Anaphylaxis is defined as an acute systemic allergic reaction that results from the sudden release of mast cell and basophil-derived mediators into the circulation. Thereaction may vary in severity from mild to life-threatening or fatal and may be rapidlyprogressive.
The phenomenon itself is old, but it was recognized and named in the beginning of the20th century by Frenchphysiologists Charles Robert Richet and Paul Portier. In 1902, Portier and Richet described the phenomenon that occurred when they injected dogs withvenom from the sea anemone in an attempt to confer sting prophylaxis. Several days later,when they gave a second nonlethal dose of the venom to the dogs, the dogs quickly died. To describe this phenomenon, Portier and Richet proposed the term anaphylaxis, whichwas derived from the Greek words a-(against) and -phylaxis (immunity, protection). the Nobel Prize in Medicine or Physiology was awarded to Richet in 1913 for his collaborative research with Portier on anaphylaxis. The list of agents that can trigger these life-threatening reactions in the population continues to grow. Common causes of anaphylaxis reactions are medications, foods,insect venoms, vaccines, and latex, with drugs and foods being the most frequent causes. The incidence of anaphylaxis is not clearly known, although there have been several studies and reviews of the literature. An analysis of published literature by Neugut et estimated that in the United States 3.3–4.3 million Americans were at risk for anaphylaxis and 1433–1503 were at risk for a fatality. They suggested that 12.4–16.8% of the U.S.population may suffer an anaphylactic reaction. Internationally, it is estimated that approx154 fatal episodes of anaphylaxis occur per 1 million hospitalized patients. However, the true incidence of anaphylaxis is probably underestimated because it is underreported. Release of potent pharmacological mediators from tissue mast cells and peripheral blood basophils is the basis for the clinical manifestations seen in anaphylaxis and anaphylactoid reactions. Anaphylaxis and anaphylactoid reactions differ in that true anaphylaxis involves antigen response to immunoglobulin (Ig)E antibody, whereas IgE is not involved in anaphylactoid reactions
PATHOPHYSIOLOGY
Anaphylaxis is a generalized, immediate IgE-mediated hypersensitivity reaction to a foreign antigen such as a protein, a hapten, or a polysaccharide. In susceptible persons, initial exposure to an antigen results in the formation of specific IgE antibodies to that antigen. These antibodies attach to receptors on the surface of mast cells and basophils. This leads to changes in the cell membrane with degranulation and release of preformed chemical mediators and generation of new potent mediators. It is these mediators that produce the clinical symptoms of anaphylaxis (Fig. 1). Mast cells are marrow-derived, tissue-resident cells that are essential for IgE-mediated inflammatory reactions. These cells are scattered in connective tissues throughout the body, but are found in especially large numbers beneath mucosal and cutaneous surfaces such as the skin, the lung alveoli, the gastrointestinal (GI) mucosa, and the nasal mucous membranes. Mast cells express on their surfaces large numbers of highaffinity Fc receptors for IgE. Therefore, the surface of each mast cell is coated with IgE molecules that have been absorbed from the circulation and serve as receptors for specific antigens. When antigens bind to the mast cell’s surface IgE molecules, it undergoes activation that leads to its subsequent degranulation and release of granule contents into the surrounding tissues. The granules contain large amounts of histamine and other inflammatory mediators.
Histamine is a major mediator of anaphylaxis, and histamine infusion has been shown to reproduce the majority of the manifestations of anaphylaxis. The activities of histamine are shown in detail in Table 1. The actions of histamine are mediated through four receptor types (H1, H2, H3, and H4). Two of these, the H1 and H2 receptors, are active in producing the symptoms of anaphylaxis. The H3 receptor has been implicated in anaphylaxis in dogs, but its role in humans has not been elucidated at this time. The overall effect of histamine on the vascular bed is to produce vasodilatation. This causes flushing and a lowering of peripheral resistance, resulting in a fall in systolic pressure. Vascular permeability also occurs, resulting from a separation of endothelial cells at the postcapillary venule level. Both H1 and H2 receptors are operative in the production of vasodilatation. Cardiac effects of histamine are mediated primarily through the H2 receptor. H2 receptor stimulation causes an increase in rate and force of atrial and ventricular contraction and decreases the fibrillation threshold. H1 receptor stimulation can cause coronary artery vasospasm and an increased rate of depolarization of the SA node. Histamine leads to constriction of smooth muscle in the bronchial tree, uterus, and GI tract. Both H1 and H2 stimulation increase glandular secretion. Like mast cells, basophils also bear high-affinity Fc receptors for IgE and contain histamine-rich cytoplasmic granules. The basophil participates in IgE-mediated reactions in a manner similar to that of the mast cell. Other chemical mediators involved in the IgE-mediated anaphylactic reaction include arachidonic acid metabolites, such as leukotrienes (LTC4, D4, E4) and the prostaglandins (PGD2, PGF2a), as well as thromboxane A2. These substances can cause contraction of airway smooth muscle, increased vascular permeability, goblet and mucosal gland secretion, and peripheral vasodilatation. Platelet-activating factor also contracts smooth muscle
and enhances vascular permeability. Thus, histamine, arachidonic metabolites, and platelet-activation factor produce smooth muscle spasm, enhance vascular permeability, and cause vasodilatation. Also, these mediators stimulate sensory nerves, activate vagal effector pathways, and alter myocardial function. The results of these events are the classic symptoms of flushing, urticaria and angioedema, wheezing, hypotension and shock, myocardial ischemia, and GI smooth-muscle contraction with nausea, vomiting, and diarrhea. Other mediators such as tryptase, chymase, mast cell kininogen, and basophil kallikrein are involved and can activate secondary inflammatory pathways
CLINICAL MANIFESTATIONS
the signs and symptoms of anaphylaxis vary greatly in onset, presentation, and course.The skin, the upper and lower airways, the cardiovascular system, and the GI tract may be affected solely or in any combination (Fig. 2). Symptoms of anaphylaxis usually begin within 5–30 min after exposure to the inciting agent. However, symptoms may be delayed for up to 1 h or more. The clinical signs and symptoms of anaphylaxis can vary. Based on a compilation of 1784 patients from a review of published series, the most commonly affected organ is the skin. Cutaneous symptoms occur in more than 90% of individuals who suffer an anaphylactic reaction. Urticaria and angioedema were the most prevalent skin manifestations, occurring in approx 85–90% of the subjects. Flushing was seen in 45–55% of cases,whereas only 4–5% had generalized pruritus without a rash. The respiratory tract, involving both the upper and the lower airways, was the next most generally involved system, with 40–60% experiencing shortness of breath, dyspnea, wheezing, or upper airway angioedema. Rhinitis occurred in approx 15–20%. Symptoms of hypotension or documented hypotension were frequent and were seen
in 30–35% of the patients. The GI tract is also regularly involved. Diarrhea, abdominal cramps, nausea, and emesis developed in 25–30% of the patients. Less frequent symptoms include headache, blurred vision, transient blindness, seizures, and substernal chest pain.It is thought that there is a direct correlation between the immediacy of the onset of the symptoms after exposure to the triggering agent and the severity of the anaphylactic episode; the more rapid the onset, the more severe the event. In some patients, the episode may appear to resolve, and then the symptoms reoccur after several hours. This is called biphasic anaphylaxis. It can occur despite appropriate treatment of the initial event. Therefore, it is recommended that patients who have a significant anaphylactic event be hospitalized for overnight observation. The decision for prolonged observation should take into account the severity of the episode, the presence of concurrent medical problems, and whether the individual has other risk factors such as β-blocker use. Death caused by anaphylaxis usually occurs as a result of respiratory obstruction and/or cardiovascular shock. In patients who die of anaphylaxis, the prominent pathological features are acute pulmonary hyperinflation, laryngeal edema, pulmonary edema, intra-alveolar hemorrhage, visceral congestion, urticaria, and angioedema. In some instances death occurs without any gross pathologicaal change and is presumed to be the result of profound cardiovascular collapse. Sudden vascular collapse is usually attributed to vasodilation or cardiac arrhythmia. Myocardial damage may occur inup to 80% of fatal cases .
RISK FACTORS
There are many factors that increase the risk of anaphylaxis in the population. Patients with atopy are at a higher risk of anaphylaxis from antigens administered by the mucosal route, such as food, compared with parenterally administered agents, such as vaccines. The longer the interval between doses for certain antigens, the less likely is a recurrence of anaphylaxis. Interruption of therapy may lead to predisposition to anaphylactic reactions, as has been documented with insulin treatment. Route of administration appears to be a risk factor, with a higher likelihood of anaphylaxis when an agent is given by injection rather than orally. Gender and age have been evaluated as potential risk factors. Women have a higher incidence of anaphylaxis in general compared to men and also have anaphylaxis more often in reaction to latex, muscle relaxants, and aspirin. Men have a higher rate of anaphylaxis in reaction to insects than do females. These higher rates based on gender may be more related to exposure than to a genetic difference. Adults tend to have a higher incidence of anaphylaxis to contrast medium, insects, plasma expand and anesthetics than children do. Again, this may be more a result of greater exposure to these agents in adults than children. The route of administration of a particular agent can exert an effect on both the frequency of occurrence and the severity. Anaphylaxis can occur with any route, including oral, subcutaneous, intramuscular, intravenous, intranasal, intraocular, Cutaneous, intravaginal, intrarectal, and intratracheal. Attacks seem to be more severe and more frequen when the route of administration is injection.
