Online Medical Reference

Anaphylaxis

Fred Hsieh

Published: December 2013

Definition and Etiology

Anaphylaxis is a serious allergic reaction that has a rapid onset and can cause death.1,2 In the past, the term anaphylactic reaction referred to symptoms triggered by immunoglobulin (Ig) E–dependent activation of immune effector cells, whereas anaphylactoid reactions were clinically similar to anaphylactic reactions but were not mediated by antigen-specific IgE. Although some experts have advocated that the term anaphylactoid be eliminated, other influential clinical practice guidelines consensus documents continue to use the term anaphylactoid – thus, anaphylactic and anaphylactoid reactions will be discussed as a single entity in this chapter.2

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Prevalence and Risk Factors

Published incidence and prevalence data are likely inaccurate because anaphylaxis is underdiagnosed, underreported, and miscoded.3,4 Some of the most recent data suggests that the incidence is approximately 50 to 200 episodes per 100,000 person-years with a lifetime prevalence ranging between 0.05% and 2%.5 It is estimated that up to 1,500 fatalities are caused by anaphylaxis per year in the United States.6 Both the incidence and prevalence of anaphylaxis have been increasing, with a disproportionate increase in cases seen in children and younger patients.7 With children especially a fivefold increase in hospital admissions for food-associated anaphylaxis has been noted over the past decade.8 Risk factors affecting the incidence of anaphylaxis have been identified (Box 1).

Box 1. Risk Factors for the Development of Anaphylaxis
Age
Children: Higher incidence of food-related anaphylaxis
Adults: Higher incidence of anaphylaxis related to antibiotics, radio–contrast media, anesthetic agents, and insect stings
Gender
Females: Anaphylaxis may be more common overall and also more common with latex, aspirin, radiocontrast media, and muscle relaxants
Males: Anaphylaxis is more common with insect venom
Socioeconomic Status
Increased frequency of anaphylaxis with higher socioeconomic status
Route of Administration
Oral antigens are less likely to trigger anaphylaxis than parenteral antigens
Oral antigens are less likely to trigger severe symptoms than parenteral antigens
Timing of Administration
Interrupted therapy is more likely to predispose to anaphylaxis
Atopy
Risk factor for anaphylactic and anaphylactoid reactions in general, but perhaps not for certain antigens – penicillin, insulin, Hymenoptera venom
Exposure History
The longer the interval since previous antigen exposure, the less likely a reaction will occur
Geography
Prescription rates for self-injectible epinephrine devices greater in northern than in southern states; rural environment may affect incidence
Comorbid Conditions
Asthma, cardiovascular disease, substance abuse, mastocytosis
Drugs
Beta blockers and ACE inhibitors can increase anaphylaxis severity
Omalizumab can lead to delayed onset and protracted progression of anaphylaxis

ACE, angiotensin-converting enzyme.

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Pathophysiology

The clinical symptoms of anaphylaxis derive from the mediators (Table 1) released by the activation of sensitized mast cells and, to a lesser extent, basophils.9 Anaphylactic reactions are triggered by the cross-linking of the high-affinity IgE receptor by receptor-bound IgE that recognizes antigens such as food, drug, or insect venom antigens.1 Non-IgE mediated triggers of anaphylaxis include activation of mast cells and eosinophils by immune complexes or cytotoxic transfusion reactions. IgG-mediated anaphylaxis (or anaphylactoid reactions) can be triggered by high molecular weight iron dextran or monoclonal antibodies such as infliximab.10,11 Exposures to hemodialysis membranes or oversulfated chondroitin sulfate-contaminated heparin are associated with complement-mediated anaphylaxis related to the generation of complement protein anaphylatoxins such as C3a and C5a.12 A variety of physical factors such as cold, heat or sunlight, drugs such as opiates, and radiocontrast media may trigger anaphylaxis from direct activation of innate immune effector cells (mast cells).1 Nonsteroidal anti-inflammatory agents can trigger anaphylaxis by altering arachdonic acid metabolism.13 Some agents, such as radiocontrast media, contaminated heparin, etc. may activate multiple pathways that lead to the activation of the contact and complement systems, promote the generation of kinins, and trigger the clinical symptoms of anaphylaxis.14 The mediators identified in Table 1 may directly contribute to increased airway resistance, fall in PO2, and vasodilation with hypotension seen during anaphylaxis.

Table 1. Relevant Mediators Released by Mast Cells and Basophils in Anaphylaxis
Mediator Action
Arachidonic Acid Metabolites
Cysteinyl leukotrienes
Prostaglandins
Platelet activating factor
Bronchoconstriction, coronary vasoconstriction, increased vascular permeability, mucus hypersecretion, eosinophil activation and recruitment
Chemokines
IL-8
MIP-1α
Eosinophil chemotactic factors
Neutrophil and eosinophil chemotaxis, inflammatory cell recruitment, activation of NADPH oxidase
Cytokines
GM-CSF
IL-3, -4, -5, -6, -10, and -13
TNF-α
Eosinophil chemotaxis and activation; inflammatory cell activation and recruitment, induction of IgE-receptor expression, induction of apoptosis
Proteases
Chymase
Tryptase
Carboxypeptidase A
Cleavage of complement proteins and neuropeptides, inflammatory-cell chemoattractant, conversion of angiotensin I to angiotensin II, activation of protease-activated receptor-2
Proteoglycans
Chondroitin sulfate
Heparin
Anticoagulation, complement inhibition, eosinophil chemoattractant, kinin activation
Other
Histamine Vasodilation, bronchial and gastrointestinal smooth muscle contraction, mucus hypersecretion
Nitric oxide Vasodilation, increased vascular permeability

GM-CSF, granulocyte-macrophage colony-stimulating factor; NADPH, reduced nicotinamide adenine dinucleotide phosphate; TNF-α, tumor necrosis factor α.

Some of the most common antigenic triggers of anaphylactic reactions are listed in Box 2. Food-triggered anaphylaxis can occur from any food at any age. Patients with food allergic reactions to eggs may have an increased theoretical risk of reactions to the egg-containing influenza vaccine, though the amount of egg ovalbumin protein has decreased in the vaccine over the years.15 Current recommendations include administration of an age appropriate trivalent inactivated influenza vaccine as a single dose to all patients, including those with a history of egg allergy, in a physician's office followed by a 30 minute observation period. Skin testing to the influenza vaccine in egg-allergic individuals is now not recommended unless the patient has a history of reactions to the vaccine itself.16 Egg-allergic children are not at increased risk for anaphylaxis with the measles–mumps–rubella vaccine because sensitivity to this vaccine may be triggered by sensitivity to gelatin and not egg.17

Box 2. Triggers of Anaphylactic Reactions
Drugs
Antibiotics
Antisera
Aspirin and other nonsteroidal anti-inflammatory drugs
Opiates
Perioperative medications
Topical benzocaine
Vaccines
Monoclonal antibodies, including biologics such as cetuximab and omalizumab
Hormones
Insulin
Progesterone
Blood and Blood Products
Antithymocyte globulin
Intravenous immunoglobulins
Enzymes
Streptokinase
Foods*
Egg
Milk
Peanuts
Shellfish
Soy
Tree nuts
Wheat
Red meat
Venom
Hymenoptera
Fire ant
Snake
Other
Dialysis membranes
Human seminal fluid
Latex
Protamine
Radiocontrast media
Oversulfated chondroitin sulfate-contaminated heparin
Therapeutic allergen extracts
Topical disinfectants

*Any food can cause anaphylaxis.

Exercise-induced anaphylaxis occurs during or immediately after physical exercise and often after eating a meal.18 Specific foods have been linked to exercise-induced anaphylaxis. Often, target foods can be tolerated without anaphylaxis in the absence of exercise, and exercise can be tolerated without ingestion of these foods. If specific foods are ingested followed by exercise, however, anaphylaxis can occur.19 A subset of patients with exercise-induced anaphylaxis can develop anaphylaxis when exercising before or after ingestion of any food, not only a specific food.

If foods, drugs, venoms, or other triggers have not been identified as a cause, then the patient may be classified as having idiopathic anaphylaxis.20

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Signs and Symptoms

After exposure to an antigenic trigger, symptoms generally develop within 5 to 30 minutes, although symptoms can occur up to several hours after the exposure (Table 2).2 One notable exception includes patients with IgE-mediated sensitization to carbohydrate moieties in red meat who develop symptoms of anaphylaxis 3 to 6 hours after ingestion.21 From 5% to 20% of patients who suffer an anaphylactic event can experience biphasic anaphylaxis during which symptoms can recur up to 8 hours after the initial event, and less than 1% of patients experience protracted anaphylaxis during which symptoms persist for up to 48 hours.22,23

Table 2. Signs and Symptoms of Anaphylaxis
Organ Symptom
Skin Urticaria and angioedema, flushing, pruritus alone (rare)
Respiratory Dyspnea, wheezing, airway angioedema, rhinitis
Gastrointestinal Nausea, vomiting, diarrhea, cramping, pain
Cardiovascular Tachycardia, hypotension, chest pain, cardiac arrest
Neurologic Headache, dizziness, seizures, sense of impending doom
Other Metallic taste in the mouth
Uterine contractions

Cutaneous manifestations of anaphylaxis are most common, with respiratory symptoms next most frequent. Death from anaphylaxis results from cardiovascular collapse, bronchospasm, or upper airway edema causing airway obstruction. Gastrointestinal and neurologic manifestations can also occur.

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Diagnosis

When considering anaphylaxis in the differential diagnosis, it is important to exclude other clinical disorders that can masquerade as anaphylaxis (Box 3).

Box 3. Masqueraders of Anaphylaxis
Cutaneous
Generalized hives and angioedema
Hypovolemic shock
Vasovagal syncope
Cardiovascular
Cardiogenic shock
Hypovolemic shock
Vasovagal syncope
Endocrinologic
Carcinoid syndrome
Medullary carcinoma of the thyroid
Pheochromocytoma
Pulmonary
Acute asthma exacerbation/Status asthmaticus
Pulmonary embolism
Airway foreign body
Neurologic
Autonomic epilepsy
Seizure disorder
Stroke
Toxic or Metabolic
Drug overdose
Monosodium glutamate ingestion or other restaurant syndromes
Red man syndrome after vancomycin infusion
Scombroid fish poisoning
Sulfite ingestion
Systemic Disorders
Acute promyelocytic leukemia
Basophilic leukemia
Hereditary or acquired angioedema
Systemic mastocytosis
Flushing syndromes
Psychiatric
Globus hystericus
Munchausen syndrome
Panic attack
Vocal cord dysfunction
Other
Foreign body aspiration
Idiopathic capillary leak syndrome

In general, anaphylaxis remains a clinical syndrome where careful review of the history and review of all relevant medical records suggests the diagnosis (Table 3)36. Measurement of selected biomarkers may assist in confirming anaphylaxis. Plasma histamine can be measured, and to be useful should be obtained 15 to 60 minutes after onset of symptoms due to the short half-life of plasma histamine; a transient elevation of peri-event serum histamine with subsequent return to baseline is suggestive.24 Serum tryptase may also be useful in confirming the diagnosis of anaphylaxis. Tryptase is a protease expressed in high concentrations in mast cells and to a much lesser extent in basophils; it is released along with histamine upon mast cell activation and degranulation. If serum specimens can be obtained between 1 and 3 hours after the onset of symptoms, an elevated serum tryptase level compared with a baseline level obtained when the patient is asymptomatic can suggest that symptoms were caused by an anaphylaxis.25 It must be noted that histamine and tryptase testing is not specific for anaphylaxis and that tryptase testing has not been consistently elevated in patients with food-induced anaphylaxis, for example.26 Other biomarkers, such as assessment of platelet activating factor, have been proposed.27

Table 3: Diagnosis of Anaphylaxis36
Anaphylaxis is likely when any one of the following three criteria is fulfilled:
Acute onset (within minutes to hours) of an illness with skin or mucosal involvement with at least one of the following: respiratory compromise and/or reduced blood pressure with associated target-organ dysfunction.
Two or more of the following occurring rapidly (minutes to hours) after exposure of a likely allergen: involvement of the skin or mucosal tissue, respiratory compromise, reduced blood pressure with associated target organ dysfunction, or persistent gastrointestinal symptoms.
Reduced blood pressure occurs after exposure to a known allergen for the specific patient; for infants and children, decreased age-specific systolic blood pressure or a greater than 30% decrease from baseline; for adults, systolic blood pressure of less than 90 mm Hg or greater than a 30% decrease from baseline.

Diagnostic testing, if possible, is critical in identifying the triggering antigen. This may be done with cutaneous or serum radioallergosorbent testing overseen by an allergy specialist.2 Often, a detailed history that reviews over-the-counter medications, ingested foods and drugs, insect stings, and physical activities before the event is the best test. Unfortunately, no clear trigger can be documented in many cases. Diagnostic skin testing should be delayed for at least 3 to 4 weeks after the event to obtain an accurate skin test in order to allow for recovery of skin mast cells.28 In certain cases a challenge or provocation test may be indicated, which is entertained after potential risks and benefits are discussed with the patient and in a facility equipped to treat anaphylaxis.2

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Treatment

Rapid recognition of an acute anaphylactic event is essential to prevent an adverse outcome.2 Initial steps to stabilize the patient should begin with an assessment of the patient's airway and cardiopulmonary status (Box 4). The airway may be secured by intubation or emergent cricothyroidotomy if angioedema from anaphylaxis leads to airway compromise. Intravenous access should be obtained, and any obvious triggering antigen (for example, an insect stinger or an IV medication) should be removed if identified. Vital signs should be monitored, and Trendelenburg positioning and oxygen should be used if necessary. Fluids should be administered for hypotension. Patients should be kept in the supine position, because deaths have occurred when moving a patient in the midst of an anaphylactic event from the supine to the upright position.29 The patient should be immediately transported to a facility experienced in managing anaphylaxis.

Box 4. Medical Management of Anaphylaxis
Epinephrine
Recumbent positioning
Vasopressor agents
Airway management with intubation if necessary
Intravenous fluids
Glucagon (in the case of beta-blocker therapy)
H1 antagonists
H2 antagonists
Steroids
Inhaled or aerosolized beta agonists

Epinephrine is the drug of choice in the treatment of anaphylaxis and should be administered immediately upon diagnosis. Fatality rates are highest in cases where epinephrine administration is delayed.26 Adult patients should receive 0.3 to 0.5 mL epinephrine 1:1,000 (0.3 to 0.5 mg) IM repeated two to three times at an interval of every 5 to 15 minutes, as up to 20% of patients requiring epinephrine for anaphylaxis require a second dose.2,30 Intramuscular administration in the lateral thigh (vastus lateralis muscle) is the recommended site of delivery. If there is no response and the patient is developing signs of shock or cardiovascular collapse, then 0.5 to 1.0 mL of epinephrine 1:10,000 (0.1 mg) IV every 10 to 20 minutes can be given. If IV access cannot be obtained, then epinephrine may be administered by the endotracheal tube. Continuous IV epinephrine infusions have also been used, but its titration should be done in an intensive care unit (ICU) setting.

Other vasopressor medications such as dopamine, norepinephrine, or phenylephrine have also been used in conjunction with colloids or crystalloids for persistent hypotension. These are typically administered in the ICU setting. Antihistamines – H1 antagonists (e.g., diphenhydramine 25 to 50 mg given PO, IM, or IV) and H2 antagonists (e.g., ranitidine 50 mg IM or IV) – can be useful as adjuncts for symptomatic treatment of hives and pruritis. Limited data suggests that a combination of H1 and H2 antagonsists may be more effective than H1 antagonists alone.31 Corticosteroids (e.g., hydrocortisone 100 mg to 1 g IV or prednisone 30 to 60 mg PO) used as adjuncts may also have a role in preventing the late-phase allergic response and may influence biphasic or protracted anaphylaxis, though the data is equivocal.32 If a patient taking beta blockers experiences anaphylaxis, an IV bolus of glucagon 1 mg may be useful to prevent refractory hypotension and relative bradycardia. Atropine, given IM or SC at 0.3 to 0.5 mg every 10 minutes for a maximum of 2 mg, may be useful for bradycardia in the presence of pharmacologic beta-blockade. Inhaled β-adrenergic aerosols may be useful in treating anaphylaxis-associated bronchospasm. Aminophylline can also be considered in patients with persistent bronchospasm on beta-blockers.

At present there is little consensus as to how long a patient must be observed after the resolution of anaphylaxis symptoms. Current guidelines suggest that prolonged observation in the ER or hospital setting for at least 8 to 24 hours after resuscitation should be considered with a moderate-severe anaphylactic reaction, the presence of wheezing in an asthmatic patient, history of an orally-ingested antigen with the possibility of continued gastrointestinal absorption and release into the circulation, and history of previous prolonged or biphasic anaphylactic response.2

A patient who has had an anaphylactic event should be given specific recommendations based on diagnostic testing to prevent and treat future episodes (Box 5).2 Patients should wear medical alert jewelry identifying their risk for anaphylaxis and should be prescribed one or more self-injectable epinephrine and instructed on the use. The epinephrine autoinjector should be activated in the mid-anterolateral part of the thigh through any clothing. These autoinjectors are available in two strengths in the United States – 0.15 mg/injection fixed dose for pediatric patients and 0.3 mg/injection fixed dose for adults. It is important that health care professionals themselves are familiar with the use of the epinephrine autoinjector in order to safely train patients and their caregivers in order to avoid unintentional injections or lost/partial dosing.33

Box 5. Prevention of Anaphylaxis
Post-event evaluation and identification of specific triggers
Avoidance of potentially cross-reactive antigens
Medical alert jewelry
Self-injectable epinephrine
Avoid beta-blockers, angiotensin-converting enzyme inhibitors if possible*
 
Education for preventive measures*
Pretreatment, desensitization, or immunotherapy as indicated*

*Specific recommendations need to be individualized for each patient based on risk-to-benefit analyses.

If an etiologic trigger has been identified, then specific instructions should be given to avoid future episodes and patients should prepare a written anaphylaxis emergency action plan.34 In some cases, further risk reduction can be achieved under the care of an allergy specialist, which can include allergen immunotherapy to selected insect venoms, drug desensitization for beta-lactam antibiotics, and premedication regimens for radiocontrast media reactions. Beta-blocker and angiotensin-converting enzyme inhibitors should be discontinued, if possible. Long-term prevention and management also includes optimization of other co-morbid conditions which may increase the risk of adverse outcomes in anaphylaxis, including management of asthma or other respiratory conditions, cardiovascular disease, systemic mastocytosis or clonal mast cell disorders, etc.

If exercise-induced anaphylaxis is diagnosed and diagnostic testing has identified a specific food trigger, then the patient must refrain from eating that food for 4 to 6 hours before or after exercise. If no specific food is identified, then the patient should limit physical exercise or stop immediately on development of prodromal symptoms. Pretreatment with H1 blockers or warm-up prior to exercise is not considered effective in preventing symptoms. The patient should always exercise with a partner, carry a mobile telephone, and exercise with one or more epinephrine auto-injectors at all times.

In the case of idiopathic anaphylaxis, the patient might benefit from long-term prednisone therapy to induce remission. Patients may be prescribed prednisone 40 to 60 mg PO daily in conjunction with hydroxyzine, albuterol, and self-injectable epinephrine followed by conversion after 1 to 6 weeks of prednisone to alternate-day dosing and reduction of the prednisone dose by 5 to 10 mg/dose each month until the taper is complete. The diagnosis and management of idiopathic anaphylaxis should be performed by an allergy specialist.20

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Outcomes

The most feared outcome of anaphylaxis is death. Although deaths resulting from anaphylaxis are rare, many are potentially preventable. Many of the deaths from anaphylaxis are iatrogenic, and the presence of asthma is a risk factor. The delayed use of epinephrine is a risk factor for a poor outcome, and physicians often inappropriately wait until after cardiac arrest has occurred before administering epinephrine.35 Nevertheless, some patients still die despite receiving epinephrine. Poor outcomes can occur regardless of the antigenic trigger, and death can occur even in idiopathic anaphylaxis.

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Conclusion

Anaphylaxis is a common medical condition affecting both adult and pediatric patients and its incidence and prevalence continue to increase, especially in younger people. Although many triggers, risk factors, and basic biochemical mechanisms have been characterized and appropriate treatments (namely self-injectable epinephrine) developed to prevent fatalities due to anaphylaxis, adverse outcomes can still occur. Aggressive recognition and prompt treatment with the first choice medication, epinephrine, remains critical to ensuring good patient outcomes. Prevention strategies based on diagnostic testing, patient education, immunomodulation where indicated, antigen avoidance, and optimization of co-morbid conditions can be helpful to prevent recurrent symptoms. Additional therapeutics and the encouragement of randomized, controlled trials for prevention and treatment strategies and new therapeutics are required to improve future outcomes.

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Summary

  • Epinephrine is the treatment of choice for anaphylaxis and should not be withheld even in patients with cardiovascular disease.
  • The incidence and prevalence of anaphylaxis is increasing and is commonly under-recognized and under-diagnosed.
  • The diagnosis of anaphylaxis remains a clinical diagnosis, but diagnostic testing can help to confirm the diagnosis and identify potential triggers.
  • An allergy and immunology specialist can assist in long-term risk-reduction in many but not all clinical conditions.

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Suggested Readings

  • Simons FE. Anaphylaxis: evidence-based long-term risk reduction in the community. Immunol Allergy Clin North Am 2007; 27:231–248, vi–vii.
  • Simons FE. Anaphylaxis, killer allergy: long-term management in the community. J Allergy Clin Immunol 2006; 117:367–377.

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