International consensus on (ICON) anaphylaxis

Definition of anaphylaxis

In these guidelines, the independently developed definitions of anaphylaxis for clinical use by healthcare professionals all include the concepts of a serious, generalized or systemic, allergic or hypersensitivity reaction that can be life-threatening or fatal. Importantly, none of the definitions include the word “shock” [2-4] (Table 2). The correct term “anaphylaxis” is preferred to “anaphylactic shock” because shock is not necessarily present in patients with anaphylaxis [23-26]. The term “anaphylaxis” should also be used in preference to terms such as “allergic reaction”, “acute allergic reaction”, “systemic allergic reaction”, “acute IgE-mediated reaction”, “anaphylactoid reaction”, or “pseudo-anaphylaxis” [2-4].

Epidemiology

None of the guidelines has a major focus in this area [2-4]; however, they all include important information about anaphylaxis epidemiology supported by relevant references [2-4,27-37] (Table 2).

Patient-specific risk factors and co-factors relevant to anaphylaxis

The guidelines concur about the importance of patient-specific risk factors and co-factors in anaphylaxis [2-4]. The WAO Guidelines emphasize risk factors related to age (infancy, adolescence, advanced age), physiologic state (pregnancy), concomitant diseases including asthma, cardiovascular diseases (CVD), and mastocytosis, and concurrent medications such as beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. The AAAAI/ACAAI Guidelines describe patient-specific risk factors such as asthma, CVD, and mastocytosis, and concurrent beta-blocker and ACE-inhibitor use. The EAACI Guidelines include a major focus on asthma as a patient risk factor (Table 2).

The guidelines also concur about the relevance of co-factors that amplify [2-4] anaphylaxis. The WAO Guidelines and EAACI Guidelines provide an overview of co-factors such as exercise, emotional stress, acute infection, fever, concomitant ingestion of ethanol or a non-steroidal anti-inflammatory drug (NSAID), disruption of routine, and perimenstrual status. The AAAAI/ACAAI Guidelines focus on exercise. The importance of risk factors [38-49] and amplifying co-factors [33,50,51] that potentially impact anaphylaxis is now widely acknowledged; indeed, co-factors are now reported to be relevant in 20-30% of anaphylactic episodes [33,50].

None of the guidelines describe the relationship between mast cell activation disorders (MCAD) and anaphylaxis, perhaps because the first international consensus document on classification of MCAD was only published in 2012 [45].

Underlying mechanisms

The WAO Guidelines provide a brief overview of IgE-dependent and IgE-independent immunologic mechanisms and direct mast cell stimulation in anaphylaxis [2]. The AAAAI/ACAAI Guidelines describe immunologic mechanisms and direct mast cell activation in the context of different triggers [3]. The EAACI Guidelines focus mainly on IgE-mediated anaphylaxis [4] (Table 2).

None of the guidelines provide optimal information on IgG-mediated anaphylaxis in humans, an emerging area of investigation [52].

Anaphylaxis triggers (Causes, Elicitors, or Inducers)

The WAO Guidelines describe triggers and idiopathic anaphylaxis concisely, and note that different triggers predominate in different age groups and different global regions [2]. The AAAAI/ACAAI Guidelines provide detailed information about many triggers including foods, stinging insect venoms, drugs, biological agents, perioperative agents, radiocontrast media, latex, subcutaneous allergen immunotherapy, and human seminal fluid; also about idiopathic anaphylaxis [3]. The EAACI Guidelines emphasize food triggers, provide information on stinging insect venom and drug triggers, and state that the relative importance of triggers varies with age and geography [4] (Table 2).

Anaphylaxis triggers such as food, venom, and drugs have been studied in Australia, Europe, North America, and beyond; for example, in Asia (China, Japan, Korea, Singapore, and Thailand), and South America (Argentina, Brazil, and Venezuela) [27-37,53-66]. In any region, the relative importance of triggers can change over time [54].

Clinical diagnosis of anaphylaxis

Collaborating organizations’ guidelines concur about making the clinical diagnosis of anaphylaxis based on recognition of sudden onset of characteristic symptoms and signs within minutes to hours after exposure to a known or likely trigger [2-4]. They all list the clinical criteria for diagnosis of anaphylaxis that were developed as an instrument for rapid assessment of patients who present with a possible diagnosis of anaphylaxis [23] and are validated for use in medical settings and in epidemiologic studies [67,68] (Table 3).

The guidelines also concur that laboratory tests are not helpful in diagnosing anaphylaxis at the time of patient presentation [2-4]. Measurement of a biologic marker such as serum total tryptase takes hours and test results are not available on an emergency basis. Elevation in biologic marker levels correlates with anaphylaxis severity [24]; platelet-activating factor levels appear to correlate better than tryptase or histamine levels do [69]. Tryptase levels are elevated in only about 60% of adults with clinically confirmed anaphylaxis [70] and are seldom elevated in children with anaphylaxis or in food-induced anaphylaxis. The reference range for tryptase levels in infants has been established [71]. Tryptase levels (or levels of any other biologic markers) within the normal reference range do not rule out anaphylaxis. Lack of availability of biologic marker measurements is not a barrier to prompt clinical diagnosis of anaphylaxis [2-4].

In addition to the above, all the guidelines provide a perspective on the differential diagnosis of anaphylaxis [2-4] (Table 3).

Prompt initial treatment of anaphylaxis

Importantly, collaborating organizations’ guidelines concur with regard to recommendations for prompt initial treatment of anaphylaxis with epinephrine (adrenaline) injected intramuscularly in the mid-outer thigh, and repeating the epinephrine dose after 5-15 minutes if the response to the first injection is not optimal [2-4] (Table 4).

The guidelines concur about the importance of preparedness to diagnose and treat anaphylaxis and about other measures such as rapid assessment of the patient, removing the trigger if possible, and calling for help. They all recommend positioning the patient supine (or semi-reclining in a position of comfort if dyspneic or vomiting) with elevation of the lower extremities [2-4].

The guidelines also concur that if indicated at any time, supplemental oxygen, intravenous (IV) fluid resuscitation with a crystalloid such as 0.9% (isotonic) saline, and cardiopulmonary resuscitation should be started without delay [2-4] and that H₁-antihistamines, H₂-antihistamines, and glucocorticoids are not initial medications of choice [72-75].

There are a few differences in emphasis among the guidelines with regard to initial treatment of anaphylaxis. The WAO Guidelines include the revised resuscitation guidelines recommendations for starting cardiopulmonary resuscitation with chest compressions before giving rescue breaths, allowing time for complete chest recoil, and minimizing interruptions for pulse checks [2,76]. The WAO Guidelines and AAAAI/ACAAI Guidelines describe epinephrine injection, calling for help, and positioning the patient appropriately as concurrent initial steps [2,3], while the EAACI Guidelines describe epinephrine injection as a first-line intervention and calling for help and positioning as second-line interventions [4]. The WAO Guidelines and the AAAAI/ACAAI Guidelines do not specifically recommend inhaled epinephrine for patients with stridor during anaphylaxis, although they note that an inhaled beta-2 agonist should be considered in patients with bronchospasm that persists despite epinephrine treatment [2,3]. The EAACI Guidelines recommend inhaled epinephrine (adrenaline) in patients with stridor and an inhaled beta-2 adrenergic agonist in patients with wheezing after, and in addition to, epinephrine injection [4] (Table 4).

None of the guidelines discuss epinephrine injection in high-risk patients after exposure to a relevant trigger but before symptoms develop and none discuss epinephrine administration to a patient diagnosed incorrectly with anaphylaxis, perhaps because there is little or no published information on either of these issues.

Epinephrine utilization in anaphylaxis remains an active area of research. The need for prompt epinephrine use to prevent escalation of mediator release in anaphylaxis has been confirmed in a new in vitro model [77]. Use of multiple epinephrine injections does not necessarily correlate with patient obesity [78]. Rates of epinephrine utilization as the initial medication for anaphylaxis in emergency departments are typically low [79]; however, they can be improved significantly with implementation of an anaphylaxis protocol [80,81].

Management of anaphylaxis refractory to initial treatment

The guidelines differ in emphasis on refractory anaphylaxis treatment. The WAO Guidelines stress the importance of prompt initial treatment to prevent escalation of symptoms [2]. They suggest that if possible, patients with anaphylaxis refractory to epinephrine, supplemental oxygen, IV fluids, and second-line medications should be transferred to the care of a specialist team for ventilatory and inotropic support and continuous electronic monitoring [2]. The AAAAI/ACAAI Guidelines provide details about interventions for cardiopulmonary arrest, airway management, and IV administration of vasopressors including epinephrine, dopamine, and vasopressin [3]. The EAACI Guidelines include brief specific instructions about when to call for Intensive Care Unit support [4] (Table 4).

Studies relevant to refractory anaphylaxis treatment are of interest. A Cochrane review of randomized controlled trials (RCT) in more than 20,000 critically ill patients with distributive shock supports administration of crystalloids such as 0.9% saline, because administration of colloids such as albumin or hetastarch did not correlate with increased survival [82]. Methylene blue administration for vasoplegia in anaphylaxis refractory to epinephrine and IV fluid resuscitation is based on case reports and extrapolation from use in other forms of shock [83].

Observation and monitoring in healthcare settings

The guidelines concur that patients with moderate or severe anaphylaxis, for example, those with moderate or severe respiratory or cardiovascular symptoms and signs should be observed and monitored for a longer duration (eg. at least 6-8 hours) than those with mild anaphylaxis. The WAO Guidelines note that duration of monitoring can also vary with patient age and co-morbidities, and with local conditions. The AAAAI and EAACI Guidelines provide additional information about biphasic anaphylaxis and protracted anaphylaxis [2-4] (Table 4).

In a prospective study in which mediator release in anaphylaxis was documented at sequential timed intervals, levels of some mediators correlated with delayed deterioration, supporting recommendations for safe observation periods after initial treatment [24].

The guidelines also concur that blood pressure, cardiac rate and function, respiratory status and oxygenation should be monitored clinically at frequent intervals (every 1-5 minutes), or if possible, continuously [2-4]. Lack of universal availability of continuous electronic monitoring and pulse oximetry remains a concern.

Post-discharge management of patients treated for acute anaphylaxis

Collaborating organizations’ guidelines concur that management of anaphylaxis does not end with treatment of the anaphylactic episode [2-4] and that post-discharge management should include follow-up with a physician, preferably an allergy/immunology specialist [2,4,84-124] (Table 5).

The WAO Guidelines state that if epinephrine auto-injectors are not available, alternative, although not preferred, recommendations for epinephrine injection need to be provided (for details, please see the subsequent section on Post-Discharge Management on page 12 of this paper) [2,6,7]. They also note the importance of anaphylaxis emergency action plans and medical identification (ID) stating anaphylaxis triggers and co-morbid diseases. The AAAAI/ACAAI Guidelines recommend prescribing more than one epinephrine auto-injector because more than one dose of epinephrine is needed in about 20% of anaphylactic episodes; additionally, they recommend action plans and medical ID [3]. The EAACI Guidelines include comprehensive information about discharge management, for example, providing a discharge letter for the family doctor, as well as providing a discharge sheet for patients that contains information about epinephrine auto-injector use, allergen avoidance, and how to contact patient support groups. They also include detailed information about management plans, evidence-based absolute indications for prescription of at least one auto-injector, and suggested indications for prescription of a second auto-injector. They suggest strategies for training patients at risk and caregivers of patients at risk. Additionally, they list gaps in the evidence supporting recommendations for long-term management of anaphylaxis [4] (Table 5).

Post-discharge management of patients at risk for anaphylaxis recurrences in the community is an active area of research [84-98]. This focuses on patient and caregiver failure to carry auto-injectors and use auto-injectors for anaphylaxis [87,88], patient, caregiver, and physician experiences in using auto-injectors [89-92], auto-injector redesign [93,94] and education and support of patients at risk [95-97], an area in which additional high-quality studies are needed [98]. Although improved rates of filling epinephrine prescriptions after discharge from some emergency departments are reported [85,86], for many patients lack of affordable auto-injectors remains a barrier to use [7].

Investigations to confirm anaphylaxis triggers

The guidelines concur that triggers should be confirmed by re-taking the history of the anaphylactic episode and using this as a guide to selection of allergens for skin prick tests, measurement of allergen-specific IgE levels in serum, and additional investigations as needed [2-4,13-15,22,53,99-106]. Intradermal tests are helpful in investigation of anaphylaxis induced by insect venoms or drugs such as beta-lactam antibiotics [103-106]. Negative skin tests and absent or undetectable allergen-specific IgE levels have a high negative predictive value; however, positive tests have a lower positive predictive value because allergen sensitization without symptoms is widespread in the general population. Ideally, tests to assess sensitization to allergens should be interpreted by an allergy/immunology specialist [2-4,13-15,22,53,64,99-106] (Table 5). Medically-supervised incremental allergen challenge tests, indicated in some patients with food or drug allergy, should be conducted only by experienced healthcare professionals in settings where anaphylaxis can be treated promptly [2-4,13,15,22,53,104,105].

None of the guidelines emphasize standardization of tests and challenges; perhaps because international consensus documents on standardization were only published in 2012 and 2013 [2-4,100,102].

Prevention of anaphylaxis recurrences

The guidelines concur about prevention of anaphylaxis recurrences by avoidance of confirmed allergens, including hidden or cross-reacting allergens [2-4,13-15,22,53,64,99,104,105],[107-111]. Vigilant avoidance prevents anaphylaxis recurrence from culprit allergens [107,108]; however, it can be time-consuming, frustrating, difficult to sustain in daily life, and associated with impaired quality-of-life; including bullying of food-allergic children [109-111].

The guidelines concur in their recommendation for immune modulation to prevent recurrences of anaphylactic episodes from stinging insect venom [2-4,14,112-116] and drugs [2-4,15,117]. The WAO Guidelines and EAACI Guidelines describe oral immunotherapy (OIT) to prevent recurrences of food-induced anaphylaxis, but concur that this approach is not yet ready for general use [2,4,13,22,119] (Table 5).

For prevention of recurrence of stinging insect venom-induced anaphylaxis, a 3-5 year course of subcutaneous immunotherapy with the relevant standardized specific venom(s) leads to long-lasting protection in most patients [2-4,14,112-115]; lifelong venom immunotherapy (VIT) is recommended in patients with mastocytosis [116].

For prevention of recurrent anaphylaxis from a drug such as an antibiotic or NSAID, or a biologic agent, when no safe substitute is available, desensitization conducted by experienced healthcare professionals using a published protocol is safe and effective for one uninterrupted course of treatment [2-4,15,104,105,117].

In carefully selected patients with symptoms after ingestion of milk, egg, peanut, or other highly allergenic food, RCT of OIT confirm that clinical desensitization can be achieved in most patients; however, sustained unresponsiveness after stopping treatment is more difficult to achieve, and adverse events, including anaphylaxis, occur [99,119,120]. OIT safety can be improved with omalizumab pre-treatment and co-treatment [99,121]. Sublingual immunotherapy to prevent food-induced anaphylaxis, although less effective than OIT, is associated with fewer adverse events [99,120].

The guidelines differ in their emphasis on pharmacologic prophylaxis of anaphylaxis from various triggers. They all describe pharmacologic interventions to prevent anaphylaxis to radiocontrast media [2-4,64,122]. The WAO and the AAAAI/ACAAI Guidelines recommend pharmacologic prophylaxis in selected patients with idiopathic anaphylaxis [2,3]. The EAACI Guidelines provide information about pretreatment with epinephrine to prevent anaphylaxis to snake anti-venom [4,123]. Surprisingly, no guidelines provide information about pharmacological prophylaxis of anaphylaxis from subcutaneous allergen immunotherapy, although H₁-antihistamine pre-treatment before venom injections during VIT reduces systemic adverse events and has a beneficial immune-modifying effect [124] (Table 5).

Anaphylaxis education

The guidelines differ in their emphasis on anaphylaxis education for patients and caregivers. The WAO Guidelines outline the principles of anaphylaxis education [2]. The AAAAI/ACAAI Guidelines discuss anaphylaxis education in the context of some specific triggers [3]. The EAACI Guidelines provide comprehensive information about anaphylaxis education, including information about long-term management, recommendations for training (with description of barriers to and facilitators of implementation), audit criteria, and resource implications [4] (Table 5).

None of the guidelines describe anaphylaxis education for personnel working in child care, schools, colleges, universities, summer camps, and sports facilities, or the hospitality or airline industries; however, a forthcoming EAACI publication addresses anaphylaxis education in the community-at-large (Muraro A, personal communication).

Follow-up with a physician

All the guidelines address the issue of follow-up with a physician [2-4], if possible with an allergy/immunology specialist. The WAO Guidelines recommend follow-up yearly for review of prevention of recurrence, epinephrine auto-injector use, and optimizing control of relevant co-morbid diseases such as asthma [2]. The AAAAI/ACAAI Guidelines discuss specific aspects of follow-up in association with some of the major triggers [3]. In addition to physician follow-up, the WAO and EAACI Guidelines note the importance of follow-up with a dietician, if relevant, and the EAACI Guidelines also suggest follow-up with a psychologist, if relevant [4] (Table 5).

Definition of anaphylaxis

In all countries, increased awareness of anaphylaxis as a serious, life-threatening, generalized or systemic, allergic or hypersensitivity reaction with sudden onset (minutes to a few hours) is needed among healthcare professionals, patients, caregivers, and the public (Table 6).

Epidemiology

For epidemiologic purposes, the validated clinical criteria for anaphylaxis diagnosis are helpful for informing International Classification of Disease (ICD)-9 and ICD-10 codes and facilitating reliable estimates of anaphylaxis prevalence in healthcare settings [27-33] and to a lesser extent in the general population [34,35].

In all countries, epidemiological and health services research can serve as a baseline for quality improvement, prioritization of anaphylaxis programs, and eventual reduction in morbidity and mortality. However, until diagnosis of anaphylaxis as such by healthcare professionals improves and recognition by patients, caregivers, and the public improves, it will remain difficult to obtain reliable epidemiologic information about anaphylaxis and its prevalence will remain under-estimated (Table 6).

At post-mortem, too, anaphylaxis can be under-diagnosed [36]; for example, when signs of anaphylaxis are absent and recognition is based only on circumstantial evidence and exclusion of other diseases [37]. Nevertheless, anaphylaxis fatality studies can sometimes provide unique information about triggers, presenting symptoms and signs, time course, and associated co-morbidities in a specific region or country.

Patient-specific risk factors and co-factors relevant to anaphylaxis

In all countries, improved recognition of patient vulnerability to anaphylaxis is needed as related to age, physiologic state (pregnancy), concomitant diseases, concurrent medications, and amplifying co-factors. In some countries, the prevalence of co-morbid diseases such as asthma or CVD might itself not be known (Table 6).

Underlying mechanisms and anaphylaxis triggers

Positive collaborations among physicians in academic centers and national allergy/immunology professional organizations in high-resource countries with those in mid- or low-resource countries are expanding our global knowledge of anaphylaxis mechanisms and triggers [36,37,56,57,123]. Despite this, in some countries, little information about anaphylaxis triggers, even the taxonomy of indigenous food plants and stinging insects, is available. Where potential triggers remain unidentified, lack of context for recognition of anaphylaxis can delay diagnosis and treatment (Table 6).

Clinical diagnosis of anaphylaxis

In all countries, improved training of healthcare professionals to recognize and treat anaphylaxis is needed, and the validated clinical criteria for anaphylaxis diagnosis need to be operationalized in order to optimize their usefulness. Where resources are limited, there can be inconsistent availability of basic services such as electricity and of equipment and supplies that aid in anaphylaxis diagnosis; for example, pulse oximeters to document oxygenation and sphygmomanometers and arm cuffs of various sizes to document blood pressure [125-130].

In such situations, assessment of hypoxemia is based on clinical indicators such as central cyanosis, nasal flaring, inability to speak or drink, grunting, lethargy, severe chest retractions, respiratory rate of more than 70 breaths/minute, and head-nodding; a capillary refill time of 2 seconds or less is documented to reflect a superior vena caval oxygen saturation of greater than 70%. Assessment of hypotension and distributive shock is based on clinical indicators such as weak or non-palpable peripheral pulses [125-127] (Table 7).

In all countries, in the differential diagnosis of anaphylaxis, healthcare professionals should be aware of common considerations such as acute asthma, acute urticaria, and panic or anxiety attacks. In some countries, pneumonia is the most common consideration in patients presenting with acute-onset respiratory distress and hypoxemia, and sepsis is the most common consideration in those presenting with acute-onset hypotension or shock [2-4,125,126] (Table 7).

Prompt initial treatment of anaphylaxis and monitoring

In all countries, at the onset of an anaphylactic episode, it can be impossible to predict the rate of escalation or resolution of symptoms. Patients can present with deceptively mild symptoms such as hives, cough, or dizziness that rapidly increase in severity and culminate in fatality within minutes. Regardless of available resources, an important message to healthcare professionals, patients, caregivers, and the public is to recognize anaphylaxis promptly and as soon as it is recognized, inject life-saving epinephrine in order to maximize the likelihood of survival [2-4].

Box: The essentials of prompt initial anaphylaxis treatment

- have an easy-to-follow and well-rehearsed protocol - remove exposure to the trigger, if relevant - inject epinephrine promptly intramuscularly in the mid-outer thigh - call for help (resuscitation team in hospital or emergency medical services in community, if available) - position the patient supine (or semi-reclining in a position of comfort if dyspneic or vomiting) and elevate the lower extremities If indicated at any time, - provide supplemental oxygen - initiate IV fluid resuscitation with 0.9% saline - perform cardiopulmonary resuscitation - monitor BP, cardiac rate and function, and oxygen saturation

See Table 8 for details.

Where resources are limited, supplemental oxygen can be provided by oxygen concentrators instead of oxygen cylinders, and nasal prongs or nasopharyngeal catheters can be substituted for oxygen masks [128,129]; however, in many hospitals, lack of availability of pulse oximetry for detecting hypoxemia and guiding oxygen therapy remains a critical concern [127]. Despite best efforts, treatment of anaphylaxis can, in some patients, be compromised by co-morbidities such as anemia and reduced ability to achieve adequate oxygenation, or severe malnutrition and reduced ability to tolerate IV fluid resuscitation [125,126] (Table 8).

Management of anaphylaxis refractory to initial treatment

Even in high-resource countries, optimal treatment of refractory anaphylaxis is not available universally; for example, in remote, inaccessible, or impoverished areas or in specific situations such as anaphylaxis on airplanes. In limited-resource situations, lack of availability of basic essentials such as epinephrine, supplemental oxygen and IV fluid resuscitation is more critical than lack of second-line medications such as antihistamines and glucocorticoids. Lack of availability of advanced life-support management can be a major barrier to survival [72-76,128] (Table 8). In any limited-resource situation, resuscitation efforts prolonged over hours using a hand-held bag valve mask (manual resuscitator) are often successful in anaphylaxis [2] (Table 8).

In mid- and low-resource countries, striving to ensure more consistent availability of medications, supplies, and equipment for anaphylaxis treatment is an important goal [2,5-7]. The World Health Organization has developed a tool kit containing evidence-based guidelines and a framework for quality improvement in the hospital care of critically ill children in such environments [126], where despite many obstacles, improvements can be documented [130].

Post-discharge management

In high-resource countries, there is an increased focus on post-discharge management after successful treatment of anaphylaxis. Where resources are limited, post-discharge management is severely compromised by lack of availability of affordable auto-injectors or factory-sealed prefilled syringes containing epinephrine [2,6,7]. There are two alternative, although not preferred, options for epinephrine self-administration. First, a 1 mL ampule of epinephrine and a 1 mL syringe can be provided; however, in a medical emergency, patients without medical training find it difficult to draw up a dose accurately and expel air from the syringe without losing the epinephrine. Second, an unsealed prefilled syringe containing the correct dose for the patient can be drawn up in advance by his/her physician; however, all or part of the dose can be lost, and epinephrine is stable for only 3-4 months in an unsealed syringe [2,6,7].

Where resources are limited, local conditions typically determine the availability of follow-up with a healthcare professional and prevention of recurrent anaphylactic episodes is often compromised by lack of availability of physicians, tests to confirm triggers, and immune modulation (Table 9).