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MD Consult: Books: Goldman: Cecil Medicine: Chapter 274 – SYSTEMIC ANAPHYLAXIS, FOOD ALLERGY, AND INSECT STING ALLERGY

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier



Lawrence B. Schwartz




Systemic anaphylaxis, a form of immediate hypersensitivity, arises when mast cells and possibly basophils are provoked to secrete mediators with potent vasoactive and smooth muscle contractile activities that evoke a systemic response. Although mast cells in any organ system may be involved, depending on the distribution of the instigating stimulus, the principal targets are the cardiovascular, cutaneous, respiratory, and gastrointestinal systems, sites where mast cells are most abundant. The terms anaphylactic and anaphylactoid refer, respectively, to mast cell activation initiated by allergen and immunoglobulin E (IgE), or classical immediate hypersensitivity, and mast cell activation initiated by alternative pathways.



Assessments of the annual incidence of systemic anaphylaxis and the prevalence of those at risk for systemic anaphylaxis are compromised by imprecise diagnostic measures. Approximately 1500 to 2000 deaths occur per year from systemic anaphylaxis in the United States. Nonfatal cases are much more common, estimated to occur at an incidence of between 10 and 100 cases per 100,000 person-years. Further analyses suggest that between 3 and 43 million people (1 to 15% of the U.S. population) may be at risk for such reactions. Drug reactions account for many of these cases. β-Lactam antibiotics and radiocontrast media provoke most such events, but the list of offending agents is lengthy and ever-increasing. During general anesthesia, systemic anaphylactic reactions occur with a frequency of about 1 in 3500, and muscle relaxants, latex, and induction drugs are the three classes of agents most commonly implicated.

Anaphylaxis to foods and insect stings each account for about 100 deaths per year. Most fatal anaphylactic reactions to injected venom proteins begin within 30 minutes after the sting. In those with suspected anaphylactic reactions, insect venom allergies can be tested by venom skin tests and by in vitro measurements of venom-specific IgE. Sting challenges have been performed experimentally but are not recommended for routine evaluations.

Food allergy is found in about 6% of children younger than 3 years of age and in half that percentage of adults, and these individuals are at risk for food-induced anaphylaxis. Most children lose their allergic sensitivities to cow’s milk, egg, wheat, or soy by 5 years of age, whereas sensitivities to peanut, tree nuts, or seafood are typically long-lasting. About 20% of children lose peanut sensitivity by school age, but a small portion of these regain peanut sensitivity later in life, particularly if they continued to avoid this food. Food allergies are evaluated by testing for food allergen-specific IgE using prick skin testing and in vitro measurements; larger wheal-and-flare responses and higher IgE titers to specific allergens are associated with more severe reactions. Oral food challenges are performed under certain circumstances, taking care to minimize the risk of systemic anaphylaxis. These food-allergic reactions involve IgE sensitization and IgE-dependent mechanisms and should be distinguished from a variety of other types of adverse food reactions, including lactose intolerance due to a deficiency in lactase, food-induced enterocolitis in infants (in reaction to cow’s milk, soy, or grains), and celiac disease associated with ingestion of gluten in wheat and other grains.

Latex provokes anaphylaxis in a small but significant group of individuals, particularly patients who have undergone multiple surgical procedures early in life such as those with spina bifida or congenital urinary tract disorders, and those with frequent exposure later in life, such as medical personnel. Estimates of the prevalence of latex hypersensitivity range from 1% to 6% in the general population and about 10% among regularly exposed health care workers. Over a 5-year period, the Food and Drug Administration (FDA) collected approximately 1100 reports of latex-induced anaphylaxis, including 15 deaths. Contact hypersensitivity is diagnosed by patch testing, and immediate hypersensitivity by latex-specific IgE tests performed in vitro. Latex allergen skin test reagents have not yet received FDA approval.





Although the mediators elicited from mast cells overlap extensively in anaphylaxis and anaphylactoid reactions, and thereby invoke similar acute therapies, understanding of differences in causation is likely to affect therapeutic interventions aimed at preventing future attacks. Cells other than mast cells also undoubtedly participate in systemic anaphylaxis, particularly those armed with antigen-specific IgE. Basophils, like mast cells, constitutively express substantial amounts of the high-affinity receptor for IgE, FcεRI; when activated through this pathway, also release mediators within minutes. Eosinophils, monocytes, antigen-presenting cells, and epithelial cells may be induced to express this receptor and thereby affect the intensity, duration, or character of anaphylactic reactions. It is theoretically possible that some cases of systemic anaphylaxis occur through one or more of these cell types without involving mast cells, but this remains controversial.

Most IgE-dependent mast cell activation events occur at local sites and result in local disease. For example, allergic conjunctivitis, allergic rhinitis, or allergic asthma typically occurs when allergen lands on the corresponding mucosal surface of a sensitive individual. Systemic anaphylaxis presumably requires the allergen (or nonallergen agonist) to distribute systemically to activate mast cells at remote sites. This is most likely to occur when allergen is administered parenterally; it is less likely after oral ingestion, inhalation, or topical cutaneous or ocular contact. Activation of mast cells in perivascular locations should have the greatest effect on systemic vascular responses, even though large amounts of mediators released locally could, in theory, spill into the circulation and affect remote sites. Accordingly, intravenous penicillin is more likely than oral penicillin to elicit a severe anaphylactic reaction. However, the precise distributions of mast cells that are activated during anaphylactic reactions are undetermined.



The most common allergens causing systemic anaphylactic reactions include drugs, insect venoms, foods, radiocontrast media, allergen immunotherapy injections, and latex ( Table 274-1 ). Most allergens are typically proteins or glycoproteins that serve as complete antigens, capable of eliciting immediate hypersensitivity reactions in a sensitized subject without further processing. The protease activity of some allergens may facilitate their penetration at mucosal sites. In contrast to complete antigens, most drugs act as haptens. They become covalently linked to self-proteins in the circulation, in tissues or on cells, emerging as multivalent allergens. Multivalency is important for immediate hypersensitivity, because cross-linking of two IgE molecules on the surface of cells brings together at least two FcεRI molecules, which then transmit an activating signal into the cell. Monovalent antigens fail to elicit mediator release because they bind IgE molecules without cross-linking them.

IgE-Mediated (Anaphylaxis) Non-IgE-Mediated (Anaphylactoid)
Insect stings Aspirin
Foods Radiocontrast media
Drugs Exercise
Latex Narcotics/vancomycin
Allergen extracts Idiopathic (?autoimmune)

An allergen exposure must lead to sensitization before an immediate hypersensitivity reaction can occur. This process, which takes 1 to 2 weeks, involves antigen processing by antigen-presenting cells, which then present peptide antigens to TH2 cells (helper T lymphocytes), which in turn select, nurture, and instruct allergen-specific B cells to switch from production of IgM or IgG to IgE. Consequently, anaphylaxis does not occur on first exposure to an allergen (sensitization phase) but may occur after subsequent exposures.

Most cases of food-induced anaphylaxis in children occur in response to egg, peanut, cow’s milk, wheat, or soy, whereas peanuts, tree nuts, and seafood account for most reactions in adults. Reactions to seeds such as sesame seem to be growing in importance, and a variety of different foods have proved to be important allergens in specific individuals. Some have the oral allergy syndrome, which results from allergic reactions with food contact that rarely progress to systemic reactions. Many of these reactions are associated with cross-reactivities between food and pollen allergens, such as melon with ragweed pollen and peach or apple with birch pollen. Also, the food epitopes associated with this syndrome are typically conformational (rather than linear) and therefore are more easily destroyed by heating, protease degradation, and acid denaturation.

Hymenoptera families primarily responsible for anaphylactic reactions include the Apidae (honey bees and bumble bees), Vespidae (hornets, yellow jackets, and paper wasps), and Formicidae (fire ants). Major allergens of honey bees include phospholipase A2 (Api m 1), hyaluronidase (Api m 2), and melitin (Api m 4). Bumble bee venom proteins exhibit immunologic cross-reactivity with those of the honey bee, even though melitin is lacking. Vespid venoms cross-react among themselves and include a protein named antigen 5, phospholipase, and hyaluronidase, the latter allergen cross-reacting with bee hyaluronidase. Fire ant venom toxicity is caused principally by various alkaloids, which are not allergenic. Immediate hypersensitivity reactions to fire ant venom target a phospholipase that cross-reacts with the comparable vespid enzyme and various other proteins that do not cross-react with vespid or bee venom proteins. Allergens in fire ant venom cross-react with those in scorpion venom. A person may exhibit an anaphylactic reaction on first exposure to an insect’s sting if previously sensitized to cross-reactive venom from a different insect. In contrast to stinging insects, allergens from biting insects of the Diptera order (mosquitoes, gnats, midges, true flies) are salivary in origin and do not cross-react with Hymenoptera venom allergens. Anaphylaxis to these salivary proteins appears to be uncommon, but precise epidemiologic data are problematic because people are often unaware of an ongoing mosquito bite, and commercial diagnostic reagents of high quality are not yet available.

Latex allergens are derived from the rubber tree, Hevea brasiliensis. Irritant dermatitis is the most frequent contact reaction and does not involve acquired immunity. Contact hypersensitivity, which results from cell-mediated immunity to haptenic chemicals added to latex during processing, produces a poison ivy–like local reaction. In contrast, immediate hypersensitivity occurs when IgE is made against proteins naturally found in this plant-derived product. Cutaneous (elastic materials), mucosal or intravascular (catheters), oral (balloon), and inhaled (powdered latex gloves) routes of exposure have been well-documented. IgE-mediated cross-reactivities between latex proteins and allergens in certain fresh foods such as banana, chestnut, avocado, kiwi, peach, bell pepper, and tomato have been reported and may necessitate avoidance of these foods.

Non–IgE-Dependent Agonists


Most non–IgE-dependent foreign agents do not require antigen processing and can elicit a mast cell activation response on first exposure. These include radiocontrast dyes, narcotics such as codeine and morphine, and vancomycin (see Table 274-1 ). The dose and rate of administration and individual variations in sensitivity are determinants of severity. For radiocontrast dyes, media of low ionic strength are less likely than those of high ionic strength to elicit a systemic reaction. Vancomycin produces a mast cell activation event known as “red man syndrome,” typically involving urticaria without cardiovascular compromise, which usually can be avoided by reducing the rate of administration of the antibiotic.

Endogenous mast cell activators include neuropeptides such as substance P, neurokinin A, calcitonin gene-related peptide, and the complement anaphylatoxins C3a and C5a. Whether a magnitude of mast cell activation sufficient to cause systemic anaphylaxis can result from endogenous secretion or generation of these peptides by themselves is unproven. For example, an anaphylactic shock–like syndrome occurred in hemodialysis patients exposed to a contaminated hemodialysis membrane that was associated with complement activation, but mast cell activation was not detected.

Aspirin hypersensitivity typically manifests as either a respiratory or a cardiovascular reaction, although sometimes overlap is observed. Respiratory reactions include bronchospasm, nasal congestion, and rhinorrhea and may extend beyond the respiratory tract to include abdominal cramping, watery diarrhea, and urticaria. Cardiovascular reactions that are identical clinically to allergen-induced systemic anaphylaxis and shock also can occur. In most cases, such reactions appear to be pharmacologically (not IgE) mediated, and in sensitive subjects they can occur in response to any of the cyclooxygenase 1 (COX1) inhibitors. Although cyclooxygenase inhibitors may shunt arachidonic acid metabolism to the lipoxygenase pathway, a mechanism to explain mast cell activation has not yet emerged. COX2-selective inhibitors appear to be relatively safe in aspirin-sensitive asthmatics and also are less likely to cause cardiovascular collapse. Less commonly, sensitivity occurs to only one of the drugs within this class and is caused by IgE against an associated unique chemical moiety.



Spontaneous episodes of anaphylaxis, those without an apparent external trigger, also occur. In some cases, such episodes may be an extension of a physical urticaria, occurring in response to stimuli such as exercise, heat, solar radiation, vibration, pressure, or cold. Exercise-dependent anaphylaxis is sometimes associated with food ingestion, occurring within several hours after eating, particularly if sensitivity to the food is present, and might be avoided by delaying exercise until several hours after eating. Progesterone-induced anaphylaxis, which tends to occur just before menses, is uncommon but has been well documented. In other cases, occurrences are not associated with an obvious stimulus. Some cases of chronic urticaria are known to be associated with IgG and IgM antibodies against FcεRI or IgE. In such cases, complement activation leading to the generation of complement anaphylatoxins at the surface of mast cells has been postulated to synergize with FcεRI-mediated activation. These reactions may occur preferentially in the skin because of the expression of anaphylatoxin receptors on the type of mast cell that is predominant in the skin but not on the type predominant in lung. An analogous, albeit speculative, autoimmune process might activate mast cells localized in blood vessel walls, the result being anaphylaxis.



Mast cells participate in both acquired and innate forms of immunity. They develop in peripheral tissues from bone marrow progenitors, primarily under the influence of stem cell factor, the ligand for the tyrosine kinase receptor called Kit. Armed with allergen-specific IgE, mast cells are activated by multivalent allergens that cross-link IgE and associated FcεRI molecules on the cell surface. This may be important in the defense against certain parasites that elicit a strong IgE response. Experiments performed in rodents suggest that mast cells also can be directly activated by certain bacterial products, leading to the secretion of mediators that recruit neutrophils. This innate immune response may restrain bacterial dissemination until a more potent acquired immune response develops. Activation of mast cells by endogenous peptides such as substance P or calcitonin gene-related peptide may influence basic biologic processes such as wound healing and angiogenesis. Whether mast cells have a critical, nonredundant role in these biologic and immunologic processes remains controversial. However, their central role in immediate hypersensitivity is clear.

Mediators released by mast cells include preformed mediators stored in secretory granules, newly generated products of arachidonic acid, and an array of cytokines and chemokines. Histamine, formed from histidine by histidine decarboxylase, is the sole biogenic amine stored in all granules of human mast cells and basophils. Histamine released by mast cells or basophils diffuses freely and interacts with H1, H2, H3, and H4 receptors. H1 receptors are found on endothelial cells, smooth muscle cells, and sensory nerves; when stimulated, they lead to bronchial and gastrointestinal smooth muscle contraction, vascular smooth muscle relaxation, increased permeability of postcapillary venules, coronary artery vasoconstriction, and pruritus—signs and symptoms often associated with systemic anaphylaxis. In the central nervous system (CNS), blockade of H1 receptors appears to cause drowsiness. H2 receptors reside on gastric parietal cells and at lower levels on inflammatory cells, bronchial epithelium, and endothelium and in the CNS. H2-receptor–mediated increased acid production in the stomach, albeit transient, may occur during systemic anaphylaxis, but it is more likely to become clinically significant if histamine levels are chronically elevated, as observed in patients with systemic mastocytosis. H3 receptors are found primarily on cells in the CNS. H4 receptors are found on hematopoietic cells such as mast cells, basophils, and eosinophils and may modulate certain aspects of inflammation, such as eosinophil recruitment. Histamine, after its secretion from mast cells and basophils, is rapidly metabolized to inactive methyl histamine and indole acetic acid.

Prostaglandin D2 (PGD2) is the principal COX-catalyzed product of arachidonic acid secreted by activated mast cells, but it is not made by basophils. It binds to the G protein–coupled receptors, CRTH2 and DP. Both COX1 and COX2 are involved in PGD2 production by mast cells. Consequently, a COX inhibitor that is bipotent might be better than one that is selective at blocking PGD2-mediated responses during anaphylaxis, which may include hypotension, bronchospasm, and inhibition of platelet aggregation.

Leukotriene C4 (LTC4), is released by both mast cells and basophils after its formation from arachidonic acid and glutathione; its formation is sequentially catalyzed first by 5-lipoxygenase and 5-lipoxygenase–activating protein and then by LTC synthase. Conversion to LTD4 and LTE4, which also are bioactive, occurs in the extracellular space. These sulfidopeptide leukotrienes bind to the G protein–coupled receptors cysteinyl leukotriene 1 (CysLT1), on bronchial smooth muscle, epithelial and endothelial cells, and leukocytes, and CysLT2, on vascular smooth muscle, endothelial and epithelial cells, leukocytes, and heart muscle. Sulfidopeptide leukotrienes cause bronchoconstriction, mucus secretion, eosinophil recruitment, vasopermeability, diminished cardiac contractility, vasoconstriction of coronary and peripheral arteries, and vasodilation of venules. Antagonists of CysLT1 (montelukast, zafirlukast) but not of CysLT2, as well as a 5-lipoxygenase inhibitor (zileuton), are currently available to patients.

Mast cells also are the sole or principal source of heparin proteoglycan and certain proteases. All express β-tryptase, and a subset also expresses chymase, mast cell carboxypeptidase, and cathepsin G (like neutrophils and monocytes). Mast cells that express only tryptase are called MCT cells; those that also express the other proteases are called MCTC cells. Mature tryptase is stored in the secretory granules of all mast cells and is released during degranulation of activated cells; levels in serum serve as a clinical marker for mast cell activation. In contrast, precursor forms of tryptase (protryptase) are spontaneously secreted by mast cells at rest; levels in serum serve as a clinical marker of the total body burden of mast cells. MCTC cells express CD88 and therefore are activated by C5a generated during complement activation. Basophils are relatively deficient in these proteases but also express CD88.

Cytokines (tumor necrosis factor-α [TNF-α]; interleukin [IL]-4, -5, -6, -8, -13, and 16; granulocyte-macrophage colony-stimulating factor [GM-CSF]; basic fibroblast growth factor [bFGF]; vascular endothelial growth factor [VEGF]) and chemokines (IL-8, monocyte chemotactic protein-1, monocyte inflammatory protein-1α) represent another dimension of the mediators released by mast cells and basophils. Although these mediators are not selectively produced by these cell types, their vasoactive and inflammatory potential could affect the severity and duration of anaphylaxis. As selective antagonists of the relevant cytokines and chemokines become available and are tested for therapeutic benefits, the roles of these mediators in the pathogenesis of anaphylaxis will be better understood.



Systemic anaphylaxis, with various combinations of hypotension, tachycardia, urticaria, flushing, bronchoconstriction, laryngeal edema, colics, diarrhea, and vomiting—often associated with a sense of doom and beginning within minutes after the provoking stimulus—can be precisely confirmed in the laboratory by demonstration of antigen-specific IgE (sensitization) and an increased level of mature tryptase (mast cell activation) in serum. Skin testing or in vitro measurements of antigen-specific IgE should be delayed for at least 2 weeks after the precipitating event to prevent false-negative results. An increased level of mature tryptase in serum, which peaks 15 to 60 minutes after the onset of anaphylaxis and then declines with a half-life of about 2 hours (normal levels being undetectable), indicates that mast cell activation has occurred. During a study of experimental insect sting–induced anaphylaxis, the increased level of mature tryptase correlated closely with the drop in mean arterial pressure, indicating that the magnitude of mast cell activation is a primary determinant of clinical severity. Although an increased serum mature tryptase level may be useful for distinguishing anaphylaxis from other conditions in the differential diagnosis, it does not occur in some cases of putative anaphylaxis, particularly after food ingestion. This observation raises questions of whether there are anaphylactic pathways that bypass mast cells, perhaps involving basophil activation. Plasma histamine, because it is rapidly metabolized, is not as practical as serum or plasma mature tryptase for detecting anaphylaxis. Urinary histamine or methylhistamine levels also may reflect overall levels of released histamine, but they are affected by ingested histamine-containing foods, histamine-producing mucosal bacteria, and variability in histamine metabolism.

Differential Diagnosis


Anaphylaxis should be distinguished from a variety of disorders with overlapping presentations. Vasovagal syncope causes diaphoresis, nausea, hypotension, and bradycardia, but without urticaria. Flushing disorders may be benign and unrelated to anaphylaxis, or they could be a manifestation of pathologic conditions such as the carcinoid syndrome, with which urticaria and profound hypotension are not typically associated, or pheochromocytoma, which causes episodic hypertension. Precise detection of these latter conditions involves determination of serum levels of serotonin and urinary levels of 5-hydroxyindole acetic acid, catecholamines, and vanillylmandelic acid. Panic attacks and vocal cord dysfunction can be a challenge to distinguish from anaphylaxis, especially by history alone, but nevertheless must be considered. Acute attacks of hereditary and acquired angioedema caused by C1 esterase inhibitor deficiency are not associated with pruritic urticaria and persist longer than attacks of anaphylaxis. Shock due to complement activation by contaminated hemodialysis tubing, without involving mast cell activation, also has been reported. Scombroidosis occurs 5 to 90 minutes after ingestion of histamine in poorly stored fish and manifests with flushing, palpitations, headache, and gastrointestinal symptoms. The condition lasts several hours, both duration and severity depending on the amount of histamine ingested, and usually responds to H1-receptor and H2-receptor antihistamines but occasionally requires epinephrine and intravenous fluids. Acute serum sickness, various cell activation syndromes, endotoxin-mediated septic shock, and superantigen-mediated toxic shock syndromes manifest with fever, which is not characteristic of anaphylaxis by itself. Also, hypoglycemia, seizure, and primary pulmonary or cardiac events should be considered.

In some cases, systemic anaphylaxis occurs together with another disorder. For example, a 65-year-old man, after being stung by a wasp, complained of dizziness and shortness of breath, was hypotensive with urticaria, and responded to treatment with subcutaneous epinephrine, but then complained of chest pressure; electrocardiography indicated an inferior wall infarction. Serum levels of both mature tryptase and cardiac enzymes were elevated, indicating that both anaphylaxis and myocardial infarction had occurred.

Systemic mastocytosis is an important condition to consider in the differential diagnosis of anaphylaxis. In adults, a somatic activating mutation in the gene for Kit in mast cell progenitors results in an excessive body burden of mast cells. In children with this disorder, the disease may regress spontaneously. Patients with too many mast cells are at increased risk for anaphylaxis, and anaphylaxis may be a presenting manifestation of systemic mastocytosis. For example, anaphylaxis in response to an insect sting, particularly in the absence of venom-specific IgE (due to direct mast cell agonists), should raise the possibility of systemic mastocytosis. Diagnostic tests for systemic mastocytosis might include a biopsy of a skin lesion suspected to be urticaria pigmentosa, a bone marrow biopsy stained for mast cells (antitryptase immunohistochemistry being most sensitive), detection by flow cytometry of mast cells in the bone marrow aspirate that express surface CD2 and CD25, and measurement of an elevated serum level (≥20 ng/mL) of total tryptase (mature plus precursor forms of tryptase) during a nonacute interval.








Fatal outcomes in anaphylaxis are principally the result of either airway constriction or hypotension. Accordingly, the acute treatment of systemic anaphylaxis requires that airway patency, blood pressure, and cardiac status be addressed ( Table 274-2 ). Intubation, tracheostomy, volume expanders, and vasopressors may be needed. Patients exhibiting signs and symptoms of hypotension should immediately assume the Trendelenburg position, which may prevent progression to anaphylactic shock or what has been called the empty ventricle syndrome—because almost all hypotensive anaphylactic deaths are preceded by syncope occurring in a sitting or upright posture. Epinephrine injected intramuscularly into the thigh (0.2 to 0.5 mg for adults, 0.01 mg/kg up to 0.3 mg for children, repeated every 5 to 30 minutes as indicated) is the most critical drug to administer, the earlier during the course of an anaphylactic event the better. Alternatively, intravenous administration of a solution of epinephrine (1 mg/100 mL solution starting at 30 to 100 mL/hour), titrated to the lowest effective rate of infusion, can be considered. Epinephrine relaxes bronchial smooth muscle and improves vasomotor tone and vasopermeability, thereby counteracting bronchospasm, hypotension, and tissue edema. However, the benefits of epinephrine need to be weighed against its disadvantages in elderly subjects and in those with cerebrovascular or coronary artery disease, hypertension, diabetes, hyperthyroidism, cardiomyopathy, or narrow-angle glaucoma, in whom it can precipitate myocardial infarction, stroke, or pulmonary edema. Also, patients taking a β-blocker may be resistant to epinephrine; in such a case, glucagon (1 mg IV, or 1 to 5 mg/hour IV) or vasopressin (5 to 40 IU IV) may be used. Oxygen should be administered by nasal cannula. Inhaled bronchodilators can relieve bronchospasm. Parenteral administration of H1-receptor (diphenhydramine, 1 to 2 mg/kg up to 50 mg) and H2-receptor (ranitidine, 300 mg IV over 5 minutes) antihistamines may prevent progression of some of the signs and symptoms, particularly urticaria and pruritus, but is not likely to reverse hypotension or tissue edema. Prednisone (20 mg PO) or Solu-Medrol (40 mg IV) may reduce the risk of a protracted reaction or the late phase of biphasic anaphylaxis but is unlikely to be of benefit acutely.

Trendelenburg position Laryngeal Edema (LE)/Bronchospasm (B)
Epinephrine (IM/IV) Epinephrine (IM) (LE/B) or nebulized bronchodilator (B)
Volume expanders
Oxygen Oxygen (LE/B)
Progressive Blockage of Airflow
Intubation (B,LE)
Tracheostomy (LE)
Urticaria Possible Prevention of Late Reactions
H1R/H2R antihistamines Glucocorticosteroids (B,LE)
Possible Prevention of
Late Reactions
Epinephrine-Resistant β-Blocker
B = bronchospasm; H1R = histamine 1 receptor; H2R = histamine 2 receptor; LE = laryngeal edema.




Patients who have experienced an anaphylactic reaction are at greatest risk for another episode. Such individuals should wear a Medic-Alert bracelet and be instructed in the use of epinephrine (e.g., EpiPen), which they should carry. Avoidance of β-blockers and ACE inhibitors is recommended, because either may worsen the severity of an anaphylactic episode, and β-blockers clearly interfere with β-agonist treatment. In subjects with recurrent anaphylaxis, prophylactic use of H1- and H2-receptor antihistamines is beneficial. A leukotriene antagonist and cyclooxygenase inhibitor theoretically would provide additional benefit, but this has not been systematically studied. Finally, cyclosporin A (3 to 5 mg/kg/day) might be considered in difficult cases of recurrent anaphylaxis because of its ability to inhibit mast cell activation in vitro. Whether glucocorticosteroids, which do not inhibit mast cell activation in vitro or immediate skin test responses to allergens in vivo, provide a major benefit in most patients with recurrent anaphylaxis is debatable.

Specific anaphylactic syndromes have unique considerations. Anti-IgE therapy can increase the threshold of sensitivity from the equivalent of half a peanut to almost nine peanuts.[1] Insect venom sensitivity can be selectively treated by immunotherapy that dramatically decreases the risk of anaphylaxis in response to future stings. Reactions to radiocontrast media can be prevented or attenuated by prior administration of prednisone and H1- and H2-receptor antihistamines. Patients who are hypersensitive to penicillin should avoid β-lactam antibiotics in general but can be desensitized if an antibiotic in this class is critically needed (e.g., penicillin for neurosyphilis). However, desensitization is temporary; once the drug has cleared, sensitivity is likely to return. Progesterone-induced anaphylaxis may respond to the luteinizing hormone–releasing hormone analog, Lupron, or to oophorectomy. Patients with systemic mastocytosis, in addition to prophylactic pharmacologic measures, should avoid using direct mast cell agonists such as codeine, morphine, and vancomycin. Aspirin-sensitive subjects can be desensitized but then must continue to ingest a daily dose of aspirin to maintain their desensitization status. Food- and latex-sensitive subjects must practice avoidance of the provocative agent, though preliminary data with anti-IgE neutralization therapy indicates that modest protection for peanut-sensitive subjects against small inadvertent exposures might be achieved. It is hoped that future research will yield more effective and long-lasting desensitization therapies than are currently available for most patients at risk for IgE- and non–IgE-mediated anaphylaxis.

Future Directions


Ongoing research will provide more precise diagnostic tools that also delineate different pathways of anaphylaxis, indicating which cell types and biochemical pathways are involved. The factors that increase risk for an anaphylactic response will be better understood. Consequently, interventions that reduce anaphylactic risk (including better desensitization regimens) and that more effectively reverse the signs and symptoms of this potentially fatal disorder will be developed.

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