This practice parameter includes algorithms for the initial evaluation and management of a patient with a history of an episode of anaphylaxis and for the treatment of an anaphylactic event in the outpatient setting. The algorithms are accompanied by annotations (numbered to correspond to the algorithms).
Guideline recommendations are presented in the form of summary statements. After each statement is a letter in parentheses that indicates the strength of the recommendation. The strength of recommendations (A-D and LB) and categories of evidence (Ia, Ib, IIa, IIb, III, IV) are defined at the end of the "Major Recommendations" field.
Note: Key highlights of the update (new and modified information) may be found at the beginning of the guideline document.
Algorithm and Annotations for Initial Evaluation and Management of a Patient with a History of Anaphylaxis
Annotation 1: Is the History Consistent with a Previous Episode of Anaphylaxis?
All individuals who have had a known or suspected anaphylactic episode require a careful and complete review of their clinical history. This history may elicit manifestations such as urticaria, angioedema, flushing, pruritus, upper airway obstruction, gastrointestinal symptoms, syncope, hypotension, lower airway obstruction, and/or other less common manifestations.
Of primary importance is the nature of the symptoms characterizing the event. Essential questions to be asked are:
- Were there cutaneous manifestations, specifically pruritus, flush, urticaria, or angioedema?
- Was there any sign of airway obstruction involving either the upper airway or the lower airway?
- Were there gastrointestinal symptoms (i.e., nausea, vomiting, or diarrhea)?
- Were syncope or presyncopal symptoms present?
The absence of cutaneous symptoms puts the diagnosis in question since the majority of anaphylactic episodes include cutaneous symptoms (see Table E1 in the original guideline document), although their absence does not rule out anaphylaxis. The history should concentrate on agents encountered before the reaction. Whenever appropriate, the information should be obtained from not only the patient but also from family members or other witnesses of the event. The complete sequence of events must be reviewed, with special attention paid to cardiorespiratory symptoms. Medical records, including medication records, can often be useful in evaluating the history, physical findings, and treatment of the clinical event. In addition, the results of any previous laboratory studies (e.g., serum tryptase) may be helpful in making the diagnosis of anaphylaxis or distinguishing it from other entities.
Annotation 1A: Consider Consultation with Allergist-Immunologist
Evaluation and diagnosis, as well as long-term management, can be complex. The allergist-immunologist has the training and expertise to obtain a detailed allergy history; coordinate laboratory and allergy testing; evaluate the benefits and risks of therapeutic options; and counsel the patient on avoidance measures. For these reasons, patients with a history of anaphylaxis should be considered for referral to an allergy/immunology specialist.
Annotation 2: Pursue Other Diagnoses or Make Appropriate Referral
Other conditions that should be considered in the differential diagnosis include: (1) vasodepressor (vasovagal/neuro-cardiogenic) syncope; (2) syndromes that can be associated with flushing (e.g., metastatic carcinoid); (3) postprandial syndromes (e.g., scombroid poisoning); (4) systemic mastocytosis; (5) psychiatric disorders that can mimic anaphylaxis such as panic attacks or vocal cord dysfunction syndrome; (6) angioedema (e.g., hereditary angioedema); (7) other causes of shock (e.g., cardiogenic); and (8) other cardiovascular or respiratory events.
Annotation 3: Is Cause Readily Identified by History?
The history is the most important tool to establish the cause of anaphylaxis and takes precedence over diagnostic tests. A detailed history of all food consumed and drugs taken over the four to six hours prior to the episode should be obtained. In addition, the labels for all packaged foods ingested by the patient in this period of time should be reviewed since a substance added to the food could be responsible. A history of any preceding bite or sting should be obtained. The patient's activities (e.g., exercise, sexual activity) preceding the event should be reviewed. Patient diaries may be a useful adjunct in confirming or identifying the cause of anaphylaxis.
Annotation 4: Consider Idiopathic Anaphylaxis
Idiopathic anaphylaxis is a diagnosis of exclusion that should be made only after other causes of anaphylaxis and other differential diagnoses have been considered.
Annotation 5: Are Further Diagnostic Tests Indicated: Allergy Skin Tests or In Vitro Tests, Challenge Tests?
Skin tests and/or, in vitro test for specific immunoglobulin E (IgE) as well as challenge tests may be appropriate to help define the cause of the anaphylaxis. However, the history may be so conclusive that none of these tests are necessary.
Annotation 6: Diagnosis Established on Basis of History; Risk of Testing; Limitation of Tests; Patient Refuses Test; Other Management Options Available; Management
There may be circumstances where skin tests or in vitro specific IgE, and/or challenge tests may not be warranted. In general, this may apply when the clinician decides to proceed with management because the history is conclusive. The history of anaphylaxis to a specific agent may be so strong that testing is unnecessary and inappropriate from the benefit: risk standpoint. If avoidance can be easily and safely accomplished, testing may not be necessary.
Testing or challenge with reagents to a suspected allergen may not be available, or the predictive value of the test may be in question. Challenge tests (and, to a lesser extent, skin tests) may be hazardous, and not acceptable from a benefit: risk standpoint, if other management options are available. Occasionally patients may refuse to have the test.
Annotation 7: Testing Identifies Specific Cause of Anaphylaxis
Skin tests or in vitro tests can determine the presence of specific IgE antibodies to foods, medications (e.g., penicillin and insulin), and stinging insects as a cause of anaphylaxis. For the majority of medications, standardized in vivo and/or in vitro testing is not available.
In general, skin testing is more sensitive than in vitro testing and is the diagnostic procedure of choice for evaluation of most potential causes of anaphylaxis (e.g., penicillin and insect stings). It is essential, however, that the correct technique for skin testing be used. When possible, standardized extracts for skin testing should be used, although occasionally fresh food extracts will be superior to available standardized extracts. If the skin testing extract has not been standardized (e.g., latex, protamine, or antibiotics other than penicillin), the clinical relevance of the results may be uncertain. If skin testing is performed, it should be done under the supervision of a physician who is experienced in the procedure in a setting with appropriate rescue equipment and medication.
The accuracy of in vitro testing depends on the reliability of the in vitro method, the ability to interpret the results, and the availability of reliable testing material. The clinical significance of skin testing or in vitro test depends on the ability to correlate the results of such testing with the patient's history.
If tests for specific IgE antibodies (i.e., skin tests, in vitro tests, or both) do not provide conclusive evidence of the cause of anaphylaxis, challenge with the suspected agent can be considered. Challenge procedures may also be appropriate in patients who develop non-IgE-mediated reactions (e.g., reactions to aspirin [ASA] or other nonsteroidal anti-inflammatory drugs [NSAIDs]). Challenge with suspected agents must be done carefully by individuals knowledgeable in the challenge procedure and with expertise in managing reactions to the challenge agent if they should occur.
Annotation 8: Reconsider Clinical Diagnosis; Reconsider Idiopathic Anaphylaxis; Consider Other Triggers; Consider Further Testing; Management
At this stage in the patient's evaluation, it is particularly important to consider other possible causes of anaphylaxis or a different diagnosis. The history and test results should be reviewed. Further testing for specific IgE antibodies should be considered. Laboratory studies that may be helpful include: serum tryptase, as well as urinary 5-hydroxyindoleacetic acid, methylhistamine, and catecholamines. Idiopathic anaphylaxis is a diagnosis of exclusion (see section on idiopathic anaphylaxis). Management of anaphylaxis should follow annotation 10 (see below).
Annotation 9: Diagnosis Made of Specific Cause of Anaphylaxis
The diagnosis of a specific cause of anaphylaxis may be supported by the results of skin tests, in vitro IgE tests, and/or challenge tests (particularly double-blind, placebo-controlled challenge tests).
Annotation 10: Management of Anaphylaxis
When anaphylaxis has occurred because of exposure to a specific agent (e.g., food, medication, or insect sting), patients should be educated about agents or exposures that would place them at risk for future reactions and be counseled on avoidance measures that may be used to reduce risk for such exposures. Patients who have had anaphylactic reactions to food should be instructed on how to read food ingredient labels to identify foods that they should avoid. Patients with anaphylaxis to medications should be informed about all cross-reacting medications that should be avoided. Should there be a future essential indication for use of incriminated medications, it may be helpful to educate patients about applicable management options (e.g., medication pretreatment and use of low osmolarity agents in patients with a history of reactions to radiographic contrast media or desensitization for drugs such as antibiotics). Patients who have had an anaphylactic reaction to an insect sting should be advised about avoidance measures to reduce the risk of an insect sting and usually are candidates for insect venom immunotherapy. Patients who have had anaphylaxis should carry self-injectable epinephrine if there is continued risk for anaphylaxis. Patients should also carry identification indicating that they have experienced anaphylaxis and indicating the responsible agent.
Algorithm and Annotations for the Treatment of an Anaphylactic Event in the Outpatient Setting
Annotation 1. Anaphylaxis Preparedness
Management recommendations are subject to physician discretion as well as practice resources and the proximity to emergency assistance. Variations in sequence and performance rely on physician judgment. A determination of when a patient should be transferred to an emergency facility depends on the skill, experience and clinical decision-making of the individual physician. Prompt recognition and appropriate, aggressive treatment are essential for the successful management of anaphylaxis.
Stocking and maintaining supplies for the treatment of anaphylaxis with regular written documentation of supplies and expiration dates and ready availability of injectable epinephrine, intravenous (IV) fluids and needles, oxygen and mask/cannula, airway adjuncts, and stethoscope and sphygmomanometer are bare essentials (an example of a supply checklist is included in Fig. E3 of the original guideline document).
Regular anaphylaxis practice drills, the makeup of which is left to the discretion and qualifications of the individual physician, are strongly recommended. It is essential to identify a person who will be responsible for calling emergency medical services and the person who will document each treatment and the time that each is rendered. Emergency medications should be up-to-date and complete. Everyone who will be directly involved in patient care should be able easily to locate necessary supplies, rapidly assemble fluids for IV administration, and be prepared to begin treatment so that no time is lost in implementing emergency measures.
Annotation 2. Patient Presents With Possible/Probable Acute Anaphylaxis
Anaphylaxis is an acute life-threatening reaction, usually but not always mediated by an immunologic mechanism, that results from the sudden systemic release of mediators from mast cells and basophils. Anaphylaxis has varied clinical presentations but respiratory compromise and cardiovascular collapse are of greatest concern, since they are the most frequent causes of fatalities. Urticaria and angioedema are the most common manifestations of anaphylaxis but may be delayed or absent especially in rapidly progressive anaphylaxis. The more rapid anaphylaxis occurs after exposure to an offending stimulus, the more likely the reaction is to be severe and potentially life-threatening.
Anaphylaxis often produces signs and symptoms within minutes of exposure to an offending stimulus but some reactions may develop later (e.g., greater than 30 min after exposure). Late phase or "biphasic" reactions, which occur 1 to 72 hr (most within 10 hr) after the initial attack, have also been reported. Protracted, severe anaphylaxis may last up to 32 hr despite aggressive treatment.
Increased vascular permeability, a characteristic feature of anaphylaxis, allows transfer of as much as 35% of the intravascular fluid into the extravascular space within 10 min. As a result, hemodynamic collapse may occur rapidly with little or no cutaneous or respiratory manifestations.
Annotation 3. Initial Assessment of Possible/Probable Anaphylaxis
Initial assessment should determine if history and physical findings are compatible with anaphylaxis. The setting of the episode and the past history may suggest or reveal the source of the reaction. Evaluation should include: level of consciousness (impairment may reflect hypoxia), upper and lower airways (dysphonia, stridor, cough, wheezing, shortness of breath), cardiovascular system (hypotension with or without syncope; and/or cardiac arrhythmias), the skin (diffuse or localized erythema, pruritus, urticaria and/or angioedema), and the gastrointestinal system (nausea, vomiting, diarrhea). In addition, some patients may have symptoms of lightheadedness, headache, uterine cramps, feeling of impending doom, and unconsciousness.
The vasodepressor (vaso-vagal) reaction probably is the condition most commonly confused with anaphylactic reactions. In vasodepressor reactions, however, urticaria is absent, the heart rate is typically bradycardic, bronchospasm or other breathing difficulty is generally absent, the blood pressure is often decreased when accompanied by symptomatic bradycardia, but it may be normal, and the skin is typically cool and pale. While tachycardia is the rule, bradycardia may occur during anaphylaxis, so bradycardia may not be as useful to separate anaphylaxis from a vasodepressor reaction as has previously been thought. Relative bradycardia (initial tachycardia followed by a reduction in heart rate despite worsening hypotension) has been reported previously in the setting of experimentally induced insect sting anaphylaxis and in other states of hypovolemia (e.g., trauma). Tachycardia may also be absent in patients with conduction defects, increased vagal tone due to a cardioinhibitory (Bezold-Jarisch) reflex, or in those who take sympatholytic medications.
Annotation 4. Consider Other Diagnosis
Other diagnoses that might present with signs and/or symptoms characteristic of anaphylaxis should be excluded. Among conditions to consider are vasodepressor (vasovagal) reactions, vocal cord dysfunction, acute anxiety (e.g., panic attack or hyperventilation syndrome), myocardial dysfunction, pulmonary embolism, foreign body aspiration, acute poisoning, hypoglycemia, and seizure disorder. Specific signs and symptoms of anaphylaxis may be in other disorders, such as urticaria/angioedema and asthma.
Annotation 5. Immediate Intervention
Anaphylaxis occurs as part of a continuum. Symptoms not immediately life-threatening may progress rapidly unless treated promptly. Treatment recommendations are subject to physician discretion and variations in sequence and performance rely on physician judgment. Additionally, a determination of when a patient should be transferred to an emergency or intensive care facility depends on available resources and the skill, experience and clinical decision-making of the individual physician.
- Assess airway, breathing, circulation, and level of consciousness (altered mentation may suggest the presence of hypoxia).
- Administer epinephrine. Aqueous epinephrine 1:1000 dilution (1 mg/mL), 0.2-0.5 mL (0.01 mg/kg in children, maximum 0.3 mg dosage) intramuscularly in the lateral aspect of the thigh or subcutaneously every 5 min, as necessary, to control symptoms and increase blood pressure. If the clinician deems it appropriate, the 5-minute interval between injections can be liberalized to permit more frequent injections. Intramuscular (IM) epinephrine injections into the thigh have been reported to provide more rapid absorption and higher plasma epinephrine levels in both children and adults than IM or subcutaneous (SQ) injections administered in the arm. However, similar studies comparing IM injections to SQ injections in the thigh have not been done. These studies were not performed in patients experiencing anaphylaxis. The generalizability of these findings to the clinical setting of anaphylaxis has not been established. There are no studies that support the use of epinephrine in the treatment of anaphylaxis when delivered by a non-parenteral route. However, alternative routes of administration have been anecdotally successful. These include, for example, inhaled epinephrine in the presence of laryngeal edema or sublingual administration if an IV route cannot be obtained. Endotracheally administered dosages have also been proposed for use when IV access is not available in intubated patients experiencing cardiac arrest.
Annotation 6. Subsequent Measures That May Be Necessary Depending on Response to Epinephrine
- Consider calling 911 and obtaining assistance.
- Place the patient in a recumbent position and elevate the lower extremities, as tolerated symptomatically. This slows progression of hemodynamic compromise, if present, by preventing orthostatic hypotension and helping to shunt effective circulation from the periphery to the head, the heart and kidneys.
- Establish and maintain an airway. Ventilatory assistance via a one-way valve facemask with oxygen inlet port (e.g., Pocket-Mask® or similar device) may be necessary. Bag valve masks of less than 700 mL are discouraged in adults in the absence of an endotracheal tube since ventilated volume will not overcome 150-200 mL of anatomic dead space to provide effective tidal volume. (Bag valve masks may be used in children provided the reservoir volume of the device is sufficient.) Endotracheal intubation or cricothyroidotomy may be considered where appropriate, provided clinicians are adequately trained and proficient in this procedure.
- Administer oxygen. Oxygen should be considered for patients with anaphylaxis who have prolonged reactions, have pre-existing hypoxemia or myocardial dysfunction, receive inhaled β-agonists as part of the treatment for anaphylaxis, or who require multiple doses of epinephrine. Continuous pulse oximetry and/or arterial blood gas determination (where available) should guide oxygen therapy, especially in high risk patients, e.g. patients with chronic obstructive pulmonary disease (COPD).
- Rapid IV fluid replacement should be started when the patient has failed to respond to the treatment as outlined above. Administration and dosage of IV fluids are discussed in the section "Fluid Resuscitation" under "Office Management of Anaphylaxis."
- Consider diphenhydramine, 1-2 mg/kg or 25-50 mg/dose (parenterally). Histamine 1 (H1) antihistamines are considered second-line to epinephrine and should not be administered in lieu of epinephrine in the treatment of anaphylaxis.
- Consider ranitidine, 50 mg in adults and 12.5-50 mg (1 mg/kg) in children, which may be diluted in 5% dextrose to a total volume of 20 mL and injected IV over 5 min. Cimetidine (4 mg/kg) may be administered IV to adults, but no pediatric dosage for the treatment of anaphylaxis has been established. In the management of anaphylaxis, a combination of diphenhydramine and ranitidine is superior to diphenhydramine alone. However, these agents have a much slower onset of action than epinephrine and should never be used alone in the treatment of anaphylaxis. Both alone and in combination these agents are second-line to epinephrine.
- Consider inhaled β-agonist (e.g., albuterol metered dose inhaler (MDI) 2-6 puffs or nebulized, 2.5-5 mg in 3 mL saline and repeat as necessary) for bronchospasm resistant to adequate doses of epinephrine.
- Glucocorticosteroids should never be used in place of or prior to epinephrine and are not helpful acutely. However, they have the potential to prevent recurrent or protracted anaphylaxis.
Annotation 7. Subsequent Measures That May Be Necessary Depending on Response to Epinephrine
When anaphylaxis is not responding to the above measures, including repeated doses of IM or SQ epinephrine, the use of IV epinephrine, vasopressors and glucagon may need to be considered (see section on "Office Management of Anaphylaxis").
Annotation 8. Interventions for Cardiopulmonary Arrest Occurring during Anaphylaxis
- Cardiopulmonary resuscitation and advanced cardiac life support measures.
- High-dose epinephrine IV (i.e., rapid progression to high dose). A common sequence is 1 to 3 mg (1:10,000 dilution) IV slowly administered over 3 min, 3 to 5 mg IV over 3 min, and then 4-10 µg/min infusion. For children, the recommended initial resuscitation dosage is 0.01 mg/kg (0.1 ml/kg of a 1:10,000 solution up to 10 µg/min rate of infusion), repeated every 3 to 5 min for ongoing arrest. Higher subsequent dosages (0.1-0.2 mg/kg; 0.1 ml/kg of a 1:1,000 solution) may be considered for unresponsive asystole or pulseless electrical activity (PEA).
- Rapid volume expansion.
- Atropine if asystole or pulseless electrical activity (PEA) is present.
- Prolonged resuscitation is encouraged, if necessary, since a successful outcome is more likely in anaphylaxis.
- Transport to emergency department or intensive care, as setting dictates.
Annotation 9. Observation and Subsequent Follow-Up
Biphasic anaphylaxis occurs in 1% to 23% of episodes of anaphylaxis, and symptoms may recur hours (most within 10 hours) after apparent resolution of the initial phase. However, observation periods must be individualized since there are no reliable predictors of biphasic or protracted anaphylaxis based on initial clinical presentation. Similarly, follow-up must be individualized and based on distance from patient's home to closest emergency facility, severity of the reaction, patient's response to treatment, and other factors. Following resolution of the acute episode, patients should be provided with autoinjectable epinephrine and receive proper instruction for self-administration in case of a subsequent episode. In circumstances where an allergist-immunologist is not already involved, it is strongly recommended that individuals who have experienced acute anaphylaxis should be referred to an allergist-immunologist for consultation regarding diagnosis, prevention, and treatment.
Annotation 10. Consider Consultation with Allergist-Immunologist
After acute anaphylaxis is resolved, patients should be assessed for future risk of anaphylaxis. The allergist-immunologist can obtain a detailed history, coordinate allergy diagnostic testing, evaluate the risks and benefits of therapeutic options, train the patient in self-administration of epinephrine, and provide counseling on avoidance measures, which is the most effective treatment for most causes of anaphylaxis.
Evaluation and Management of Patients with a History of Anaphylaxis
- The history is the most important tool to determine whether a patient has had anaphylaxis and the cause of the episode. (C)
- A thorough differential diagnosis should be considered, and other conditions should be ruled out. (C)
- Laboratory tests can be helpful to confirm a diagnosis of anaphylaxis or rule out other causes. Proper timing of such tests (e.g., serum tryptase) is essential. (B)
- In the management of a patient with a previous episode of anaphylaxis, education is necessary. Emphasis on early treatment, specifically the self-administration of epinephrine, is essential. (C)
- The patient can be instructed to wear and/or carry identification denoting his or her condition (e.g., Medic Alert jewelry), and can also be instructed to have telephone numbers for paramedic rescue squads and ambulance services on hand. A written action plan can be helpful in this regard. (C)
Office Management of Anaphylaxis
- Anaphylaxis is an acute, life-threatening systemic reaction with varied mechanisms, clinical presentations, and severity that results from the sudden systemic release of mediators from mast cells and basophils. (B)
- The more rapidly anaphylaxis develops, the more likely the reaction is to be severe and potentially life-threatening. (C)
- Prompt recognition of signs and symptoms of anaphylaxis is crucial. If there is any doubt, it is generally better to administer epinephrine. (C)
- Epinephrine and oxygen are the most important therapeutic agents administered in anaphylaxis. Epinephrine is the drug of choice, and the appropriate dose should be administered promptly at the onset of apparent anaphylaxis. The consensus of experts is that, in general, treatment in order of importance is: epinephrine, patient position, oxygen, IV fluids, nebulized therapy, vasopressors, antihistamines, corticosteroids, and other agents. (C)
- Appropriate volume replacement either with colloid or crystalloids and rapid transport to the hospital is essential for patients who are unstable or refractory to initial therapy for anaphylaxis in the office setting. (B)
- Medical offices and facilities in which anaphylaxis is possible should have a well established plan of action to deal with anaphylaxis that is regularly practiced and the appropriate equipment to treat anaphylaxis. The more rapid the treatment, the better the outcome. Therefore, personnel in a medical office dealing directly with the patient's medical care should be familiar with the manifestations of anaphylaxis and be able to recognize an event quickly. Access to therapy should be immediately available. (B)
- Physicians and office staff should maintain clinical proficiency in anaphylaxis management. (D)
- In addition, telephone numbers for paramedical rescue squads and ambulance services might be helpful to have on hand. (C)
Anaphylaxis to Foods
- Food is the most common cause of anaphylaxis in the outpatient setting and food allergens account for 30% of fatal cases of anaphylaxis. (D)
- The most commonly implicated foods responsible for food-induced anaphylaxis include: peanuts, tree nuts, fish, shellfish, cow's milk, soy and egg. In addition sesame seed has recently been identified as a significant cause of food-induced anaphylaxis. (C)
- Common themes associated with fatal food anaphylaxis include: reactions commonly involved peanuts and tree nuts; cutaneous and respiratory symptoms are frequently observed; victims are typically teenagers and young adults; patients have a prior history of food allergy and asthma; and there is a failure to promptly administer epinephrine. (C)
- As is the case of anaphylaxis following other agents, asthma is a risk factor for more severe food-induced anaphylaxis. (C)
- Biphasic anaphylactic reactions can occur in up to 25% of fatal and near-fatal food reactions. (C)
- Serum tryptase measurements may not be elevated in cases of food-induced anaphylaxis. (C)
- The rapid use of injectable epinephrine has been shown to be effective in the initial management of food-induced anaphylaxis but subsequent doses may be needed. (C)
- Patients who experience anaphylaxis should be observed for longer periods if they have experienced food-induced anaphylaxis. (C)
- Food-dependent, exercise-induced anaphylaxis is a unique clinical syndrome in which anaphylaxis occurs within a few hours of specific food ingestion or any meal, and exercise. (C)
- Patients with food allergy should pay close attention to food advisory labeling (e.g., "may contain"), which have become more prevalent. (C)
Natural Rubber Latex (NRL)-Induced Anaphylaxis
- There are three groups that are at high risk of reaction to latex: health care workers; children with spina bifida and genitourinary abnormalities; and workers with occupational exposure to latex. (C)
- In vitro assays for IgE to NRL are typically recommended as a first step in evaluating latex sensitivity. However, due to their suboptimal diagnostic predictive value, positive and negative results must be interpreted based on the history. If the test is positive with a high clinical likelihood, latex sensitivity would be reasonable to pursue. In contrast, if the test is negative with a high clinical likelihood, latex sensitivity still must be considered. (C)
- A standardized commercial skin test reagent for NRL is not available in the United States. In this regard, allergists have prepared NRL extracts from gloves to use for clinical testing. It should be noted, however, that such extracts prepared from gloves demonstrate tremendous variability in content of NRL allergen. Nevertheless, skin prick test with NRL extract to identify IgE-mediated sensitivity should be considered if patients are members of high risk groups or have a clinical likelihood of NRL allergy and have negative in vitro tests. (C)
- Patients with spina bifida (regardless of a history of NRL allergy) and patients with a positive history of NRL allergy ideally should have all medical-surgical-dental procedures performed in a NRL safe environment. (D)
- A NRL-safe environment is an environment in which no NRL gloves are used in the room or surgical suite and there is limited NRL accessories (catheters, adhesives, tourniquets, and anesthesia equipment or devices) which come in contact with the patient. (D)
- In health care settings, general use of NRL gloves with negligible allergen content, powder-free NRL gloves, and nonlatex gloves and medical articles should be considered in an effort to minimize patient exposure to latex. Such an approach can diminish NRL sensitization of health care workers and patients and reduce the risk of reactions to NRL in previously sensitized individuals. (D)
- Patients with a diagnosis of NRL allergy by history and/or skin testing can wear a medical identification bracelet, carry a medical identification card, or both. If patients have a history of anaphylaxis to NRL, it is important for them to carry auto-injectable epinephrine. (D)
Anaphylaxis during General Anesthesia, the Intraoperative Period, and the Postoperative Period
- The incidence of anaphylaxis during anesthesia has been reported to range from 1 in 4000 to 1 in 25,000. Anaphylaxis during anesthesia can present as cardiovascular collapse, airway obstruction, and/or skin manifestations. (C)
- It can be difficult to differentiate between immune and nonimmune mast cell–mediated reactions and pharmacologic effects from the variety of medications administered during general anesthesia. In addition, cutaneous manifestations of anaphylaxis are less likely to be apparent when anaphylaxis occurs in this setting. (B)
- The evaluation of IgE-mediated reactions to medications used during anesthesia can include skin testing to a variety of anesthetic agents. (B)
- The management of anaphylactic reactions that occur during general anesthesia is similar to the management of anaphylaxis in other situations. (B)
- Thiopental allergy has been documented by skin tests. (B)
- Neuromuscular blocking agents, such as succinylcholine, can cause nonimmunologic histamine release, but there have also been reports of IgE-mediated reactions in some patients. (B)
- Reactions to opioid analgesics are usually caused by direct mast cell–mediator release rather than IgE-dependent mechanisms. (B)
- Antibiotics that are administered perioperatively can cause immunologic or nonimmunologic reactions. (B)
- Protamine can cause severe systemic reactions through IgE-mediated or nonimmunologic mechanisms. (B)
- Blood transfusions can elicit a variety of systemic reactions, some of which might be IgE-mediated or mediated through other immunologic mechanisms. (B)
- Methylmethacrylate (bone cement) has been associated with hypotension and various systemic reactions, although no IgE mechanism has been documented. (C)
Seminal Fluid Anaphylaxis
- Coital anaphylaxis caused by human seminal fluid has been shown to be due to IgE-mediated sensitization to seminal plasma proteins of varying molecular weight. (C)
- Post-coital local reactions to human seminal plasma are probably IgE-mediated based on successful response to rapid seminal plasma desensitization. (C)
- History of atopic disease is the most consistent risk factor for seminal fluid-induced anaphylaxis. (C)
- The diagnosis of seminal plasma anaphylaxis may be confirmed by skin testing with fresh whole human seminal plasma or its fractions obtained from the male partner. It is essential to exclude other underlying causes such as allergens in natural rubber latex condoms, or in drugs or foods passively transferred via seminal plasma. (D)
- Greater than 90% of the allergenic proteins range between 12 to 75 kd. Prostate specific antigen has been demonstrated to be a relevant allergen in some cases. (C)
- Systemic and localized reactions to seminal plasma can be prevented by correct use of condoms. Nevertheless, in the event of barrier failure, sexual partners should be prepared to treat acute anaphylaxis. (C)
- Subcutaneous immunotherapy to properly prepared fractions of seminal plasma collected from male partners has been successful in preventing anaphylaxis to seminal plasma. (C)
- Successful intravaginal graded challenge with whole seminal plasma of the male partner has been reported in a few cases but the duration of protection is unknown. This treatment approach may be considered prior to pursuing desensitization using relevant seminal plasma protein fractions. (C)
- Patients with seminal plasma allergy may be able to conceive without undergoing desensitization, by artificial insemination with washed spermatozoa. (C)
- Exercise is the immediate trigger for the development of symptoms in exercise-induced anaphylaxis (EIA). Typical symptoms include extreme fatigue, warmth, flushing, pruritus, and urticaria, occasionally progressing to angioedema, wheezing, upper airway obstruction, and collapse. (A)
- The pathophysiologic events during exercise that precipitate symptoms are not known, although promising lines of research exist. (C)
- Some patients experience symptoms only if other contributing factors or "co-triggers" are present in association with exercise. These co-triggers include ingestion of specific foods, or in some patients, ingestion of any food, nonsteroidal anti-inflammatory drugs, and high pollen levels. (C)
- The clinical history should focus on identification of these possible co-triggers. Evaluation for sensitization to food allergens, particularly grains and seafood, should be performed. The diagnosis is usually made based upon history and exclusion of other disorders. Exercise challenge testing does not consistently reproduce symptoms. (C)
- All patients with exercise-induced anaphylaxis must be advised to stop exercising immediately at the first sign of symptoms because continued exertion causes the attacks to worsen. In addition, all patients should carry epinephrine auto injectors and exercise with a partner who can recognize symptoms and administer epinephrine if necessary. (D)
- Prophylactic medications are not effective for preventing attacks in the majority of patients, although a small subset do appear to benefit from daily administration of H1 antihistamines. (D)
- The prognosis of patients with exercise-induced anaphylaxis is generally favorable, although at least one fatality has been reported. Most patients experience fewer and less severe attacks over time. It is unclear if this is the result of trigger avoidance or a change in the underlying condition. (C)
- The symptoms of idiopathic anaphylaxis are identical to those of episodes related to known causes. (C)
- Patients with idiopathic anaphylaxis should receive an intensive evaluation, including a meticulous history to rule out a definite cause of the events. (C)
- There might be a need for specific laboratory studies to exclude systemic disorders, such as indolent systemic mastocytosis. This might include a measurement of serum tryptase when the patient is asymptomatic, measurement of total tryptase during or within 4 hours of an acute episode, and the ratio of mature (β) tryptase to total tryptase during an episode. To exclude hereditary angioedema or acquired C1 inhibitor deficiency, a C4 concentration can be obtained as it will be reduced during or in the absence of severe angioedema in those conditions but normal in idiopathic anaphylaxis. (C)
- There might be a need for selective skin testing for detection of anti-food IgE antibodies when foods have been ingested within 2 hours of the onset of an episode. (C)
- Empiric use of oral corticosteroids combined with H1 antagonists has been demonstrated to reduce the frequency/severity of episodes. (C)
- Patients with idiopathic anaphylaxis should carry epinephrine, know the indications for self-administration, and can carry information denoting their condition. (C)
Anaphylaxis to Allergen Immunotherapy Extract (Vaccine)
- There is a small risk of near-fatal and fatal anaphylactic reactions to allergen immunotherapy. (C)
- Patients with asthma, particularly if poorly controlled, are at higher risk for serious potentially life-threatening anaphylaxis to allergen immunotherapy injections. (C)
- It is unclear whether patients taking beta-adrenergic blocking agents are at increased risk of having a serious systemic reaction to allergen immunotherapy injections. (B)
- Anaphylaxis in patients taking beta-adrenergic blocking agents may be more difficult to treat. (C)
- Allergen immunotherapy vaccines should be administered only by health care professionals trained in the recognition and treatment of anaphylaxis, only in health care facilities with the proper equipment for the treatment of anaphylaxis, and in clinics with policies and procedures that minimize the risk of anaphylaxis. (D)
Anaphylaxis to Drugs and Biological Agents
- Low-molecular-weight medications induce an IgE-mediated reaction only after combining with a carrier protein to produce a complete multivalent antigen. (B)
- Penicillin is the most common cause of drug-induced anaphylaxis. (C)
- Penicillin spontaneously degrades to major and minor antigenic determinants, both of which should be included in skin testing for penicillin hypersensitivity. (B)
- The negative predictive value of penicillin skin testing with both major and minor determinants (for immediate-type reactions) is between 97% and 99% (depending on the reagents used), and the positive predictive value is at least 50%. (B)
- The degree of cross-reactivity between penicillin and cephalosporins appears to be low. (C)
- The degree of cross-reactivity between penicillin and cephalosporins or carbapenems appears to be low. (C)
- Patients with a history of penicillin allergy who have negative penicillin skin test responses can safely receive cephalosporins. (B)
- Patients who need to receive cephalosporins and who have a history of penicillin allergy and positive penicillin skin test responses can (1) receive an alternate (non–beta-lactam) antibiotic; (2) receive a cephalosporin through graded challenge; or (3) receive a cephalosporin through rapid desensitization. (C)
- Aztreonam does not cross-react with other beta-lactams, except ceftazidime, with which it shares a common R-group side chain. (B)
- Diagnosis of IgE-mediated reactions to non–beta-lactam antibiotics is limited by a lack of knowledge of the relevant allergenic determinants and/or metabolites. (C)
- Aspirin and nonsteroidal anti-inflammatory drugs are the second most common cause of drug-induced anaphylaxis. (C)
- Anaphylactic reactions to aspirin and other nonsteroidal anti-inflammatory drugs appear to be medication specific. (D)
- Anaphylactic reactions to omalizumab have occurred, and post-marketing data indicate that there is an incidence of approximately 0.2% in treated patients. These reactions have been unusual in that they can be delayed in onset and progressive. (C)
- Based on the fact that anaphylactic reactions to omalizumab can be delayed, an observation period of two hours for the first three injections, and 30 minutes thereafter for subsequent injections is indicated. (D)
- All patients receiving omalizumab should be prescribed an automatic epinephrine injector and instructed in its use. The physician should ensure that the patient has such an injector with them, at the time of the visits to the office for injection. (D)
- A pre-assessment (before the injection of omalizumab) of the patient's current health status should be made. This should include vital signs, an assessment of asthma control, and measurement of lung function. (D)
Stinging Insect Hypersensitivity
- Anaphylaxis to insect stings has occurred in 3% of adults and 1% of children who have been stung, and can be fatal even on the first reaction. (B)
- Cutaneous systemic reactions are most common in children, hypotensive shock is most common in adults, and respiratory manifestations occur equally in all age groups. (B)
- The chance of a systemic reaction to a sting is low (5-10%) in patients who have large local reactions and in children with mild (cutaneous) systemic reactions. (A)
- Venom skin tests are most sensitive for diagnosis but in vitro testing is an important complementary test. (A)
- The degree of sensitivity on skin or in vitro tests does not reliably predict the severity of a sting reaction. (B)
- Since asymptomatic venom sensitization can be detected in up to 25% of adults, diagnosis cannot be made on skin testing alone; the history is essential. (C)
- Patients discharged from emergency care of anaphylaxis should be given or prescribed auto-injectable epinephrine and receive instruction in its proper use and indications for use as well as advised to set-up an appointment with an allergist-immunologist. Patients should understand, however, that using autoinjectable epinephrine is not a substitute for emergency medical attention. (A)
- Venom immunotherapy (VIT) should be recommended for patients with systemic sensitivity to stinging insects as this treatment is highly (90% to 98%) effective. (B)
- Most patients can discontinue VIT after 5 years, with low residual risk of a severe sting reaction. (A)
- There is a need to develop tests that are: 1) markers of susceptibility that can serve as a screening test to identify patients at high risk of sting anaphylaxis; and 2) markers of tolerance induction to identify patients who can safely discontinue venom immunotherapy. (D)
Prevention of Anaphylaxis
- Avoidance management should be individualized, taking into consideration factors such as age, activity, occupation, hobbies, residential conditions, access to medical care, and the patient's level of personal anxiety. (C)
- Even in cases when the allergen is known, avoidance measures may not always be successful. Therefore, patients should be instructed in self-management of anaphylaxis. (C)
- Venom immunotherapy (VIT) is successful in preventing anaphylaxis in up to 98% of patients who have previously experienced venom-induced anaphylaxis. (A)
- Pharmacologic prophylaxis should be used in select situations, e.g. to prevent recurrent anaphylactic reactions to radiographic contrast material and fluorescein, as well as to prevent idiopathic anaphylaxis. In these specific situations, prophylaxis with glucocorticosteroids and antihistamines markedly reduces the occurrence of subsequent reactions. (C)
- Desensitization to medications that are known to have caused anaphylaxis can be effective. The desensitization is temporary, and if the medication is required in the future, the desensitization process must be repeated. (C)
- Patient education might be the most important preventive strategy. Education can emphasize hidden allergens, cross-reactivity between various allergens and drugs, unforeseen risks during medical procedures, and when and how to use self-administered epinephrine. Physicians should educate patients about the risks of future anaphylaxis, as well as the benefits of avoidance measures. (B)
Category of Evidence
Ia Evidence from meta-analysis of randomized controlled trials
Ib Evidence from at least one randomized controlled trial
IIa Evidence from at least one controlled study without randomization
IIb Evidence from at least one other type of quasiexperimental study
III Evidence from non-experimental descriptive studies, such as comparative studies
IV Evidence from expert committee reports or opinions or clinical experience of respected authorities or both
Strength of Recommendation
A Directly based on category I evidence
B Directly based on category II evidence or extrapolated recommendation from category I evidence
C Directly based on category III evidence or extrapolated recommendation from category I or II evidence
D Directly based on category IV evidence or extrapolated recommendation from category I, II, or III evidence
LB (Lab Based)