INTRODUCTION — Anaphylaxis is a potentially life-threatening emergency that requires immediate diagnosis and treatment. (See "Anaphylaxis: Emergency treatment".)
Patients who have experienced anaphylaxis (or suspected anaphylaxis) require evaluation to confirm the diagnosis and determine the cause(s) and possible contributing factors, such as other medical conditions (comorbidities) and concurrent medications.
REFERRAL TO AN ALLERGY/IMMUNOLOGY SPECIALIST — Referral to a board-certified allergy specialist is indicated in all cases of certain or suspected anaphylaxis [1-5]. A thorough evaluation is required to accomplish the following objectives:
●Confirm the diagnosis
●Confirm or determine the cause
●Assess cofactors that might have contributed to the episode, such as exercise, alcohol, or nonsteroidal anti-inflammatory drug (NSAID) ingestion
●Determine if there were other factors that contributed to the severity of anaphylaxis (eg, comorbidities, concurrent medications), which could be modified to help reduce the patient's risk of a subsequent severe anaphylactic episode
●Determine if the cause of the patient's anaphylaxis is amenable to immunotherapy in the case of stinging insect allergy, in order to reduce the long-term risk of anaphylaxis recurrences
●Educate the patient/family/caregiver about avoidance measures and recognition and management of recurrent episodes (see "Long-term management of patients with anaphylaxis")
In a retrospective review of 573 adults and children evaluated in the emergency department for anaphylaxis, only 38 percent received follow-up evaluation by an allergy/immunology specialist . Of those who did, the diagnosis of anaphylaxis or the suspected trigger for anaphylaxis was altered as a result of the evaluation in 35 percent. In addition, 2 percent of patients were diagnosed with a mast cell activation disorder, and 6 percent underwent immunotherapy or desensitization.
A prospective study of adults and children seen in an emergency care setting identified 226 cases of suspected anaphylaxis, of whom 124 were confirmed after diagnostic work-up in an allergy center . The causative agents were medications (41 percent), stinging insect venom (27 percent), and food (21 percent), with no cause identified in 11 percent. Mastocytosis was diagnosed in 7.7 percent of adults. One or more cofactors was identified in 58 percent, including infection, exercise, NSAIDs, and alcohol.
In another study, review of medical records from a pediatric emergency department identified 133 cases of anaphylaxis by National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria. Only 70 children (53 percent) had been given the diagnosis of anaphylaxis in the emergency department, with the remainder described as urticaria, allergic reaction, or angioedema . Forty-four (33 percent) had been discharged from the emergency department without information about the probable cause and thus no instructions on how to avoid future episodes. Allergy evaluations were subsequently performed in 89 percent, and a cause was identified in 92 percent of those evaluated. Food was the culprit in 90 percent of reactions, although 26 percent of children were confirmed to be allergic to a food other than that suspected in the emergency department.
CONFIRMING THE DIAGNOSIS OF ANAPHYLAXIS — The initial task in evaluating a patient with a history of a recent episode of anaphylaxis is to ensure that the diagnosis is correct. Anaphylaxis presents with the sudden onset of signs and symptoms, usually in more than one body system, within minutes to a few hours of exposure to a trigger or sometimes spontaneously [1-5]. It potentially involves more than 40 signs and symptoms (table 1) . The diagnosis and immediate management of anaphylaxis is reviewed in detail elsewhere. (See "Anaphylaxis: Emergency treatment".)
The steps involved in confirming the diagnosis of anaphylaxis, after the acute event, are depicted in the algorithm (algorithm 1). Each of these steps is discussed in detail in the sections that follow.
The diagnosis of anaphylaxis is confirmed if the nature and timing of the event are consistent with the known signs and symptoms and chronology of anaphylaxis [1-5]. However, the diagnosis of anaphylaxis is not always easy to make, particularly if it is the initial episode. Because anaphylaxis is a potentially fatal medical emergency [10,11], even if the diagnosis is uncertain, the patient should be equipped to self-treat a potential recurrence, and if another episode occurs, the clinician should plan to re-evaluate the patient and ascertain if exposures common to both the episodes can be detected. (See "Long-term management of patients with anaphylaxis".)
History of exposures and activities — The clinical history is supremely important in making the diagnosis of anaphylaxis, determining the cause(s), and assessing the patient for contributing factors that might increase the risk of severe or fatal anaphylaxis.
Each past episode of anaphylaxis should be carefully reviewed, starting with the 24-hour period before the onset of symptoms and paying particular attention to the one to two hours immediately preceding symptom onset. Important information can be obtained from family members, caregivers, friends, or other witnesses, emergency medical personnel, and emergency department and hospital records.
●Exposures – Anything that was ingested, injected, or otherwise taken into the body during this period should be noted. Foods are the most common trigger of immunoglobulin E (IgE)-mediated anaphylaxis in children, teenagers, and young adults, while insect stings and medications are more common triggers in middle-aged or older adults. The table provides a comprehensive list of potential anaphylaxis causes, categorized by the pathophysiologic mechanism involved (table 2) [4,5,10-27]. The mechanisms of anaphylaxis are reviewed in detail elsewhere. (See "Pathophysiology of anaphylaxis" and "History and physical examination in the patient with possible food allergy" and "Clinical manifestations of food allergy: An overview" and "An approach to the patient with drug allergy" and "Bee, yellow jacket, wasp, and other Hymenoptera stings: Reaction types and acute management".)
●Chronology – The chronology of events (time elapsed between exposure to trigger and onset of first symptom[s]) should be consistent with the diagnosis of anaphylaxis. IgE-mediated anaphylaxis usually develops within minutes to one hour or so of exposure. However, there are rare exceptions to this, such as IgE-mediated reactions to the carbohydrate galactose alpha-1,3-galactose (alpha-gal) in red meat, which develop four to six hours after ingestion . (See "Allergy to meats", section on 'IgE-mediated reactions'.)
●Baseline state of health and activities – Patients should be asked about their general health and their activities in the 24 hours preceding symptom onset [10,11,29]. Relevant history includes any illness and any medications taken as treatment, fever, or menstrual state. These factors may render patients more susceptible to anaphylaxis and/or exacerbate anaphylaxis symptoms.
Physical activity should be reviewed [1,4,5,16]. Exercise can be the only trigger for an anaphylactic episode (exercise-induced anaphylaxis) or it may only induce symptoms when preceded by ingestion of food or medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs). Sometimes specific foods, such as shellfish, wheat, or celery, combined with exercise, will trigger symptoms (food-dependent, exercise-induced anaphylaxis), while in other cases, any food ingestion followed shortly by exercise can trigger an episode. (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)
Uncommonly, allergen exposure can occur through kissing or intercourse . (See "Management of food allergy: Avoidance", section on 'Interpersonal contact'.)
●Environmental conditions – Exposure to unusual environmental conditions should be reviewed because anaphylaxis symptoms can be triggered or exacerbated by heat or cold [5,16]. (See "Physical (inducible) forms of urticaria" and "Cold urticaria".)
Nocturnal anaphylaxis — A small number of allergens can cause primarily nocturnal anaphylaxis, awakening patients from sleep:
●Alpha-gal in red meat, which most commonly presents with anaphylaxis beginning four to six hours after a meal containing beef, pork, or lamb. (See "Allergy to meats", section on 'IgE-mediated reactions'.)
●Allergens in the saliva of kissing bugs that typically bite during the night. (See "Reactions to bites from kissing bugs (primarily genus Triatoma)", section on 'Allergic reactions'.)
●Allergens in the bites of pigeon ticks (Argas reflexus), which feed by night and are mostly encountered in middle and southern European cities where pigeons are prevalent [30-33].
Comorbidities — Certain chronic health conditions increase the risk of severe or fatal anaphylaxis [9,34-40]:
●Asthma, especially if symptoms are not optimally controlled, is an important risk factor for severe or fatal anaphylaxis [11,34,35]. (See "Food-induced anaphylaxis", section on 'Risk factors' and "Fatal anaphylaxis", section on 'Asthma'.)
●Other pulmonary and cardiac diseases, including chronic obstructive pulmonary disease (COPD) and coronary artery disease, increase the risk of severe anaphylactic reactions and fatality [1,2,4,36,37].
●Mastocytosis or other mast cell disorders are associated with increased risk of life-threatening or fatal anaphylaxis [38-40]. These disorders should be considered particularly in patients with severe anaphylaxis. (See "Mast cell disorders: An overview".)
Concurrent medications and other substances — All medications and substances ingested or used (prescription, over-the-counter, and recreational) in the 24 hours immediately preceding the anaphylaxis episode should be reviewed. Some medications may affect the patient's likelihood of developing anaphylaxis, the ability to respond with compensatory physiologic changes, or the response to treatment (table 3) [41-44].
●Ethanol, NSAIDs, and opiates can exacerbate anaphylaxis symptoms by causing nonimmunologic mast cell activation [1,10,29].
●Beta-adrenergic blockers administered orally or topically (eg, eye drops) may potentially make anaphylaxis more difficult to treat by causing unopposed alpha-adrenergic effects and hypertension and reduced bronchodilator response to the beta-adrenergic effects of endogenous or exogenous epinephrine . (See "Anaphylaxis: Emergency treatment", section on 'Glucagon for patients taking beta blockers'.)
●Angiotensin-converting enzyme (ACE) inhibitors potentially interfere with endogenous compensatory mechanisms, resulting in more severe or prolonged symptoms . Angiotensin II receptor blockers are less likely to have this effect. However, this is not optimally documented .
●The combination of ACE inhibitors and beta-blockers may synergistically increase the risk of severe anaphylaxis .
If a patient is taking a medication that might have contributed to anaphylaxis or interfered with its treatment, discontinuing use of that medication should be considered. The overall benefits and risks of that drug need to be assessed and discussed not only with the patient but also with other health care professionals involved in his/her care. Where appropriate, substitution should be considered [41-44]. This is reviewed separately. (See "Long-term management of patients with anaphylaxis".)
Review of treatment — Emergency medical services records and emergency department records should be reviewed, specifically with regard to symptoms and signs of anaphylaxis, as well as all medications that were given and the times at which they were administered. Epinephrine is highly effective when injected intramuscularly promptly after symptom onset. Therefore, the timing of epinephrine injection(s), the dose in relationship to the patient's weight, and the route and site of injection are important in the interpretation of the clinical response [1-5]. (See "Anaphylaxis: Emergency treatment", section on 'Treatment errors'.)
A review of the patient's, family's, or caregiver's response to the anaphylactic episode may help to identify behaviors that contributed to the severity of the episode and could be modified to reduce future risk.
●Patients experiencing food-induced anaphylaxis in a restaurant or other public setting sometimes go to the restroom and separate themselves from those who can assist them, potentially leading to delay in injecting epinephrine, contacting emergency medical services, and even fatality.
●Patients who collapse during anaphylaxis are sometimes propped up in the sitting position by well-meaning family or friends, resulting in inadequate cardiac preload, pulseless electrical activity, and sudden death . (See "Fatal anaphylaxis".)
●Patients with exercise-induced anaphylaxis sometimes try to run for help at the onset of symptoms, although continued exertion after symptom onset is likely to exacerbate the episode . (See "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis" and "Exercise-induced anaphylaxis: Management and prognosis".)
Laboratory test results obtained at the time of anaphylaxis — The results of serum tryptase measurements obtained at the time of the anaphylactic episode should ideally be obtained and reviewed [1,47-49]. Tryptase levels are mentioned briefly here as an example and are discussed in detail separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)
The diagnosis of anaphylaxis is based on a history of sudden onset and rapid evolution of characteristic symptoms and signs, usually in more than one organ system (see "Anaphylaxis: Emergency treatment"). An elevated serum tryptase level supports the diagnosis, but a normal level cannot refute the diagnosis.
●Serum tryptase level results are not available on an emergency basis, because the assay takes several hours to perform but are nonetheless important to obtain to assist in retrospective confirmation of anaphylaxis and to rule out mast cell disorders.
●The blood sample for serum tryptase measurement is optimally obtained 1 to 3 hours after the onset of anaphylaxis symptoms. A second measurement of baseline serum tryptase at least 24 hours after resolution of the clinical signs and symptoms of anaphylaxis should be performed for comparison.
●If the event-related tryptase level is greater than 11.4 ng/mL or elevated by at least 20 percent above baseline plus 2 ng/mL and tryptase returns to normal after the event, then the diagnosis of anaphylaxis is confirmed. If the level is greater than 11.4 ng/mL in both acute and baseline sera, the diagnosis of mastocytosis or other mast cell disorders should be considered [1,50].
●Serum tryptase is most often elevated in anaphylaxis triggered by insect stings or medications and in patients with anaphylaxis from any cause who are hypotensive or in shock. Tryptase levels may not be elevated in food-induced anaphylaxis or in patients with anaphylaxis who are normotensive. Tryptase levels that are within normal limits cannot be used to rule out the clinical diagnosis of anaphylaxis. (See "Food-induced anaphylaxis".)
●Serum tryptase levels are not specific for anaphylaxis. They may be elevated in patients with acute myeloid leukemia or renal failure and in some healthy individuals (eg, those with hereditary alpha-tryptasemia). The differential diagnosis of elevations in serum tryptase is discussed in more detail separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Elevations of tryptase in nonanaphylactic patients'.)
TESTING FOR ALLERGEN CAUSE(S) — Every effort should be made to identify the cause of a patient's anaphylaxis, as this greatly increases his or her chances of avoiding this exposure and preventing recurrence of anaphylaxis (algorithm 2). In addition, attributing anaphylaxis incorrectly to the "wrong" allergen potentially puts the patient at greater risk from exposure to the true culprit allergen.
The list of reported causes of anaphylaxis, including foods, medications, and insect stings or bites continues to lengthen (table 2) [4,18,19]. The clinical history, gathered as described above, is the best means of identifying a suspect cause and possible cofactors. (See 'History of exposures and activities' above.)
Attempts should be made to verify the cause even when the clinical history strongly implicates a single, apparently isolated exposure, such as an insect sting [5,20,21]. In this example, the results of venom-specific skin tests and/or immunoglobulin E (IgE) levels are needed to identify the allergen and also determine if there are other related venoms to which the patient is also sensitized. Such tests are important because a course of subcutaneous injections with the relevant stinging insect venom(s) (honey bee, yellow jacket, wasp, or hornet) or whole body extract (fire ant) will significantly reduce the patient's risk of recurrence of anaphylaxis to a sting.
In many cases of anaphylaxis, the trigger is not immediately apparent. Sometimes patients draw their own conclusions about what the likely cause was and report this as an established allergy to future clinicians. It is important for health care professionals to ask patients with past anaphylaxis if the cause was verified by an allergist or proven in some other way, since the patient may be avoiding the wrong allergens and may be at risk for future recurrences.
Sensitization to allergens — In patients with anaphylaxis attributed to an IgE-mediated allergy, positive allergen skin tests and/or elevated allergen-specific IgE levels in serum confirm sensitization to the allergen(s) tested. (See "Overview of skin testing for IgE-mediated allergic disease" and "Overview of in vitro allergy tests".)
●Skin testing with allergen extracts is the traditional method for demonstrating sensitization. Extracts are commercially available for most foods, venoms, and penicillin but not for other antibiotics [1,5,20,21]. In patients with a strong history of food-induced anaphylaxis, if tests with commercial extracts are negative or not available, the suspect food itself can be used for skin prick testing.
●In vitro testing provides quantitative results expressed in standardized units [18,19]. Specific IgE levels measured using different assay systems are not exactly interchangeable [18,19]. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Overview of in vitro allergy tests".)
Various enzyme-linked immunosorbent assays (ELISAs) for quantification of allergen-specific IgE levels in serum have replaced radioallergosorbent tests (RASTs) in clinical laboratories, although the term "RAST" remains in use.
●If anaphylaxis to a medication, biologic agent, or vaccine is suggested by the history, skin tests and/or in vitro tests should be performed with the implicated agent and with the relevant excipients that it contains [22-27]. (See "An approach to the patient with drug allergy", section on 'Objective testing' and "Allergic reactions to vaccines".)
Patients with a recent history of a sudden onset multisystem clinical reaction to a specific food, drug, or venom in combination with a positive skin test and/or an elevated specific IgE level to that substance do not require a challenge for definitive diagnosis. In such patients, challenges are likely to trigger anaphylaxis [18,19]. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Overview of in vitro allergy tests".)
The results of skin tests and in vitro tests for allergen-specific IgE must always be interpreted in the context of the patient's clinical history for the following reasons:
●A positive test result documents sensitization (presence of IgE antibody) to the allergen. However, it does not necessarily prove that the allergen is the causative trigger for symptoms . For reasons that are poorly understood, it is possible to have clinically irrelevant positive tests. For example, more than 25 percent of all adults in the general population have one or more positive skin test responses to stinging insect venoms, yet most of these individuals do not experience anaphylaxis after a sting. However, given a clinical history of a sting shortly before the onset of symptoms of anaphylaxis, any venom sensitization is considered relevant (ie, establishes IgE-mediated venom allergy as the cause of the event).
●False-negative tests are also possible. In patients with a history of anaphylaxis but negative tests to the implicated allergen, incremental challenge/provocation tests may be required to exclude or confirm a specific allergen as the cause [18,19,22,23]. These procedures are time-consuming and associated with some risk to the patient. They should only be conducted in appropriately staffed and equipped facilities by health care professionals with training and experience in patient selection, patient assessment on the day of challenge, and in the recognition and treatment of anaphylaxis. (See "Oral food challenges for diagnosis and management of food allergies" and "An approach to the patient with drug allergy", section on 'Graded challenge and drug provocation'.)
●There may also be a "refractory period" for skin tests and possibly serum-specific IgE tests after an anaphylactic episode, ranging from one to four weeks [51,52]. If an individual has experienced anaphylaxis triggered by an allergen suggested by the history, yet has negative skin test responses and undetectable specific IgE levels in serum shortly after the episode, the tests should be repeated four to six weeks later [4,5]. The interpretation of skin testing and in vitro testing for allergic disease is reviewed in detail elsewhere. (See "Overview of skin testing for IgE-mediated allergic disease" and "Overview of in vitro allergy tests".)
Testing for related allergies — If a specific trigger can be identified, it is sometimes necessary to determine if the patient is sensitive to similar substances. This information is used to help the patient avoid all relevant substances and to identify safe alternatives. Examples include the following:
●A patient with anaphylaxis in response to a yellow jacket sting should undergo testing with venoms from all members of the flying Hymenoptera species and be offered immunotherapy that included all the venoms to which he/she is sensitized.
●A patient with anaphylaxis to certain tree nuts is likely to react to certain cross-reacting tree nuts but not to others.
THE PATIENT WITH AN IDENTIFIABLE CAUSE — All patients with anaphylaxis must be taught how to recognize and manage anaphylaxis if and when it recurs, including correct use of epinephrine autoinjectors. This is true even when a trigger has been identified because accidental ingestions of foods are common, and insect stings cannot be avoided. This is discussed in detail separately. (See "Long-term management of patients with anaphylaxis" and "Prescribing epinephrine for anaphylaxis self-treatment" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)".)
Patients with an identifiable cause must also be given instructions about avoidance. The educational process, as well as tools and resources to assist patients and clinicians, are reviewed elsewhere. (See "Long-term management of patients with anaphylaxis" and "Management of food allergy: Avoidance" and "Latex allergy: Management", section on 'Individual avoidance'.)
Anaphylaxis to stinging insects can be prevented by immunotherapy with the relevant insect venom(s), and anaphylaxis to certain medications can be prevented by desensitization. A complete list of the available desensitization therapies is found elsewhere. (See "Long-term management of patients with anaphylaxis", section on 'Interventions to reduce sensitivity'.)
THE PATIENT WITH NO IDENTIFIABLE CAUSE — In some cases, no trigger can be identified by history or tests to explain a patient's anaphylactic episode. In this situation, it is important to reconsider the differential diagnosis of anaphylaxis and to consider the possibility of a hidden or novel trigger. In addition, hereditary alpha tryptasemia, a heritable disorder that exists in up to 5 percent of the general population, as well as rare mast cell disorders (including systemic mastocytosis and monoclonal mast cell activation syndrome), should be excluded, especially in patients with repeated episodes of anaphylaxis or anaphylaxis-like symptoms [38-40]. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Hereditary alpha tryptasemia' and "Mast cell disorders: An overview".)
The diagnosis of idiopathic anaphylaxis is assigned when no trigger can be identified and mast cell disorders have been excluded . In two studies of patients treated for anaphylaxis in the emergency department and subsequently evaluated by allergists, a cause could not be identified in approximately 10 percent [7,8]. Consideration is then given to daily prophylactic use of H1 antihistamines or for more severe or frequent episodes, prophylaxis with glucocorticoids and potentially other medications. (See "Idiopathic anaphylaxis".)
All patients with anaphylaxis, whether or not a trigger is identified, must be taught how to recognize and manage anaphylaxis if and when it recurs, including prompt use of epinephrine autoinjectors [2,4]. This is discussed in detail separately. (See "Long-term management of patients with anaphylaxis" and "Prescribing epinephrine for anaphylaxis self-treatment" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)".)
DIFFERENTIAL DIAGNOSIS OF ANAPHYLAXIS — The differential diagnosis of anaphylaxis is broad. It includes common entities, such as acute asthma, acute generalized hives, anxiety/panic attack, syncope/faint, and choking on/aspiration of a foreign body, as well as less common entities, such as vocal cord dysfunction, flushing syndromes, and postprandial syndromes [1,4,5]. The differential diagnosis also varies with age and physiologic state [12-15]. Relevant topics include the following:
●(See "Anaphylaxis in infants".)
●(See "Approach to flushing in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anaphylaxis".)
SUMMARY AND RECOMMENDATIONS
●Patients who have experienced anaphylaxis should be referred to an allergy/immunology specialist to confirm the diagnosis, confirm or determine the causes(s), and determine relevant patient risk factors for severe or fatal anaphylaxis (eg, comorbidities or concurrent medications that could be modified to reduce the patient's risk of recurrences in the future). In addition, some forms of anaphylaxis are amenable to prevention through immunomodulation. (See 'Referral to an allergy/immunology specialist' above.)
●Evaluation involves retaking a detailed medical history of each episode of symptoms and reviewing relevant medical records and laboratory test results. (See 'Confirming the diagnosis of anaphylaxis' above.)
●Every effort should be made to confirm the specific cause for anaphylaxis suggested by the patient's history in order to provide appropriate recommendations for avoidance, begin immunotherapy or desensitization (if relevant), and prevent future anaphylaxis episodes. (See 'Testing for allergen cause(s)' above.)
●If no cause is identified, the differential diagnosis of anaphylaxis should be reconsidered, and the possibility of a hidden or novel trigger should be explored. All patients with episodes of anaphylaxis and no identifiable causes should be assessed for a mast cell disorder. (See 'The patient with no identifiable cause' above and "Idiopathic anaphylaxis".)
●All patients with anaphylaxis require regular education about how to recognize and manage recurrent anaphylaxis and about avoidance of confirmed allergen triggers. (See "Long-term management of patients with anaphylaxis".)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge F Estelle R Simons, MD, FRCPC, who contributed to earlier versions of this topic review.
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