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Anaphylaxis is an acute systemic (multi-system) and severe type I hypersensitivity allergic reaction in humans and other mammals. The term comes from the Greek words ανα ana (again) and φύλαξις phylaxis (protection). Minute amounts of allergens may cause a life-threatening anaphylactic reaction. Anaphylaxis may occur after ingestion, skin contact, injection of an allergen or, in some cases, inhalation.

Anaphylactic shock, the most severe type of anaphylaxis, occurs when an allergic response triggers a quick release of large quantities of immunological mediators (histamines, prostaglandins and leukotrienes) from mast cells, leading to systemic vasodilation (associated with a sudden drop in blood pressure) and edema of bronchial mucosa (resulting in bronchoconstriction and difficulty breathing). Anaphylactic shock can lead to death in a matter of minutes if left untreated.

Due in part to the variety of definitions, between 1% and 15% of the population of the United Statesmarker can be considered "at risk" for having an anaphylactic reaction if they are exposed to one or more allergens, especially penicillin and insect stings. Most of these people successfully avoid their allergens and will never experience anaphylaxis. Of those people who actually experience anaphylaxis, up to 1% may die as a result. Anaphylaxis results in approximately 1,500 deaths per year in the U.S. (one out of every 1,600 of the 2.4 million deaths from all causes each year in the U.S.;). The most common presentation includes sudden cardiovascular collapse (88% of reported cases of severe anaphylaxis). In England, mortality rates for anaphylaxis have been reported as up to 0.05 per 100,000 population, or around 10-20 a year.

Anaphylactic reactions requiring hospital treatment appear to be increasing, with authorities in England reporting a threefold increase between 1994 and 2004.

Researchers studying mechanisms of allergic reaction typically distinguish between "true anaphylaxis" and "pseudo-anaphylaxis" or an "anaphylactoid reaction." The symptoms, treatment, and risk of death are identical, but "true" anaphylaxis is always caused directly by degranulation of mast cells or basophils that is mediated by immunoglobulin E (IgE), and pseudo-anaphylaxis occurs due to all other causes.


Anaphylaxis is a severe, whole-body allergic reaction. After an initial exposure "sensitizing dose" to a substance like bee sting toxin, the person's immune system becomes sensitized to that allergen. On a subsequent exposure "shocking dose", an allergic reaction occurs. This reaction is sudden, severe, and involves the whole body.

Hives and angioedema (swelling of the lips, eyelids, throat,or tongue) often occur. Angioedema may be severe enough to block the airway. Prolonged anaphylaxis can cause heart arrhythmia.

Anaphylaxis can occur in response to any allergen. Common triggers include insect bites or stings, food allergies, and drug allergies. Pollens and other inhaled allergens rarely cause anaphylaxis. In ophthalmology, the dye fluorescein used in some eye exams is a well-known trigger. Some people have an anaphylactic reaction with no identifiable cause, in which case the anaphylactic reaction is said to be idiopathic.

Some drugs (polymyxin, morphine, x-ray dye and others) may cause an "anaphylactoid" reaction (anaphylactic-like reaction) on the first exposure. This is usually due to a toxic reaction, rather than the immune system mechanism that occurs with "true" anaphylaxis. The symptoms, risk for complications without treatment, and treatment are the same, however, for both types of reactions. Some vaccinations are also known to cause "anaphylactoid" reactions. Antitoxins and antivenins may cause similar reactions. In certain individuals, strenuous physical activity can induce anaphylaxis.


Symptoms of anaphylaxis are related to the action of Immunoglobulin E (IgE) and other anaphylatoxins, which act to release histamine and other mediator substances from mast cells (degranulation). In addition to other effects, histamine induces vasodilation of arterioles and constriction of bronchioles in the lungs, also known as bronchospasm (constriction of the airways).

Tissues in different parts of the body release histamine and other substances. This causes constriction of the airways, resulting in wheezing, difficulty breathing, and gastrointestinal symptoms such as abdominal pain, cramps, vomiting, and diarrhea. Histamine causes the blood vessels to dilate (which lowers blood pressure) and fluid to leak from the bloodstream into the tissues (which lowers the blood volume). These effects result in shock. Fluid can leak into the alveoli (air sacs) of the lungs, causing pulmonary edema.

Symptoms can include the following:


Diagnosis is based on fulfilling three main clinical criteria (British Resuscitation Council). Firstly, sudden onset and rapid progression. Secondly a life-threatening problem with either Airway and/or Breathing and/or Circulation. Finally skin or mucosal changes, for example widespread urticaria.

The time between ingestion of the allergen and anaphylaxis symptoms can vary for some patients depending on the amount of allergen consumed and their reaction time. Symptoms can appear immediately, or can be delayed by half an hour to several hours after ingestion. However, symptoms of anaphylaxis usually appear very suddenly and progress quickly once they do begin.

Apart from its clinical features, blood tests for tryptase (released from mast cells) might be useful in diagnosing anaphylaxis.

In some cases, it is unclear from the patient interview what triggered the anaphylaxis. In this setting, skin allergy testing (with or without patch testing) or RAST blood tests can sometimes identify the cause.


Emergency treatment

Anaphylaxis is a life-threatening medical emergency because of rapid constriction of the airway, often within minutes of onset, which can lead to respiratory failure and respiratory arrest. Brain and organ damage rapidly occurs if the patient cannot breathe. Due to the severe nature of the emergency, patients experiencing or about to experience anaphylaxis require the help of advanced medical personnel. First aid measures for anaphylaxis include rescue breathing (part of CPR). Rescue breathing may be hindered by the constricted airways, but if the patient stops breathing on his or her own, it is the only way to get oxygen to him or her until professional help is available.

The primary treatment for anaphylaxis is administration of epinephrine (adrenaline). Epinephrine prevents worsening of the airway constriction, stimulates the heart to continue beating, causes vasoconstriction in order to increase blood pressure, and may be life-saving. Epinephrine acts on Beta-2 adrenergic receptors in the lung as a powerful bronchodilator (opens the airways), relieving allergic or histamine-induced acute asthmatic attack or anaphylaxis. If the patient has previously been diagnosed with anaphylaxis, he or she may be carrying an EpiPen, Anapen or Twinject for immediate administration of epinephrine. However, use of an EpiPen or similar device only provides temporary and limited relief of symptoms.

Tachycardia (rapid heartbeat) results from stimulation of Beta-1 adrenergic receptors of the heart increasing contractility (positive inotropic effect) and frequency (chronotropic effect) and thus cardiac output. Repetitive administration of epinephrine can cause tachycardia and occasionally ventricular tachycardia with heart rates potentially reaching 240 beats per minute, which itself can be fatal. Extra doses of epinephrine can sometimes cause cardiac arrest. This is why some protocols advise intramuscular injection of very small amounts of epinephrine.

Some patients with severe allergies routinely carry preloaded syringes containing epinephrine, diphenhydramine (Benadryl), and dexamethasone (Decadron) whenever they go to an unknown or uncontrolled environment.

Clinical care

Paramedic treatment in the field includes administration of epinephrine intramuscular; antihistamines IM (such as chlorphenamine or diphenhydramine; steroids, such as hydrocortisone, methylprednisolone (SoluMedrol), or dexamethasone; IV fluid administration and in severe cases, pressor agents (which cause the heart to increase its contraction strength) such as dopamine for hypotension, administration of oxygen, and intubation during transport to advanced medical care.

In severe situations with profuse laryngeal edema (swelling of the airway), cricothyrotomy or tracheostomy may be required to maintain oxygenation. In these procedures, an incision is made through the anterior portion of the neck, over the cricoid membrane, and an endotracheal tube is inserted to allow mechanical ventilation of the patient.

The clinical treatment of anaphylaxis by a doctor and in the hospital setting aims to treat the cellular hypersensitivity reaction as well as the symptoms. Antihistamine drugs such as diphenhydramine or chlorphenamine (which inhibit the effects of histamine at histamine receptors) are continued but are usually not sufficient in anaphylaxis, and high doses of intravenous corticosteroids such as dexamethasone or hydrocortisone are often required. Hypotension is treated with intravenous fluids and sometimes vasopressor drugs. For bronchospasm, bronchodilator drugs (e.g. salbutamol, known as Albuterol in the United States) are used. In severe cases, immediate treatment with epinephrine can be lifesaving. Supportive care with mechanical ventilation may be required.

It is also possible to undergo a second reaction after medical attention or using an Epipen. The possibility of biphasic reactions (recurrence of anaphylaxis, sometimes called a "rebound reaction") requires that patients be monitored for four hours after being transported to medical care for anaphylaxis. Most anaphylactic patients are sent home or released after this monitoring period.

Planning for emergency treatment

The Asthma and Allergy Foundation of Americamarker advises patients prone to anaphylaxis to have an "allergy action plan" on file at school, home, or in their office to aid others in case of an anaphylactic emergency, and provides a free"plan" form. Action plans are considered essential to quality emergency care. Many authorities advocate immunotherapy to prevent future episodes of anaphylaxis.

Beta-blockers may aggravate anaphylactic reactions and interfere with treatment.


Immunotherapy with Hymenoptera venoms is effective against allergies to bees, wasps, hornets, yellow jackets, white faced hornets, and fire ants.

The greatest success with prevention of anaphylaxis has been the use of allergy injections to prevent recurrence of sting allergy. The risk to an individual from a particular species of insect depends on complex interactions between likelihood of human contact, insect aggression, efficiency of the venom delivery apparatus, and venom allergenicity. Venom immunotherapy reduces risk of systemic reactions below 3%. One simple method of venom extraction has been electrical stimulation to obtain venom, instead of dissecting the venom sac.

A vaccine has been in the works to prevent anaphylaxis from peanuts and tree nuts. Despite showing significant promise to prevent individuals with the allergy from developing anaphylaxis if eating a small amount of the food, the FDA has not yet approved the vaccine.


Classified as a type I hypersensitivity, anaphylaxis is triggered when an antigen binds to IgE antibodies on mast cells based in connective tissue throughout the body, which leads to degranulation of the mast cells (the release of inflammatory mediators). These immune mediators cause many symptoms, including common symptoms of allergic reactions, such as itching, hives, and swelling. Anaphylactic shock is an allergic reaction to an antigen that causes circulatory collapse and suffocation due to bronchial and tracheal swelling.

Different classes of antibodies are produced by B cells to bind and destroy substances that the immune system has identified as potentially dangerous pathogens. Each B cell produces thousands of identical antibodies that can attack a single, small part of a pathogen. In susceptible individuals, antibodies may be produced against innocuous antigens or allergens, such as components of common foods or plants. One class, the IgE antibodies, can trigger anaphylaxis. Production of IgE antibodies may persist for months, even in the complete absence of the allergen. These IgE antibodies associate with a receptor on the surface of mast cells. If the antibody binds to its specific antigen, then the antibody triggers degranulation of the mast cell.

Mast cells become the major effector cells for immediate hypersensitivity and chronic allergic reactions.

Mast cells are large cells found in particularly high concentrations in vascularized connective tissues just beneath epithelial surfaces, including the submucosal tissues of the gastrointestinal and respiratory tracts, and the dermis that lies just below the surface of the skin. They contain large granules that store a variety of mediator molecules including the vasoactive amine, histamine. Histamine causes dilation of local blood vessels and smooth-muscle contraction. Other molecules in the mast cell granules include lipid inflammatory mediators such as prostaglandin D2¬ and leukotriene C4 as well as tumor necrosis factor-α (TNF-α), a cytokine. The importance of TNF-α is most noted in the activation of the endothelium. TNF-α, the prototype of the TNF family cytokines, can induce endothelial cells to present E-selectin and ICAM-1, both of which are cell adhesion molecules (CAM) that mediate the “roll and stick” mechanism of leukocyte extravasation, termed diapedesis. While this process is essential for the recruit of leukocytes to a localized area during an inflammatory response, it can be catastrophic in cases of systemic infection. Point in case, the presence of said infection in the bloodstream, or sepsis, is accompanied by the release of TNF-α by macrophages in liver, spleen, and other systemic sites. The systemic release of TNF-α causes vasodilatation, which leads to a loss of blood pressure and increased vascular permeability, leading to a loss of plasma volume and eventually to shock.

TNF-α, along with the other aforementioned mast cell granule contents become exocytosed upon activation of the mast cell. Activation is achieved only when IgE, bound to the high-affinity Fcε receptors (FcεR1), are cross-linked by multivalent antigen. The FcεR1 is a tetrameric receptor composed of a single α chain, responsible for binding the IgE, associated with a single β chain and a disulfide linked homodimer of γ chains that initiate the cell signal pathway. Once the FcεR1 are aggregated by the cross-linking process, the immunoreceptor tryrosine-based activation motifs (ITAMs) in both the β and γ chains are phosphorylated by LYN, a protein tryrosine kinase (PTK) belonging to the Src family. The ITAM domain is simply conserved sequence motif generally composed of two YXXL/I sequences separated by about six to nine amino acids, where Y is tyrosine, L is leucine, I isoleucine and X any amino acid. Their phosphorylation in the β and γ chains provide high-affinity docking sites for the SH2 domains of additional LYN and the SYK (spleen tyrosine kinasse), respectively. These SH2 domains (Src homology 2 domian) are found in a numerous cell-signaling proteins and bind to phosphotyrosine through a very specific sequence. As the signal continues to propagate through the pathway, the membrane bound molecule, named linker for activation of T cells (LAT), is phosphoyraleted by the LYN and SYK and acts as a scaffold protein, organizing other molecules that complete the degranulation of mast cells, as well as promote further cytokine production. The most notable of these LAT affected molecules is Phospholipase C (PLC). As in many cell signaling pathways PLC hydrolyzes the phosphodiester bond in phosphoatidylinositol-4,5-bisphosphate [PI(4,5)P¬¬2] to yield diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP¬¬3)¬. A well-characterized second messenger, IP¬3¬, signals the release of calcium from the endoplasmic reticulum. The influx of cytosolic Ca2+ and phosphoatidylserine further active Phosphokinase C (PKC) bound to DAG. Together, it is the cytosolic Ca2+ and PKC signal the degranulation of the mast cell.4

Although less well mapped, similarly prevailing cell signaling molecules, such as Ras, a monomeric G protein, SOS (son of sevenless homologue) and MAPK (mitogen-activated protein kinase) lead to the upregulation of cytokines and the previously mentioned eicosanoids, prostaglandin D2¬ and leukotriene C4.

While this cell single pathway is sufficient to induce degraluation, it is not the only effective mechanism. Studies with LYK deficient mice have shown that degranulation is still inducible. Consequently, several alternative pathways leading to mast cell degranulation have been mapped. The first of which, dubbed the “complementary” pathway, determined that the crosstalk between LYK and another Src family PTK, called FYN, is an essential interaction to degranulation, along with the preferential activity of Phosphoatidylinositol 3-kinase (PI-3K) over PLC. Studies have also elucidated subsequent pathways that utilize the integration of G-protein-coupled receptors to mediate the degranulation and cytokine production mechanism of activated mast cells.

IgE binding to FcεR1 in the absence of a specific antigen still induces the up-regulation of FcεR1 surface expression in mast cells through autocrine signaling of cytokines. However, not all IgE are equally capable of inducing such as secretion. Therefore, researchers have divided all invariant IgEs into two major categories: highly cytokinergic(HC), where the production and secretion of various cytokines and other activation events including degranulation is inducible, and poorly cytokinergic (PC) in which no autocrine signaling is observed. The former, HC IgE, brings forward a reaction in which cytokines are exocytosed and act as autocrine and paracrine signaling molecules. As such, mast cells with bound HC IgE attract other mast cells even in the absence of antigen crosslinking. While the exact structural features that account for the function differences between HC and PC IgE has yet to be determined their effects are thought to be the result of intracellular cell signaling. IgE binding to FcεR1 leads to a greater stability of the mast cell and increased production of surface receptors. The newly expressed FcεR1 then aggregate on the surface, independent of antigen binding. The cell signaling pathway then initiates and appears to involve components used in the alternative mechanisms. Mast cell migration is dependent on soluble factors such as adenosine, leukotriene B¬4 and other chemokines, whose secretion is dependent upon the activity of LYN and SYK. The degranulation of mast cells in the absence of antigen, can then be initiated by G-protein-couple receptors (GPCR) stimulated by soluble factors agonists and completed by downstream activity of PI3K.

Compared to pseudoanaphylaxis

Pseudoanaphylaxis presents with the same clinical signs and symptoms as true anaphylaxis, but it does not involve IgE antibodies. Instead, mast cell degranulation is triggered either by the activation of the complement system or by a pharmacological reaction on the mast cell's surface. Histamine, which is released in both true IgE-based allergic reactions and in these anaphylactoid reactions, is responsible for the resulting signs and symptoms, which are consequently identical.

The complement system contains three proteins (C3a, C4a, and C5a) that are called anaphylatoxins because of their role in triggering pseudoanaphylaxis. The most common trigger for this mechanism is an intravenous infusion of an iodine-containing radiological contrast medium.

The mechanism by which other substances, commonly called histamine liberators, trigger mast cell degranulation, is poorly understood. Some substances are known to be effective liberators in susceptible people, including egg white, strawberries, and a variety of medications.


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