Originally Posted: July 2004
Richard F. Lockey, MD
Professor of Medicine, Pediatrics and Public Health
Director of the Division of Allergy and Immunology
Joy McCann Culverhouse Chair of Allergy and Immunology
University of South Florida College of Medicine and the James A. Haley Veterans' Hospital
Tampa, Florida, USA
This disease summary is provided for informational purposes for physicians only.
Anaphylaxis is an acute, potentially life-threatening hypersensitivity reaction, involving the release of mediators from mast cells, basophils and recruited inflammatory cells. Anaphylaxis is defined by a number of signs and symptoms, alone or in combination, which occur within minutes, or up to a few hours, after exposure to a provoking agent. It can be mild, moderate to severe, or severe. Most cases are mild but any anaphylaxis has the potential to become life-threatening.
Anaphylaxis develops rapidly, usually reaching peak severity within 5 to 30 minutes, and may, rarely, last for several days.
The term anaphylaxis is often reserved to describe immunological, especially IgE-mediated reactions. A second term, non-allergic anaphylaxis, describes clinically identical reactions that are not immunologically mediated. The clinical diagnosis and management are, however, identical.
The initial manifestation of anaphylaxis may be loss of consciousness. Patients often describe "a sense of doom." In this instance, the symptoms and signs of anaphylaxis are isolated to one organ system, but since anaphylaxis is a systemic event, in the vast majority of subjects two or more systems are involved.
Gastro-intestinal: Abdominal pain, hyperperistalsis with faecal urgency or incontinence, nausea, vomiting, diarrhea.
Oral: Pruritus of lips, tongue and palate, edema of lips and tongue.
Respiratory: Upper airway obstruction from angioedema of the tongue, oropharynx or larynx; bronchospasm, chest tightness, cough, wheezing; rhinitis, sneezing, congestion, rhinorrhea.
Cutaneous: Diffuse erythema, flushing, urticaria, pruritus, angioedema.
Cardiovascular: Faintness, hypotension, arrhythmias, hypovolemic shock, syncope, chest pain.
Ocular: Periorbital edema, erythema, conjunctival erythema, tearing.
Genito-urinary: Uterine cramps, urinary urgency or incontinence.
Severe initial symptoms develop rapidly, reaching peak severity within 3-30 minutes. There may occasionally be a quiescent period of 1–8 hours before the development of a second reaction (a biphasic response). Protracted anaphylaxis may occur, with symptoms persisting for days. Death may occur within minutes but rarely has been reported to occur days to weeks after the initial anaphylactic event.
1. IgE-Mediated Reactions
In theory, any food glycoprotein is capable of causing an anaphylactic reaction. Foods most frequently implicated in anaphylaxis are:
- Peanut (a legume)
- Tree nuts (walnut, hazel nut/filbert, cashew, pistachio nut, Brazil nut, pine nut, almond)
- Shellfish (shrimp, crab, lobster, oyster, scallops)
- Milk (cow, goat)
- Chicken eggs
- Seeds (cotton seed, sesame, mustard)
- Fruits, vegetables
Food sensitivity can be so severe that a systemic reaction can occur to particle inhalation, such as the odors of cooked fish or the opening of a package of peanuts.
A severe allergy to pollen, for example, ragweed, grass or tree pollen, can indicate that an individual may be susceptible to anaphylaxis or to the oral allergy syndrome (pollen/food syndrome) (manifested primarily by severe oropharyngeal itching, with or without facial angioedema) caused by eating certain plant-derived foods. This is due to homologous allergens found between pollens and foods. The main allergen of all grasses is profilin, which is a pan-allergen, found in many plants, pollens and fruits, and grass-sensitive individuals can sometimes react to many plant-derived foods.
Typical aero-allergen food cross-reactivities are:
- Birch pollen: apple, raw potato, carrot, celery and hazelnut
- Mugwort pollen: celery, apple, peanut and kiwifruit
- Ragweed pollen: melons (watermelon, cantaloupe, honeydew) and banana
- Latex: banana, avocado, kiwifruit, chestnut and papaya
Food-associated, exercise-induced anaphylaxis may occur when individuals exercise within 2-4 hours after ingesting a specific food. The individual is, however, able to exercise without symptoms, as long as the incriminated food is not consumed before exercise. The patient is likewise able to ingest the incriminated food with impunity as long as no exercise occurs for several hours after eating the food.
Antibiotics and Other Drugs
PENICILLIN, CEPHALOSPORIN, AND SULPHONAMIDE ANTIBIOTICS
Penicillin is the most common cause of anaphylaxis, for whatever reason, not just drug-induced cases. Penicillin and other antibiotics are haptens, molecules that are too small to elicit immune responses but which may bind to serum proteins and produce IgE antibodies. Serious reactions to penicillin occur about twice as frequently following intramuscular or intravenous administration versus oral administration, but oral penicillin administration may also induce anaphylaxis. Neither atopy, nor a genetic history of allergic rhinitis, asthma or eczema, is a risk factor for the development of penicillin allergy.
Muscle relaxants, for example, suxamethonium, alcuronium, vecuronium, pancuronium and atracurium, which are widely used in general anesthesia, account for 70-80% of all allergic reactions occurring during general anesthesia. Reactions are caused by an immediate IgE-mediated hypersensitivity reaction.
Hymenoptera venoms (bee, wasp, yellow-jacket, hornet, fire ant) contain enzymes such as phospholipases and hyaluronidases and other proteins which can elicit an IgE antibody response.
Latex is a milky sap produced by the rubber tree Hevea brasiliensis. Latex-related allergic reactions can complicate medical procedures, for example, internal examinations, surgery, and catheterization. Medical and dental staff may develop occupational allergy through use of latex gloves.
Examples of miscellaneous agents which cause anaphylaxis are insulin, seminal proteins, and horse-derived antitoxins, the latter of which are used to neutralize venom in snake bites. Individuals who have IgA deficiency may become sensitized to the IgA provided in blood products. Those selective IgA deficient subjects (1:500 of the general population) can develop anaphylaxis when given blood products, because of their anti-IgA antibodies (probably IgE-anti-IgA).
Elective Medical Procedures
2. Cytoxic and Immune Complex – Complement-Mediated Reactions
Whole Blood, Serum, Plasma, Fractionated Serum Products, Immunoglobulins, Dextran
Anaphylactic responses have been observed after the administration of whole blood or its products, including serum, plasma, fractionated serum products and immunoglobulins. One of the mechanisms responsible for these reactions is the formation of antigen-antibody reactions on the red blood cell surface or from immune complexes resulting in the activation of complement. The active by-products generated by complement activation (anaphylatoxins C3a, C4a and C5a) cause mast cell (and basophil) degranulation, mediator release and generation, and anaphylaxis. In addition, complement products may directly induce vascular permeability and contract smooth muscle.
Cytotoxic reactions can also cause anaphylaxis, via complement activation. Antibodies (IgG and IgM) against red blood cells, as occurs in a mismatched blood transfusion reaction, activate complement. This reaction causes agglutination and lysis of red blood cells and perturbation of mast cells resulting in anaphylaxis.
3. Non-immunologic Mast Cell Activators
Radiocontrast Media, Low-molecular Weight Chemicals
Mast cells may degranulate when exposed to low-molecular-weight chemicals. Hyperosmolar iodinated contrast media may cause mast cell degranulation by activation of the complement and coagulation systems. These reactions can also occur, but much less commonly, with the newer contrast media agents.
Narcotics are mast cell activators capable of causing elevated plasma histamine levels and non-allergic anaphylaxis. They are most commonly observed by anesthesiologists.
4. Modulators of Arachidonic Acid Metabolism
Aspirin, Ibuprofen, Indomethacin and other Non-steroidal Anti-inflammatory Agents (NSAIDs)
IgE antibodies against aspirin and other NSAIDs have not been identified. Affected individuals tolerate choline or sodium salicylates, substances closely structurally related to aspirin but different in that they lack the acetyl group.
5. Sulfiting Agents
Sodium and Potassium Sulfites, Bisulfites, Metabisulfites, and Gaseous Sulfur Dioxides
These preservatives are added to foods and drinks to prevent discoloration and are also used as preservatives in some medications. Sulfites are converted in the acid environment of the stomach to SO2 and H2SO3, which are then inhaled. They can produce asthma and non-allergic hypersensitivity reactions in susceptible individuals.
6. Idiopathic Causes
Exercise alone can cause anaphylaxis as can food-induced anaphylaxis, Exercise-induced anaphylaxis can occur during the pollinating season of plants to which the individual is allergic.
Catamenial anaphylaxis is a syndrome of hypersensitivity induced by endogenous progesterone secretion. Patients may exhibit a cyclic pattern of attacks during the premenstrual part of the cycle.
Flushing, tachycardia, angioedema, upper airway obstruction, urticaria and other signs and symptoms of anaphylaxis can occur without a recognizable cause. Diagnosis is based primarily on the history and an exhaustive search for causative factors. Serum tryptase and urinary histamine levels may be useful, in particular, to rule out mastocytosis.
A = Airway
Ensure and establish a patent airway, if necessary, by repositioning the head and neck, endotracheal intubation or emergency cricothyroidotomy. Place the patient in a supine position and elevate the lower extremities. Patients in severe respiratory distress may be more comfortable in the sitting position.
B = Breathing
Assess adequacy of ventilation and provide the patient with sufficient oxygen to maintain adequate mentation and an oxygen saturation of at least 91% as determined by pulse oximetry. Treat bronchospasm as necessary. Equipment for endotracheal intubation should be available for immediate use in event of respiratory failure and is indicated for poor mentation, respiratory failure, or stridor not responding immediately to supplemental oxygen and epinephrine.
C = Circulation
Minimize or eliminate continued exposure to causative agent by discontinuing the infusion, as with radio-contrast media, or by placing a venous tourniquet proximal to the site of the injection or insect sting. Assess adequacy of perfusion by taking the pulse rate, blood pressure, mentation and capillary refill time. Establish I.V. access with large bore (16- to 18-gauge) catheter and administer an isotonic solution such as normal saline. A second I.V. may be established as necessary. If a vasopressor, such as dopamine becomes necessary, the patient requires immediate transfer to an intensive care setting.
The same ABC mnemonic can be used for the pharmacologic management of anaphylaxis:
A = Adrenalin = epinephrine
Epinephrine is the drug of choice for anaphylaxis. It stimulates both the beta-and alpha-adrenergic receptors and inhibits further mediator release from mast cells and basophils. Animal and human data indicate that platelet activating factor (PAF) mediates life-threatening manifestations of anaphylaxis. The early use of epinephrine in vitro inhibits the release of PAF in a time-dependent manner, giving support to the use of this medication with the first signs and symptoms of anaphylaxis. The usual dosage of epinephrine for adults is 0.3-0.5 mg of a 1:1000 w/v solution given intramuscularly every 10-20 minutes or as necessary. The dose for children is 0.01 mg/kg to a maximum of 0.3 mg intramuscularly every 5-30 minutes as necessary. Lower doses, e.g., 0.1 mg to 0.2 mg administered intramuscularly as necessary, are usually adequate to treat mild anaphylaxis, often associated with skin testing or immunotherapy. Epinephrine should be given early in the course of the reaction and the dose titrated to the clinical response. For severe hypotension, 1 cc of a 1:10,000 w/v dilution of epinephrine given slowly intravenously is indicated. The patient's response determines the rate of infusion.
B = Benadryl (diphenhydramine)
Antihistamines are not useful for the initial management of anaphylaxis but may be helpful once the patient stabilizes. Diphenhydramine may be administered intravenously, intramuscularly or orally. Cimetidine offers the theoretical benefit of reducing both histamine-induced cardiac arrhythmias, which are mediated via H2 receptors, and anaphylaxis-associated vasodilation, mediated by H1 and H2 receptors. Cimetidine, up to 300 mg every 6 to 8 hours, may be administered orally or slowly I.V. Doses must be adjusted for children.
C = Corticosteroids
Corticosteroids do not benefit acute anaphylaxis but may prevent relapse or protracted anaphylaxis. Hydrocortisone (100 to 200 mg) or its equivalent can be administered every 6 to 8 hours for the first 24 hours. Doses must be adjusted for children.
Prevention of Anaphylaxis
Agents causing anaphylaxis should be identified when possible and avoided. Patients should be instructed how to minimize exposure.
Beta-adrenergic antagonists, including those used to treat glaucoma, may exacerbate anaphylaxis and should be avoided, where possible. Angiotensin-converting enzyme (ACE) inhibitors may also increase susceptibility to anaphylaxis, particularly with insect venom-induced anaphylaxis.
Epinephrine is the drug of choice to treat anaphylaxis. Individuals at high risk for anaphylaxis should be issued epinephrine syringes for self-administration and instructed in their use. Intramuscular injection is recommended since it results in prompt elevation of plasma concentrations and has prompt physiological effects. Subcutaneous injection results in delayed epinephrine absorption. Patients must be alerted to the clinical signs of impending anaphylaxis and the need to carry epinephrine syringes at all times and to use it at the earliest onset of symptoms. Unused syringes should be replaced immediately when they reach their use-by/expiration date, as epinephrine content and bioavailability of the drug decreases in proportion to the number of months past the expiration date.
Pre-treatment with glucocorticosteroids and H1 and H2 antihistamines is recommended to prevent or reduce the severity of a reaction where it is medically necessary to administer an agent known to cause anaphylaxis, for example, radio-contrast media.
Other important patient instructions include:
a) Personalized written anaphylaxis emergency action plan
b) Medical Identification (e.g., bracelet, wallet card)
c) Medical record electronic flag or chart sticker, and emphasis on the importance of follow-up investigations by an allergy/immunology specialist
The differential diagnosis for anaphylaxis includes:
- respiratory difficulty or circulatory collapse, including vasovagal reactions
- globus hystericus
- status asthmaticus
- foreign body aspiration
- pulmonary embolism
- myocardial infarction
- carcinoid syndrome
- hereditary angioedema
- overdose of medication
- cold urticaria
- cholinergic urticaria
- sulfite or monosodium glutamate ingestion
Upper airway obstruction, bronchospasm, abdominal cramps, pruritus, urticaria and angioedema are absent in vasovagal reactions. Pallor, syncope, diaphoresis and nausea usually indicate a vaso-vagal reaction but may occur in either condition.
If a reaction occurs during a medical procedure, it is important to consider a possible reaction to latex or medication used for or during anesthesia.
The prevalence of food-induced anaphylaxis varies with the dietary habits of a region. A United States survey reported an annual occurrence of 10.8 cases per 100,000 person years. By extrapolating this data to the entire population of the USA, this suggests approximately 29,000 food-anaphylactic episodes each year, resulting in approximately 2,000 hospitalizations and 150 deaths. Similar findings have been reported in the United Kingdom and France. Food allergy is reported to cause over one-half of all severe anaphylactic episodes in Italian children treated in emergency departments and for one-third to one-half of anaphylaxis cases treated in emergency departments in North America, Europe and Australia. It is thought to be less common in non-Westernized countries. A study in Denmark reported a prevalence of 3.2 cases of food anaphylaxis per 100,000 inhabitants per year with a fatality rate of approximately 5%.
Risk factors for food anaphylaxis include asthma and previous allergic reactions to the causative food.
Food-associated, exercise-induced anaphylaxis
This is more common in females, and over 60% of cases occur in individuals less than 30 years of age. Patients sometimes have a history of reacting to the food when younger and usually have positive skin tests to the food that provokes their anaphylaxis.
Anaphylaxis caused by radio-contrast media
Mild adverse reactions are experienced by approximately 5% of subjects receiving radio-contrast media. U.S. figures suggest that severe systemic reactions occur in 1:1000 exposures with death in 1:10,000-40,000 exposures.
One percent to 5% of courses of penicillin therapy are complicated by systemic hypersensitivity reactions. Point two percent is associated with anaphylactic shock, and mortality occurs in 0.02% of the cases. If a patient has a strongly positive skin test or circulating IgE antibody to penicillin, there is a 50-60% risk of an anaphylactic reaction upon subsequent challenge. In patients with a case history suggestive of penicillin allergy and negative skin tests, the risk of anaphylaxis is very low. Atopy and mold sensitivity are not risk factors for the development of penicillin allergy.
Anaphylaxis to muscle relaxants occurs in approximately 1 in 4,500 of general anesthesia, with fatalities occurring in 6% of these cases. Risk factors are female sex (80% of cases). Atopy is not a risk factor; previous drug allergy may be a risk factor. In patients with a history of anaphylaxis, skin tests to different muscle relaxants may be helpful. If the test result is positive, the muscle relaxant should not be used. A negative result provides evidence that the muscle relaxant can probably be administered safely.
Insect venom anaphylaxis
Studies from Australia, France, Switzerland and the USA suggest incidences of systemic reactions to Hymenoptera stings ranging from 0.4% to 4% of the population. In the USA, at least 40 deaths occur each year as a result of Hymenoptera stings.
Allergy / immunology specialists play a uniquely important role to confirm the etiology of anaphylaxis, prepare the patient for self administration of epinephrine, educate the patient and/or family about allergen avoidance, and rule out any underlying condition, such as mastocytosis, which can predispose a patient to develop anaphylaxis. Referral to an allergist / immunologist is indicated for patients with this disease.