensus
Help should be called promptly and simultaneously with patient's assessmentVDExpert consensus
Patients experiencing anaphylaxis should be positioned supine with elevated lower extremities if they have circulatory instability, sitting up if they have respiratory distress, and in recovery position if unconsciousVD [45]
High-flow oxygen should be administered by face mask to all patients with anaphylaxisVDExpert consensus
Intravenous fluids (crystalloids) should be administered (boluses of 20 ml/kg) in patients experiencing cardiovascular instabilityVDExpert consensus
Inhaled short-acting beta-2 agonists should additionally be given to relieve symptoms of bronchoconstrictionVD [22]
Third-line interventions
Oral H1- (and H2)-antihistamines may relieve cutaneous symptoms of anaphylaxisIB [73, 74]
Systemic glucocorticosteroids may be used as they may reduce the risk of late-phase respiratory symptoms. High-dose nebulized glucocorticoids may be beneficial for upper airway obstructionVDExpert consensus
Monitoring and discharge
Patients who presented with respiratory compromise should be closely monitored for at least 6–8 h, and patients who presented with circulatory instability require close monitoring for 12–24 hVDExpert consensus
Before discharge, the risk of future reactions should be assessed and an adrenaline auto-injector should be prescribed to those at risk of recurrenceVDExpert consensus
Patients should be provided with a discharge advice sheet, including allergen avoidance measures (where possible) and instructions for the use of the adrenaline auto-injector. Specialist and food allergy specialist dietitian (in food anaphylaxis) follow-up should be organized. Contact information for patient support groups should also be providedVDExpert consensus

Box 8.

Checklist for managing anaphylaxis

1. Stay with patient
2. Look for signs of anaphylaxis
3. Administer adrenaline if signs of anaphylaxis
4. Repeat adrenaline as necessary
5. Other treatments as indicated (e.g., oxygen, beta-2 agonist, fluids, antihistamine, corticosteroid)
6. Look for trigger (e.g., food, drug, venom)
Adrenaline is effective for all symptoms

First-line intervention

Adrenaline

Adrenaline must be administered to all patients experiencing anaphylaxis; it should also be administered to those with clinical features that are likely to evolve into anaphylaxis [22, 45, 46, 62-64] (C). In an effort to increase the use of adrenaline, these guidelines place adrenaline as the first intervention for anaphylaxis. Adrenaline exerts effects on (i) α-1 receptors causing peripheral vasoconstriction, thereby reversing hypotension and mucosal edema; (ii) β-1 receptors by increasing both the rate and force of cardiac contractions, thereby reversing hypotension; and (iii) β-2 receptors reversing bronchoconstriction and reducing the release of inflammatory mediators [62]. There are no absolute contraindications to treatment with adrenaline in a patient experiencing anaphylaxis; benefits outweigh the risks in the elderly and patients with pre-existing cardiovascular disease [6].

Adrenaline should be given by intramuscular injection into the mid-outer thigh [65, 66] (A). The safety profile of intramuscular adrenaline is excellent although patients may experience transient pallor, palpitations, and headache. Intramuscular adrenaline (1 mg/ml) should be given at a dose of 0.01 ml/kg of body weight to a maximum total dose of 0.5 ml [3]. When using adrenaline auto-injectors, patients weighing between 7.5–25 kg should receive 0.15 mg dose with patients being moved to 0.3 mg dose at 25–30 kg [67]. There are no data to inform us which patients should receive a 0.5-mg dose auto-injector, if this is available. The adrenaline dose can be repeated after at least a 5-min interval (D).

Patients who require repeated intramuscular doses of adrenaline may benefit from an adrenaline infusion [64] (D). Adrenaline infusion must be given by those experienced in the use of vasopressors in their daily clinical practice, for example anesthetists, ED, and critical care doctors. Intravenous adrenaline in patients with adequate circulation may cause life-threatening hypertension, myocardial ischemia, and arrhythmias. Patients who are given intravenous adrenaline should be monitored with continuous ECG, pulse oximetry, and frequent noninvasive blood pressures.

The use of subcutaneous or inhaled adrenaline in the treatment of anaphylaxis is not recommended [68, 69]. One caveat is stridor from laryngeal edema where nebulized adrenaline (2–5 ml, 1 mg/ml) can be used in addition to intramuscular adrenaline [3] (D).

Second-line interventions

Removal of the trigger and call for help

The likely trigger of the anaphylaxis should be immediately removed, if possible [69] (D). Help should be called from the emergency medical services in the community or resuscitation team in hospital [69] (D).

Posture

Patients experiencing anaphylaxis should be kept still and positioned according to their presenting features: (i) with the most frequent presentation of respiratory distress, position sitting up (D); (ii) with circulatory instability, position lying on back with the lower extremities elevated to conserve the circulatory volume [45] (D); (iii) if pregnant, place semi-recumbent on the left side with lower extremities elevated [70] (D); and (iv) where unconscious, place in the recovery position (D). Patients should avoid sudden abrupt change to a more upright posture (D).

Oxygen

High-flow oxygen should be administered by face mask to all patients with anaphylaxis (D).

Fluid support

Intravenous fluids should be administered to patients with cardiovascular instability [71], as adrenaline may not be effective without restoring the circulatory volume (D). Crystalloids are the fluid of choice and should be given in boluses of 20 ml/kg (D).

Inhaled short-acting beta-2 agonists

Inhaled short-acting beta-2 agonists can be additionally given to relieve symptoms of bronchoconstriction in patients with anaphylaxis [22] (D). Although intramuscular adrenaline is first-line treatment in the emergency setting, in controlled circumstances in hospital with clinical staff experienced in managing anaphylaxis (e.g., oral food challenge in an allergy clinic), mild wheeze may initially be treated with inhaled short-acting beta-2 agonists alone; intramuscular adrenaline should be given if there is no response within 5 min (D).

Third-line interventions

H1- and H2-antihistamines

Systemic antihistamines are commonly used in anaphylaxis but have only been demonstrated to relieve cutaneous symptoms in studies where only a minority of participants were experiencing anaphylaxis [72]. The combination of systemic H1- and H2-antihistamines may confer additional benefits over-and-above systemic H1-antihistamines alone in relieving some cutaneous symptoms in those experiencing acute allergic reactions [73, 74]. There are case reports that intravenous antihistamines may cause hypotension; this may be related to the speed of administration [75]. Oral H1- (and H2)-antihistamines are therefore only recommended for the relief of cutaneous symptoms of anaphylaxis (B).

Glucocorticosteroids

Oral or intravenous glucocorticosteroids are commonly used in anaphylaxis and are thought to possibly prevent protracted anaphylaxis symptoms, particularly in patients with concomitant asthma, and also biphasic reactions; however, this has not been proven and they have a slow onset of action. Oral or parenteral glucocorticosteroids may be given once first- and second-line therapies have been administered (D). High doses of nebulized budesonide may be effective for airway edema (D); this is therefore recommended for patients presenting with stridor.

Other potential treatments

Glucagon

Parenteral administration of glucagon may be useful in treating patients with anaphylaxis who are unresponsive to adrenaline, particularly in those taking beta-blockers [76] (D).

Monitoring and discharge arrangements

Patients who presented with respiratory compromise should be closely monitored for at least 6–8 h, and patients who presented with hypotension require close monitoring for at least 12–24 h (D). Before discharge, the risk of future reactions should be assessed and an adrenaline auto-injector prescribed to those at risk of recurrence (D). Patients should be provided with a discharge advice sheet, including allergen avoidance measures (where possible), instructions for when and how to use the adrenaline auto-injector; referral to an allergy specialist to investigate possible triggers, assess and, where possible, to intervene to minimize the risk of further reactions, and ensure that patients and caregivers are optimally equipped and trained to manage any further reactions; and, if food is involved, referral to a specialist dietitian (D). Contact information for patient support groups should ideally be provided to signpost sources of further useful information.

Long-term management of anaphylaxis

The long-term management of patients who have experienced anaphylaxis starts with the confirmation of triggering allergens using validated in vivo and/or in vitro tests interpreted in light of a detailed allergy history. Preventive strategies to avoid recurrence include allergen avoidance [3] and allergen immunotherapy where possible should be implemented. Finally, education should be provided covering self-treatment of anaphylaxis recurrence in the community, and management of relevant concomitant diseases [6] (Box 9). An allergy specialist dietitian can help identify food triggers and provide avoidance advice. Patients should be carefully instructed about hidden allergens, cross-reactions to other allergens, and situations that constitute a special hazard such as eating out (see Food Allergy Guidelines for further details) [77] (Box 9). Most recommendations are based on expert opinion (Box 10).

Box 9.

Summary of the long-term management in the community of patients at risk of anaphylaxis

• Provision of individualized management plan written clearly in simple, nonmedical language; it should include:
personal identification data: name and address; contact details of the parents, guardian, or next of kin, allergist, family doctor and the local ambulance service; and preferably a photograph
clear identification of the source of the allergens to be avoided and allergen avoidance advice
clear identification of any nonallergen triggers or cofactors, such as exercise, and avoidance advice
anaphylaxis emergency action plan
• Copy of plan should be kept by the patient, any caregivers, school staff, and family doctor.
• Provision of emergency kit with copy of anaphylaxis emergency action plan and medications for self-treatment, e.g.
adrenaline auto-injector for treating anaphylaxis, where appropriate
fast-acting, nonsedating, antihistamine for treating cutaneous allergic reactions, where appropriate
• Venom immunotherapy and desensitization in drug allergy as appropriate
• Training of patients and caregivers, this should include:
instructions on appropriate allergen avoidance measures, including consultation with an allergy dietitian, where appropriate
instructions on prompt recognition of symptoms of anaphylaxis
training on when and how to use an adrenaline auto-injector, where appropriate
reinforcement with revision at regular yearly intervals
• Psychological support as required
• Implementation of the patient's management plan in the community (e.g., nursery, school)

Box 10.

Long-term management: recommendations

RecommendationEvidence levelGradeKey references
Anaphylaxis management plan
An anaphylaxis management plan should be used from the time of diagnosis to prevent future reactions, and aid recognition and treatment of any further reactionsIIIC [79, 80]
Venom immunotherapy
Subcutaneous venom immunotherapy is recommended in venom-allergic patients with a previous episode of anaphylaxis and adults with systemic cutaneous reactionsIA [56, 90-93]
Training
Training in the recognition and management of anaphylaxis should be offered to all patients and caregivers of children at risk of anaphylaxis ideally from the time of diagnosisVD [3, 6]
Training in the recognition and management of anaphylaxis, including the use of adrenaline auto-injectors, should be offered to all professionals dealing with patients at risk of anaphylaxisIVC [115]
Training packages should be developed with the target groupsVDExpert consensus
Training should cover allergen avoidance, symptoms of allergic reactions, when and how to use an adrenaline auto-injector, and what other measures are needed within the context of an anaphylaxis management planVD [3, 6, 79, 125]
Training may involve more than one session to allow revision, an interactive scenario-based approach, a standardized program with manual and educational material and simulation tools. Content and language should be tailored to be understood and memorizedVD [3, 126]
Psychological interventions
Educational interventions should ideally incorporate psychological principles and methods to address anxiety so that children and families may function well at home, at school/work, and socially despite their risk of future reactions and should ideally be part of their educational training. This can be done in a group format. Some patients, with severe anxiety of ongoing duration, may need more in-depth one-to-one psychological interventionVD [110, 123, 124]

Anaphylaxis management plans

Anaphylaxis management plans should cover avoidance advice, contact details for advice plus an anaphylaxis emergency action plan with likely presenting symptoms, and how to respond to each. Studies have shown that after the inception of a management plan, accidental reactions are less common, at least in children with peanut or tree nut allergies [78, 79]. A management plan used by a multidisciplinary allergy clinic had a positive effect on parental knowledge of avoidance measures and emergency treatment of reactions in another study [80]. Anaphylaxis management plans should be used from diagnosis to aid recognition and treatment of any further reactions and should be regularly updated [81, 82] (C) (Box 11).

Box 11.

Example of an individualized anaphylaxis emergency action plan

  1. This is only one example of an anaphylaxis action plan. The plan should be individualized, for example patients with previous rapid-onset life-threatening anaphylaxis may be instructed to use their self-injectable adrenaline earlier in the development of any subsequent allergic reaction.

If you think you/your child/other are having an anaphylactic reaction after possible contact with an allergic trigger
Or after possible contact with an allergic trigger, any of the following symptoms may indicate that you/your child/other is experiencing an anaphylactic reaction
Airway problems swelling of tongue
swelling/tightness in the throat
difficulty swallowing
difficulty talking and/or hoarse voice
Breathing problems difficulty breathing
noisy breathing, wheeze, and/or persistent cough
Reduced consciousness feeling faint, dizziness, confused state, or loss of consciousness pale and floppy (young children)
Then
1. Immediately administer adrenaline auto-injector into the upper outer thigh
2. Call an ambulance stating that the patient is having an anaphylactic reaction
3. Lay person having the reaction down (with legs up if possible); if there is difficulty in breathing, allow them to sit up but not stand
4. If no improvement after 5 min, administer a second adrenaline auto-injector.
When in doubt, administer the adrenaline auto-injector

Indications for adrenaline auto-injectors

There are six absolute indications for a prescription of an adrenaline auto-injector (Box 12): (i) previous anaphylaxis with food, latex, aeroallergens such as animals or other unavoidable triggers (C); (ii) EIA (C); (iii) previous idiopathic anaphylaxis (C); (iv) co-existent unstable or moderate to severe, persistent asthma with food allergy (C); (v) venom allergy in adults with previous systemic reactions (unless receiving maintenance VIT) and children with more than systemic cutaneous reactions (C); and (vi) underlying mast cell disorder and any previous systemic reaction (C). The asthma indication is extrapolated from data emerging from retrospective studies [15, 83-86]. There are a large number of relative indications based on case series or expert consensus (Box 12). As a guide, the presence of one should lead to the consideration of the prescription of an adrenaline auto-injector; in the presence of two or more, strong consideration should be given to prescription; a specialist allergy review may help to balance the advantages and disadvantages of prescribing. Prescription practices differ considerably [87], and there may be additional local indications such as lipid-transfer protein sensitization in the Mediterranean region.

Box 12.

Indications for prescription of an adrenaline auto-injector

RecommendationEvidence levelGradeKey references
  1. a

    Excluding pollen food syndrome (oral allergy syndrome).

Absolute indications for at least one adrenaline auto-injector
Previous anaphylaxis triggered by food, latex, or aeroallergensIVC [127, 128]
Previous exercise-induced anaphylaxisIVC [58]
Previous idiopathic anaphylaxisIVC [61]
Co-existing unstable or moderate to severe, persistent asthma and a food allergyaIVC [15, 83-86]
Venom allergy in adults with previous systemic reactions (not receiving maintenance VIT) and children with more than cutaneous/mucosal systemic reactionsIVC [56, 129, 130]
Underlying mast cell disorders or elevated baseline serum tryptase concentrations together with any previous systemic allergic reactions to insect stings, even in VIT-treated patientsIVC [52, 56, 103, 130]
Consider prescribing at least one adrenaline auto-injector with any of the following additional factors (especially if more than one is present)
Previous mild-to-moderate allergic reactiona to peanut and/or tree nutIVC[51, 79]
Teenager or young adult with a food allergya IVC [22, 45, 46, 63, 131]
Remote from medical help and previous mild-to-moderate allergic reaction to a food, venom, latex, or aeroallergensVD [131]; Expert consensus
Previous mild-to-moderate allergic reaction to traces of fooda VD [22, 45, 46, 63, 131]

There are no high-quality data to help decide how many adrenaline auto-injectors should be available to individual patients. The percentage of patients who required a further dose of intramuscular adrenaline after the administration of an auto-injector was 0–15–32% in different patient groups [15, 61, 83, 84, 88, 89] (Box 13) with the additional adrenaline given by healthcare professionals in over 80% of cases. Co-existent asthma was found to be a risk factor for additional adrenaline in one study [84]. The challenge is therefore to identify the patients who need to have access to more than one auto-injector. Indications for two auto-injectors are suggested in Box 14. There may also be practical, psychological, or policy considerations as to why a specific patient needs more than one auto-injector.

Box 13.

Rate of usage of adrenaline auto-injectors by patients

ReferenceStudy designAuto-injector prescriptionUsed an auto-injector during follow-upa Reactions where initial intramuscular adrenaline dose was followed by additional dosesb
Notes
  1. a

    Refers to individual patients.

  2. b

    Refers to individual allergic reactions (often more than one per patient). Additional doses were usually given by a healthcare professional.

[61] Retrospective clinic populationAll4% (41/969) over a 12-month period32% (13/41)
[88] Retrospective clinic populationAll22% (15/68) over a 20-month period15% (2/13)
[89] Prospective clinic populationNot all3% (23/785) over an average of 48 months0% (0/23)
[84] Prospective clinic populationNot all19% (78/413) over an average of 24 months19% (18/95)
[15] Patient surveyNot all27% (500/1885)18% (90/500)
[83] Patient surveyNot all35% (22/63)18% (4/22)

Box 14.

Suggested indications for prescription of a second adrenaline auto-injector

Suggested indications for prescribing a second auto-injector for the patient to carry include:Evidence levelGradeKey references
  1. a

    Excluding pollen food syndrome (oral allergy syndrome).

Co-existing unstable or moderate to severe, persistent asthma and a food allergya IVC [84]
Co-existing mast cell diseases and/or elevated baseline tryptase concentrationIVC [129, 130]
Lack of rapid access to medical assistance to manage an episode of anaphylaxis due to geographical or language barriersVDExpert consensus
Previous requirement for more than one dose of adrenaline prior to reaching hospitalVDExpert consensus
Previous near fatal anaphylaxisVDExpert consensus
If available auto-injector dose is much too low for body weightVDExpert consensus

Immunomodulatory approaches

Venom immunotherapy

Systematic reviews [90-92] and meta-analyses [93] have demonstrated the effectiveness of subcutaneous venom immunotherapy (VIT) in children and adults (A). Patients treated with VIT have a better health-related quality of life than those just provided with an adrenaline auto-injector [94, 95]. Subcutaneous VIT is therefore recommended in venom allergy for both children and adults with anaphylaxis plus adults with systemic cutaneous reactions (A). Some children with cutaneous sting reactions, where VIT is not indicated, may benefit from having access to an auto-injector [56]. The recent systematic review has found VIT to only be cost-effective in populations at high risk of further exposure [93], but the analysis did not incorporate quality of life [96]. Rush protocols (i.e., over a few days) are as equally efficacious as slower regimens [97]. More adverse effects have been reported with an ultra-rush (few hours) compared to a rush protocol [52] and with rush compared to cluster protocols [98].

Drug desensitization

Drug desensitization is defined as the induction of a temporary state of clinical tolerance of a compound responsible for a hypersensitivity reaction. It is undertaken by administering increasing doses of the medication concerned (e.g., antibiotic, insulins, sulfonamides, chemotherapeutic and biological agents) over a short period of time (from several hours to a few days), until the total cumulative therapeutic dose is achieved and tolerated. It should only be used by trained doctors when alternatives are less effective, not available, or contraindicated after considering the risks and benefits. It is mainly undertaken in IgE-mediated reactions, but also in reactions where drug-specific IgE levels have not been demonstrated (e.g., acetyl salicylic acid). Desensitization induces a temporary tolerant state, which can only be maintained by continuous administration of the medication.

Food oral immunotherapy

There are currently no established oral immunotherapy treatment protocols for food-induced anaphylaxis. Recent data suggest that immunotherapy may increase the amount of a tolerated dose over time [99]. Significant systemic side-effects can occur, and currently, these protocols are not recommended in clinical practice [see related Food Allergy Guidelines [77]].

Prophylaxis

Adrenaline admixture with snakebite antivenom

The use of subcutaneous adrenaline alone as a premedication with snakebite antivenom reduces the risk of anaphylaxis to the snake antivenom administration [100, 101] (A). The use of hydrocortisone alone does not reduce severe adverse reaction to snake antivenom [102] (A).

Pharmacological interventions for the prevention of anaphylaxis to iodinated contrast media

The routine use of prophylactic systemic premedication (H1- and/or H2-antihistamines or glucocorticosteroids) cannot be recommended in unselected people undergoing procedures with radiocontrast media as they do not prevent life-threatening reactions [103] (A). There are no available data to support the use of premedication in patients with a previous reaction to another allergen [104].

Training

Who should be trained

As anaphylaxis usually occurs in the community [105-107], all patients at risk of anaphylaxis and their caregivers should be provided with educational resources and training to be able to self-manage reactions ideally from the time of diagnosis (D) (Box 9). Adolescent patients require particular attention given the challenges associated with this period of life [108-111].

What training should cover

Training should cover patient-specific avoidance strategies at home, in the social environment and when traveling [112] (D), recognition of symptoms and warning signals, when and how to administer self-injectable adrenaline and other measures needed to manage the reaction (e.g., call for help, positioning) (D). Training should emphasize the need to continually carry the auto-injector where one has been prescribed [113] (D).

How they should be trained

Several studies indicate that for most patients, the standard prescription and formal instruction on how to prevent and treat anaphylaxis by a physician are insufficient to achieve compliance with respective practical measures, including carrying an adrenaline auto-injector [114] and appropriately using it [61]. This is compounded by the inability of many clinicians to correctly use an adrenaline auto-injector [3, 115]. Training should be offered to all professionals dealing with patients at risk of anaphylaxis (C). Educational training has been shown to be clinically effective in chronic allergic diseases such as asthma and atopic eczema or dermatitis [116, 117]. Patient education programs are especially effective when using a written action plan [118], a multidimensional and multidisciplinary approach [119], or involved repeated regular medical reviews [120] in other conditions. A multidisciplinary approach [80] and the provision of educational printed and online materials for food allergy [121] have both been shown to improve knowledge, correct use of auto-injectors, and reduce reactions using a before-and-after study design. Repeated instructions on how to use an adrenaline auto-injector improved correct use in one center [122] (see Supporting Information Table S3).

Psychological interventions

Information about the future risk of anaphylaxis may lead to stress and anxiety in patients and caregivers [110, 123, 124]. Research suggests that this should be addressed by alleviating uncertainty using psychological principles and methods to maximize quality of life as part of the educational training [123] (Box 11) (D). This can be done in a group format. Some patients, with severe anxiety of ongoing duration, may need more in-depth one-to-one psychological intervention [123] (D) (see Supporting Information Table S4).

Summary and future perspectives

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

Anaphylaxis is an important clinical emergency which all healthcare professionals should be able to recognize and manage. Anaphylaxis is a clinical diagnosis based on a constellation of presenting features. Allergy tests are usually helpful in accurately identifying the trigger. First-line treatment is intramuscular adrenaline, which may be repeated if required. Second-line interventions include removing the trigger, calling for help, correct positioning of the patient, high-flow oxygen, intravenous fluids, inhaled short-acting bronchodilators, and nebulized adrenaline. The evidence base for these and other potential interventions is neither comprehensive nor robust. Patients should be monitored after recovery to observe for possible biphasic reactions. Before discharge, an assessment should be made of the risk of further reactions; where appropriate, the patient should be equipped with an adrenaline auto-injector. The absolute indications for an adrenaline auto-injector are (i) previous anaphylaxis with food, latex, aeroallergens such as animals, and other unavoidable triggers; (ii) previous EIA; (iii) previous idiopathic anaphylaxis; (iv) co-existent unstable or moderate to severe, persistent asthma with food allergy; (v) untreated venom allergy in adults with previous systemic reactions (unless on maintenance VIT) and children with more than systemic cutaneous reactions; and (vi) underlying mast cell disorder and any previous systemic reaction. Specialist allergy follow-up is essential to investigate possible triggers as well as potential cofactors, to perform a risk assessment, prevent future episodes by developing personalized risk reduction strategies, including allergen immunotherapy where indicated, as well as a personalized emergency response plan for future allergic reactions. Patients with food allergy should also have advice from a dietitian. Training the patient and caregivers is essential and should cover avoidance strategies, recognition of symptoms and warning signals, when and how to administer medication including self-injectable adrenaline. Other professionals within health care, education, and childcare should also be trained to recognize and appropriately manage anaphylaxis.

Two recent, related EAACI systematic reviews of the anaphylaxis literature [1, 2] have revealed a lack of high-quality evidence in this area preventing the development of firm recommendations. It is important that these gaps are prioritized to maximize the benefit of future research to patient care [132]. Large prospective cohort studies of patients at risk of anaphylaxis in real-life settings are required to provide a clearer understanding of the magnitude of risk associated with each factor to allow us to personalize avoidance advice and auto-injector prescription (Box 15). For patients experiencing anaphylaxis, we need further pharmacokinetic studies to determine the optimal dose and dosing interval, especially for adult patients (Box 15). Further work on other routes of adrenaline administration should be encouraged as adjuvants to intramuscular adrenaline. Additionally, randomized controlled studies are required to assess the effectiveness of systemic glucocorticosteroids in preventing late manifestations of anaphylaxis and whether the addition of antihistamines improves the respiratory and/or cardiovascular features of anaphylaxis. Finally, we need evidence to assess the effectiveness of training and anaphylaxis management plans in improving outcome in patients (Box 15).

Box 15.

Anaphylaxis: gaps in the evidence

GapPlan to addressPriority
Anaphylaxis epidemiology and clinical presentation
Clinical definition and diagnostic criteria for allergic anaphylaxis that are easy to use in practice by emergency room medical staffConsensus process2
Universally accepted, epidemiological definition and associated coding criteria to allow accurate modeling of anaphylaxis casesConsensus process3
Accurate estimation of the incidence, prevalence, burden, and mortality rate of anaphylaxis in different populations across EuropeApplication of new definition and criteria plus study of routine clinical diagnostic data4
Clearer understanding of the magnitude of risk factors for future occurrence of anaphylaxisLarge prospective cohort studies of patients at risk of anaphylaxis1
Emergency management
First-line intervention: adrenaline
Optimal dose and dosing intervals of intramuscular adrenaline in patients experiencing anaphylaxisPharmacokinetics studies1
Role of other routes of adrenaline (e.g., inhaled, sublingual) in anaphylaxisRandomized controlled trials2
Data comparing the pharmacokinetics of different adrenaline auto-injector devicesRandomized controlled trials4
Second-line interventions
Role of second-line drugs in the treatment of anaphylaxis, namely oxygen and inhaled beta-2 agonistsRandomized controlled trials5
Comparative efficacies of crystalloids and colloids in the treatment of cardiovascular instability during anaphylaxisRandomized controlled trials6
Third-line interventions
Role of third-line interventions in the treatment of anaphylaxis, namely H1-antihistamines and systemic glucocorticosteroidsRandomized controlled trials3
Long-term management, training, and psychological interventions
Anaphylaxis management plans
Multiple different anaphylaxis management plans and emergency action plans in useConsensus process with all stakeholders5
Evidence on the effectiveness of anaphylaxis management plans, particularly in different subgroup (e.g., age, allergy type, different risk levels)Pragmatic large randomized controlled trials2
Evidence on the utility of management plans (e.g., with quality of life questionnaires)Pragmatic randomized controlled trials7
Adrenaline auto-injectors
Who should have an adrenaline auto-injector and how many should they have access to?Large prospective studies, well-phenotyped participants, clear criteria for anaphylaxis1
Whether a stock supply of adrenaline auto-injectors in locations such as schools might improve the management of anaphylaxis in the community?Large cluster randomized controlled trials8
Venom immunotherapy
It is unclear if venom immunotherapy is able to prevent fatal reactions, because of the rarity of this outcomeControlled studies would be unethical
Cost-effective evaluation of the treatment in relation to quality of life rather than survival rateHealth economic analysis9
Comparative studies on the effect of different build-up protocols (traditional versus rush and ultra-rush) with the same extract focusing on safetyRandomized controlled trials comparing approaches10
Prophylactic interventions
Studies to compare the effectiveness of prophylactic premedication toprevent life-threatening reactions due to iodinated contrast media in patients with a history of a previous immediate reactions or potential risk factors for reactionsLarge randomized controlled trial11
Studies looking at the impact of other immunomodulatory interventions on reducing the risk of further episodes of anaphylaxis, for example monoclonal anti-IgE (e.g., omalizumab)Randomized controlled trials to assess
Training
Evidence on the efficacy of training of patients and direct caregivers/parents of children and other groups such as teachers, day care workers, nurses, and physiciansRandomized controlled trial to assess the impact of training3
Evidence on the optimal content, trainers (e.g., physicians, allergy specialist dietitians), duration, repetition and format of training and whether it should vary for patients of different ages and different future riskDevelopment of training program with stakeholders and formal assessment of effectiveness4
Psychological interventions
Short- and long-term efficacy of different psychological interventions and their influence on quality of life, knowledge, anxiety, compliance with carriage of in-date adrenaline auto-injectors, performance in an emergency situation, and social functioning in at-risk patients and their caregivers and how differing personalities impact the efficacy of the interventionsRandomized controlled trial assessing the impact of approach6

Expert Panel

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

We are grateful to the expert panel for providing expert feedback; C. Camargo (Harvard Medical School, Boston), J. Gardener (Royal Free Hospital, London), G. Hedlin (Karolinska Institutet, Stockholm), M. Levin (Red Cross War Memorial Children's Hospital, Cape Town), P. Lieberman (Nova Southeastern University, Davie), R. Loh (Princess Margaret Hospital, Subiaco), H. Mosbech (Copenhagen University Hospital, Copenhagen), J. Ring (Klinik und Poliklinik für Dermatologie und Allergologie am Biederstein der TU München, Munich), M. Said (Allergy & Anaphylaxis Australia Inc, Australia), E. Simons (University of Manitoba, Winnipeg), J. Soar (North Bristol NHS Trust, Bristol) and M. Triggiani (Università degli Studi di Napoli ‘Federico II’, Napoli).

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

We would like to acknowledge the support of EAACI and the EAACI Food Allergy and Anaphylaxis Guidelines Group in developing these guidelines. We would like to thank Toby Pitts-Tucker and Catherine Crowley for their assistance in preparing the guidelines. We would also like to thank our expert panel and everyone who provided comments on the draft guidelines (in particular Moira Austin, Carlo Caffarelli, Rollo Clifford, Lene Heise Garvey, Lars Gottberg, Joanna Lange, Barbara Rogala, Francesca Saretta, Peter Standring, Alessandra Ometto, and David Reading) and the EAACI Executive Committee for their helpful comments and suggestions.

Author contributions

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

Antonella Muraro, Chair of the EAACI Food Allergy and Anaphylaxis Guidelines Initiative, has steered and coordinated the publication. Graham Roberts facilitated the anaphylaxis guidelines group and edited the guidelines document with support from Margitta Worm. M. Beatrice Bilò, Knut Brockow, Montserrat Fernández Rivas, Alexandra F. Santos, Zaraquiza Zolkipli, and Aziz Sheikh coordinated drafting of the evidence table, recommendations, gaps, and text for specific sections. Sangeeta Dhami and Sukhmeet Panesar undertook the supporting systematic reviews under the supervision of Aziz Sheikh. All authors participated in the discussion of the evidence table, recommendations, gaps, and specific sections and approved the final version.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information

Graham Roberts has provided scientific advice for Danone and ALK-Abelló; Thermo Fisher and ALK-Abelló have provided consumables for his research activities. Antonella Muraro has provided scientific advice for Meda. Margitta Worm has provided scientific advice for ALK-Abelló. M. Beatrice Bilò has provided scientific advice for Meda. Knut Brockow has provided scientific advice for ALK-Abelló, Meda, Thermo Fisher, and Stallergenes. Montserrat Fernández Rivas has provided scientific advice to GSK; ALK-Abelló has provided consumables for her research activities. Carsten Bindslev-Jensen has received funding from Thermo Fisher, HAL, Stallergenes, and Anergis, ALK, Novartis, MSD, Schering-Plough for his research activities. Victoria Cardona has provided scientific advice for ALK-Abelló. Pascal Demoly has provided scientific advice for Stallergenes, ALK-Abelló, Circassia, Allergopharma, Chiesi, Menarini, and Pierre Fabre Médicament; Tony DuBois has provided scientific advice for ALK-Abelló and received funding from ALK-Abelló to support his research activities. Audrey DunnGalvin has received funding from Novartis for her research. Philippe Eigenmann has provided scientific advice for Danone, Novartis, ALK, DBV technologies, and Stallergenes; he has received funding for research activities from LETI, Nestlé, and Thermo Fisher. Susanne Halken has provided scientific advice for ALK-Abelló. Marek Jutel has been an investigator for clinical studies led by Allergopharma, Stallergenes, Novartis, GSK, and Medimmune. Franziska Ruёff has been an investigator for clinical studies led by Allergopharma, HAL, Novartis, and Pierre Fabre and has received travel grants and honoraria as a speaker from ALK-Abelló, Bencard, HAL, Novartis, and Thermo Fisher. Frans Timmermans has received unrestricted grants from ALK-Abelló, MSD, MEDA for the activities of European Anaphylaxis Taskforce – Nederlands Anafylaxis Netwerk which he manages. Berber Vlieg–Boerstra has provided scientific advice for Danone and Mead Johnson; she has received research grants from Nutricia Advanced Medical Nutrition and ALK-Abelló. Sukhmeet Panesar, Sangeeta Dhami, and Aziz Sheikh have received funding for coordinating guidelines production and generating the systematic reviews from EAACI. Aziz Sheikh has provided scientific advice to ALK-Abelló, Meda, Lincoln Medical, Thermo Fisher, Pfizer, and Stallergenes; he is on the Anaphylaxis Campaign UK's Scientific Committee, World Allergy Organization's Anaphylaxis Special Committee, UK Resuscitation Council's Anaphylaxis Committee, and the BSACI's Standard of Care Committee. Laurie Harada works for Anaphylaxis Canada whose educational activities have been supported by Pfizer and Sanofi. Alexandra F. Santos, Zaraquiza Zolkipli, Cezmi Akdis, Kirsten Beyer, Abdul Bellou, Gideon Lack, Bodo Niggemann, Andy Clark, and Thomas Werfel have no conflict of interests.

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  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Methods
  4. Epidemiology
  5. Clinical presentation and diagnosis
  6. Emergency management of anaphylaxis
  7. Summary and future perspectives
  8. Expert Panel
  9. Acknowledgments
  10. Author contributions
  11. Conflicts of interest
  12. References
  13. Supporting Information
FilenameFormatSizeDescription
all12437-sup-0001-Table-S1.docWord document80KTable S1. Emergency management recommendations: barriers and facilitators to implementation, audit criteria and resource implications of recommendations.
all12437-sup-0002-Table-S2.docWord document43KTable S2. Long-term management recommendations: barriers and facilitators to implementation, audit criteria and resource implications of recommendations.
all12437-sup-0003-Table-S3.docWord document52KTable S3. Training recommendations: barriers and facilitators to implementation, audit criteria and resource implications of recommendations.
all12437-sup-0004-Table-S4.docWord document42KTable S4. Psychological intervention recommendations: barriers and facilitators to implementation, audit criteria and resource implications of recommendations.

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