Anaphylaxis is the clinical manifestation of immediate hypersensitivity. The definition of anaphylaxis is, “a serious allergic reaction that is rapid in onset and may cause death.” This adverse event occurs rapidly, often dramatically, and is unanticipated. Anaphylaxis is the most severe form of allergy and is a true medical emergency. Death may occur suddenly through airway obstruction or irreversible vascular collapse. Anaphylaxis is a modern disease with sparse case reports from the 17th to the19th centuries. In the 20th century anaphylaxis predominately occurred in health care settings from injections of biological agents, such as tetanus and diphtheria antitoxins. In the 1950s and 1960s anaphylaxis was from medications, diagnostic agents, insect venoms, and food (1–4). Publications of idiopathic anaphylaxis (IA) occurred in the 1970s, followed in the 1980s by anaphylaxis triggered by exercise, exercise and food, and by natural rubber latex. Contemporary reports of anaphylaxis are from biologicals including cetuximab and omalizumab (1–4).

In 1902 Portier and Richet observed that injecting a previously tolerated sea anemone antigen into a dog produced a fatal reaction as opposed to the anticipated prophylaxis. They called this phenomenon anaphylaxis, the antonym of prophylaxis (Greek ana, backward, and phylaxis, protection). They observed two factors likely essential for anaphylaxis: increased sensitivity to a toxin after previous injection of the same toxin and an incubation period of at least 2 weeks to 3 weeks. Richet was recognized as the founder of the new science of allergy and was awarded the Nobel Prize in 1913 and honored on a French stamp issued in 1987 (5–7).

Anaphylaxis is caused by rapid release of mediators from mast cells and peripheral blood basophils. Classic terminology included anaphylaxis as IgE-mediated and anaphylactoid (anaphylaxis-like, pseudoallergic) as non-IgE-mediated. The World Allergy Organization’s nomenclature eliminates the term anaphylactoid and classifies anaphylactic events as immunologic and nonimmunologic (8). Immunologic anaphylaxis includes IgE fixing to FcεRI receptors on surface membranes of tissue mast cells and blood basophils. Receptor-bound IgE molecules aggregate on allergen re-exposure resulting in cellular activation and mediator response. This is the immediate hypersensitivity response
(IgE-dependent). IgE also enhances the expression of FcεRI on mast cells and basophils. Immunologic-induced anaphylaxis can also occur through activation of complement by immune complexes containing IgG or IgM; anaphylotoxins including C3a, C4a, and C5a are thereby produced. Nonimmunologic anaphylaxis (IgE-independent) occurs from factors acting directly on mast cells with exact mechanisms not fully understood. These include radiocontrast media (RCM), opioids, vancomycin, radiation, exercise, cold water or air exposure, and ethanol. Anaphylaxis may involve more than one mechanism as with insect venom constituents, which can act through specific IgE as well as complement activation. IA occurs spontaneously and is not caused by an unknown allergen; autoimmunity may be involved. Munchausen anaphylaxis is a purposeful self-induction of true anaphylaxis. All forms of anaphylaxis present the same, requiring similar rigorous diagnostic and therapeutic intervention (8). Refer to Table 14.1 for examples and types of anaphylaxis.

The development of modern drugs, biological and diagnostic agents, and the use of herbal and natural remedies have resulted in increased incidence of anaphylaxis. These agents used by physicians, pharmacists, and the general public require acute awareness of the problem and knowledge of preventative and therapeutic measures.

The following factors are associated with the incidence of anaphylaxis. Studies are limited discussing the role of genetics factors in anaphylaxis (10–15).

Comorbidities that increase the risk of anaphylactic fatality include asthma, cardiovascular disease, mastocytosis, thyroid disease, hyperhistaminemia, acute infection, decreased host defenses, reduced level of platelet-activating factor acetylhydrolase activity, and activating Kit mutations (1,2,11,14). Psychiatric disease and emotional stress may impair recognition of the clinical presentation. Multiple concurrent factors may be in play such as an elderly patient with cardiovascular disease taking a new medication. Concurrent triggers may also have to be present, such as food plus exercise (11).

The incidence of anaphylaxis in the general population has been underestimated because it is under reported, under recognized, and under diagnosed by physicians and patients. Contributing to the under recognition and under treatment of the disease is frequent inability to confirm the clinical diagnosis. Mild episodes, although potentially fatal, often are not evaluated by a physician, especially an allergist-immunologist, and may even resolve spontaneously with the patient not reporting the episode to a physician. The International Classification of diseases coding may fail to identify all individuals with anaphylaxis. Differences in reports of anaphylaxis event frequency is likely due to the lack of standardized diagnostic criteria and studies involving selected groups, rather than the general population. Despite these limitations, the lifetime prevalence of anaphylaxis appears to be increasing from all triggers and is estimated to be 0.05% to 2%, with an average annual incidence of 21 per 100,000 person-years (16). The estimated case-fatality rate is 0.65%. Incidence based on prescriptions for automatic epinephrine injectors was an estimated 1% of the population of Manitoba, Canada (17). Further evidence of an increasing incidence is based on routine United Kingdom hospital admission data suggesting a 700% increase in severe anaphylaxis between 1991 and 2004 (18).

In the community, food-induced anaphylaxis is the leading cause of anaphylactic events treated in hospital emergency departments and estimates of incidence vary widely. Estimates range from 1,080 to 30,000 emergency department visits per year in the United States (19). Americans that have food-related anaphylaxis each year experience 2,000 hospitalizations and 150 deaths; the annual incidence of food-related anaphylaxis is between 7.6 and 10.8 cases per 100,000 person years (19,20).

Hospitalized patients are at increased risk of anaphylaxis over the general population. An international multicenter study of 481,752 patients estimated that in-hospital anaphylaxis occurs in 1 of every 5,100 admissions; smaller study estimates anaphylaxis initiates or complicates 1 of every 2,700 hospital admissions.(21) The Boston Collaborative Drug Surveillance Program reported 0.87 anaphylactic fatalities per 10,000 patients in 1973 (22). Other hospital studies estimate anaphylaxis to occur in one of every 3,000 patients and is responsible for more than 500 deaths per year. Weiler estimated that of 300 individuals expected to have anaphylaxis each year in a community of 1 million, 3 are expected to die (17).

In the hospital setting, medications are the most common cause of immunologic-induced anaphylaxis and radiocontrast media (RCM) is the most commom cause of nonimmunologic-induced anaphylaxis. Within medications, β-lactam antibiotics are the most common cause. Penicillin has been reported to cause fatal anaphylaxis at a rate of 0.002% (23). Life-threatening reactions after administration of RCM occur in approximately 0.1% of procedures. Fatal reactions occur in about 1:10,000 to 1:50,000 intravenous procedures. As many as 500 deaths per year occurred after RCM administration when high osmolality agents were used; the
incidence of anaphylaxis and fatality is less if low osmolality agents are used (24,25). The history of a previous RCM reaction is a strong risk factor for a subsequent reaction with risk ranging from 16% to 44% (24,25). Seafood or shellfish allergy is not related to RCM allergy. These two iodine-containing entities have become falsely associated. RCM, iodine, and iodide do not cause IgE-mediated allergy, while shellfish allergens are tropomyosin proteins which cause IgE-mediated allergy.

The next most common cause of anaphylaxis is Hymenoptera stings, with an incidence of 23 deaths per 150 million stings. The National Office of Vital Statistics estimated an average death rate of 0.28 per 1 million persons per year from Hymenoptera stings (26).

Fatalities from allergen immunotherapy and skin testing are rare, with 6 fatalities from allergen skin testing and 24 fatalities (1:2.8 million injections) from immunotherapy reported from 1959 to 1984 (27). In another study, 17 fatalities (1:2 million injections) associated with immunotherapy occurred from 1985 to 1989 (28). In 2004 Bernstein et al. identified 41 immunotherapy fatalities spanning a 12-year period (1990–2001) or an average of 3.4 fatal immunotherapy reactions per year and a fatality rate of 1 per 2.5 million injections (29). Fatality due to skin testing is extremely rare with 6 reported deaths from intradermal testing where all but one patient were asthmatic (27). There was one reported death from percutaneous testing following skin-prick testing with 90 commercial foods (29).

The number of cases of IA in the United States was estimated by Patterson to be between 20,592 and 47,024 (30). IA in the series by Yocum et al. was 32%, similar to 37% in a review by Kemp et al. (16).

Occupation, race, season of the year, and geographic location are not predisposing factors for anaphylaxis. However, they may provide the nature of the inciting agent and circumstances of the event. There are gender differences in the risk for anaphylaxis. Males are at greater risk below the age of 15 and females above the age of 15. Anaphylaxis occurs more frequently in women exposed to intravenous muscle relaxants, RCM, latex, and aspirin; IA has a female predominance (31). The male to female ratio for insect sting anaphylaxis is 60:40 as discussed in Chapter 15. Most studies conclude that an atopic person is at no greater risk than the nonatopic person for developing IgE-mediated anaphylaxis from penicillin, insect stings, insulin, and muscle relaxants (1,2,32). Atopy is a risk factor for anaphylaxis from ingested antigens, latex, exercise anaphylaxis, IA, and RCM (1,2,33–35). The frequency of anaphylaxis is thought to be increased during pollen season for atopic individuals receiving immunotherapy (57,70). In the population-based study of Yocum et al., 53% of Olmstead County residents with an anaphylactic episode from all causes were atopic (16). The authors concluded that atopy is probably more prevalent among individuals having anaphylaxis than the general population. Generally, a cause is suspected in two-thirds of anaphylaxis cases, with the remaining one-third being idiopathic (1,2,16).

Not all persons who have had anaphylaxis have it again on reexposure to the same substance. Those who do may react less severely than at the initial event. Factors suggested to explain this include the interval between exposures, the route of exposure, and the amount of the substance received. The percentage of persons at risk for recurrent anaphylactic reactions has been estimated to be 10% to 20% for penicillins, 16% to 44% for RCM, and 40% to 60% for insect stings (23,36,37).

Humans vary greatly in the onset and course of anaphylaxis. Symptoms typically occur within 5 to 60 minutes of the inciting event. Many, up to 40, possible signs and symptoms may occur and differ among individuals and from one episode to another. Anaphylaxis is the most severe form of allergy and is appropriately called the killer allergy (2). Death may occur suddenly through upper airway edema and asphyxiation, intractable bronchospasm, or irreversible vascular collapse (1,38,39).

The skin, respiratory tract, cardiovascular system, and gastrointestinal tract may be affected solely or in combination. In order of frequency the clinical manifestations of anaphylaxis are as follows: cutaneous, >90%; respiratory, 55% to 60%; cardiovascular, 30% to 35%; gastrointestinal, 25% to 30%; and miscellaneous, 5.8% (40,41). Cutaneous manifestations include urticaria and angioedema, usually lasting less than 24 hours, often preceeded by pruritus, flushing, “skin burning,” and a sense of impending doom. The respiratory manifestations include dyspnea, wheezing, and chest tightness. Difficulty swallowing or speaking are the result of oropharyngeal and/or laryngeal edema. Early laryngeal edema may manifest as hoarseness, dysphonia, or “lump in the throat,” and may be followed by stridor resulting in suffocation. Respiratory failure may occur from airflow obstruction, pulmonary edema, or from the acute respiratory distress syndrome (ARDS), in which case, an initially elevated cardiac output becomes depressed, the vascular permeability increases, resulting in hypovolemia and cardiovascular collapse. Shock occurs in 30% of anaphylaxis cases (1,2,16). The progression of shock from the onset to the severe state is as follows: declining blood pressure, increasing pulse, declining cardiac output, and diminished intravascular volume. During shock, blood flow may be diverted away from the skin resulting in the initial absence of cutaneous manifestations (14). In a patient presenting
with unexplained shock, urticaria may occur with restoration of the blood pressure, leading to the diagnosis of anaphylaxis. The cardiovascular changes are associated with complaints of “being lightheaded” and “feeling faint.” In one series of anaphylactic deaths, 70% died of respiratory complications and 24% of cardiovascular failure (42). Gastrointestinal manifestations include nausea, vomiting, intense diarrhea (rarely bloody), and cramping pain in the abdomen. Neurological manifestations of confusion, dizziness, syncope, seizures, and loss of consciousness may occur as a result of cerebral hypoperfusion or as a direct toxic effect of mediator release (23).

Anaphylaxis from an ingested antigen can occur immediately, usually occurs within the first 2 hours and, occasionally, can be delayed for several hours (19). Initial signs and symptoms may include cutaneous erythema, angioedema, and pruritus, especially of the hands, feet, and groin. There can be a sense of oppression, impending doom, cramping abdominal pain, and a feeling of faintness or light headedness. The skin findings of urticaria and angioedema are the most frequent manifestations, and typically last less than 24 hours. Respiratory symptoms, the next most common manifestation, may progress to include mild airway obstruction from laryngeal edema and, more severely, to asphyxia. Early laryngeal edema may manifest as hoarseness, dysphonia, or “lump in the throat.” Edema of the larynx, epiglottis, or surrounding tissues can result in stridor and suffocation. Grave concern is the concurrent appearance of airway obstruction and cardiovascular symptoms. Myocardial infarction may be a complication of anaphylaxis (43). Other manifestations include nasal, ocular, and palatal pruritus; sneezing; diaphoresis; disorientation; and fecal or urinary urgency or incontinence. The initial manifestation of anaphylaxis may even be loss of consciousness; death may follow in minutes (1). Sudden fatality has also been attributed to postural change during anaphylaxis, such as sitting or standing as opposed to remaining recumbent with elevated lower extremities (90). Late deaths may occur days to weeks after anaphylaxis, and are often manifestations of reperfusion injury experienced early in the course of anaphylaxis (1,2,16). In general, the later the onset of anaphylaxis, the less severe the reaction (16,24). In some patients, anaphylaxis resolves spontaneously or with treatment only to be followed by another episode of anaphylaxis, termed biphasic anaphylaxis. Protracted anaphylaxis may occur with persistence of symptoms for up to 48 hours despite therapy (44,45).

Biphasic anaphylaxis incidence ranges from less than 1% to 20% and occurs 1 hour to 78 hours after the initial event. It is more common for the second response to occur within 8 hours after the resolution of the original episode. The initial trigger can be immunologic, nonimmunologic, or idiopathic. The oral route appears to be a predisposing factor; however, biphasic responses can occur after parenteral or inhaled antigen exposure. This second response may be less severe, similar to, or more severe than the initial episode; death can occur. Possible risk factors include hypotension or laryngeal edema during the initial episode, delay of more than 30 minutes between exposure to offending antigen and the appearance of initial symptoms, oral antigen trigger, elderly individuals with cardiovascular disease, and patients taking β-adrenergic antagonists. Studies vary on whether therapeutic intervention of the initial event affects the incidence of the second. Therapeutic intervention variables include a delay or inadequate dosing of epinephrine and absence or too small a dose of corticosteroids with the initial event (44,45).

Persistent, also referred to as protracted or recurrent, anaphylaxis lasts 5 hours to 48 hours despite therapy. The estimated rate of persistent anaphylaxis is 23% to 28%, though other investigators suggest it is less common. Protracted anaphylaxis and biphasic anaphylaxis cannot be predicted from the severity of the initial event necessitating an appropriate duration of observation and communication with the patient (46). Spontaneous recovery frequently occurs, likely from endogenous compensatory mechanisms, particularly from increased secretion of angiotensin II and epinephrine (2,47).

Concurrent chemical or medication use may affect recognition of anaphylaxis including ethanol, recreational drugs, sedatives, and narcotics. Psychiatric disease, central nervous system diseases, and vision or hearing impairment may also impede the recognition of clinical manifestations of anaphylaxis (11).

The anatomic and microscopic findings must be examined relative to the underlying illness for which the patient was being treated, the drugs administered, and the effect of secondary changes related to hypoxia, hypovolemia, and postanaphylaxis therapy (1,2). Anaphylactic death is usually caused by respiratory arrest with or without cardiovascular collapse (48). The prominent pathologic features of fatal anaphylaxis in humans are acute pulmonary hyperinflation, laryngeal edema, upper airway submucosal transudate, pulmonary edema and intraalveolar hemorrhage, visceral congestion, urticaria, and angioedema. In some patients no specific pathologic findings are found, especially if death is from rapid cardiovascular collapse.

Microscopic examination reveals noninflammatory fluid in the lamina propria of the areas just described, increased airway secretions, and eosinophilic infiltrates in bronchial walls, the laminae propria of the gastrointestinal tract, and sinusoids of the spleen (2,48). Sudden vascular collapse usually is attributed to vessel dilation or cardiac arrhythmia, but myocardial infarction may be sufficient to explain the clinical
findings. Myocardial damage may occur in up to 80% of fatal cases. During prolonged anaphylaxis, activation of the contact system can occur with the formation of kinins, coagulation pathway, and complement cascade activation which may prompt either blood clotting, lysis, and even disseminated intravascular coagulation (DIC) as a cause of death (14,49).

The diagnosis of anaphylaxis is clinical, but the following laboratory findings may assist in unusual cases or in ongoing management. A complete blood count may show an elevated hematocrit secondary to hemoconcentration. Blood chemistries may reveal elevated creatinine phosphokinase, troponin, aspartate aminotransferase, or lactate dehydrogenase if myocardial damage has occurred. Acute elevation of plasma or urine histamine and serum tryptase can occur, and complement abnormalities have been observed. Plasma histamine is elevated within 5 minutes to 10 minutes of mast cell activation and returns to baseline within 30 to 60 minutes. This short half-life limits the reliability for anaphylaxis diagnosis unless collection occurs within 15 to 60 minutes of onset. Urinary histamine metabolites, including methyl-histamine, may be found for up to 24 hours after the onset of anaphylaxis. Mast cell–derived tryptase with a half-life of several hours achieves a peak level at 1 hour and remains elevated for up to 6 hours following anaphylaxis. Optimal times for collecting serum tryptase levels range from 15 to 180 minutes of the onset of anaphylaxis. The peak tryptase level (typically within 1 hour of anaphylaxis onset) usually correlates with with severity of symptoms, particularly with the nadir of mean arterial pressure. Larger releases of tryptase can be detected longer and have been reported to be elevated for many hours after severe anaphylaxis. Tryptase is not elevated in other causes of death; however it is elevated in individuals with excessive number of mast cells, such as in mastocytosis. The β-tryptase level is more specific than total tryptase; however, this assay is not widely available. The ratio of total tryptase to β-trypyase is helpful in differentiating anaphylaxis from mastocytosis. A ratio of 10 or less suggests anaphylaxis and a ratio of 20 or greater indicates mastocytosis. This differentiation is very helpful when anaphylaxis occurs in a patient with mastocytosis who has a high baseline tryptase level. A normal serum total tryptase does not exclude anaphylaxis. Food-induced anaphylaxis is seldom associated with elevation of serum tryptase, possibly due to basophil predominance over mast cells. Serum tryptase may not be detected within the first 15 to 30 minutes of onset of anaphylaxis; therefore, persons with sudden fatal anaphylaxis may not have elevated tryptase in their postmortem sera. Unfortunately, even with optimal timed sampling, plasma histamine and tryptase levels remain within normal limits. If available comparison to stored or post event serum tryptase levels may be useful as well as serial tryptase levels. Future availability of measuring other mast cell and basophil activation markers will be useful. These include: mature β-tryptase, mast cell carboxypeptidase A3, chymase, platelet-activating factor (PAF), PAF-acetylhydrolase activity, as well as an anaphylaxis panel of such markers (11,50,51). The ImmunoCap (Phadia AB, Uppsala, Sweden) may be used on postmortem serum to measure specific IgE to antigens such as Hymenoptera or suspected foods. Together the postmortem serum tryptase and the determination of specific IgE may elucidate the cause of an unexplained death. Serum should be obtained preferably antemortem or within 15 hours of postmortem for tryptase and specific IgE assays, with sera frozen and stored at −20°C (1,2). A chest radiograph may show hyperinflation, atelectasis, or pulmonary edema. The most common electrographic changes other than sinus tachycardia or infarction include T-wave flattening and inversion, bundle branch blocks, supraventricular arrhythmia, and intraventricular conduction defects (1).

Anaphylaxis is initiated when a host interacts with a foreign material. This foreign material can be almost anything as long as it is able to trigger the release of mediators from tissue mast cells and circulating basophils. The exposure can be topical, inhaled, ingested, or parenteral. Immunologic anaphylaxis includes IgE fixing to FcεRI receptors on surface membranes of tissue mast cells and blood basophils. Receptor-bound IgE molecules aggregate and cross-link upon allergen re-exposure resulting in cell activation and mediator release. Immunologic and nonimmunologic initiation of anaphylaxis may involve other receptor activation than FcεRI receptors, such as G protein-coupled receptors or Toll-like receptors (16,40). This type of receptor is a heptahelical transmembrane molecule that can transduce extracellular signals by way of G proteins to intracellular second messenger systems (52,53). Mast cells and basophils initiate as well as amplify the acute allergic response. Activated mast cells are regulated by a balance of positive and negative intracellular molecular events extending beyond kinases and phosphatases, such as lyn and syk kinases which initiate a signal transduction analogous to that induced by T- and B-cell receptors. Sphingosine kinase is a determinate of mast cell responsiveness. Mast cell and basophil activation leads to rapid release of inflammatory mediators including histamine, proteases such as tryptase, mast cell carboxypeptidase A3 and chymase, PAF, prostaglandins (PGD2), leukotrienes, chemokines, and cytokines. In addition, stem cell factor and its c-kit receptor, are important in IgE-antigen-induced mast cell degranulation and cytokien production. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed on
mast cells and are inhibitory. Basophil activation, control, and involvement are not as well understood with a recent discovery of a mAb directed against an intermediate form of pro-major basic protein 1 (11,54–56).

Preformed mast cell and basophil granule mediators are released by exocytosis within minutes. Arachidonic acid metabolite synthesis occurs within minutes including prostaglandins and leukotrienes. Activation of inflammatory cytokines and chemokines takes hours. Histamine is the most important preformed and stored vasoactive mediator in mast cell and basophil cytoplasmic granules. On its release, histamine acts on histamine receptors (H1>H2) on target organs to increase vascular permeability, causing flushing, itching, urticaria, angioedema, and vasodilation with lowered peripheral resistance and shift in fluid to the extravascular space. Histamine also enhances glandular secretions causing rhinorrhea and bronchorrhea. H1 increases mucous viscosity. H2 increases mucous production, gastrointestinal smooth muscle constriction, increased heart rate, and increased cardiac contraction. The heart is a shock organ in anaphylaxis as the chemical mediators act directly on the myocardium.

The H1 receptors mediate coronary artery vasoconstriction and increase vascular permeability. H2 receptors increase atrial and ventricular contractile forces, atrial rate, and coronary artery vasodilation. H1 and H2 receptor interaction likely mediates decreased diastolic pressure and increased pulse pressure. PAF decreases coronary blood flow, delays atrioventricular conduction, and has depressor effects on the heart (46,57). H1 receptor stimulation may cause coronary artery vasospasm and resultant myocardial infarction even if the coronary arteries are normal. Mast cell accumulation occurs at coronary plaque sites contributing to thrombosis. Antibodies attached to mast cell receptors causing degranulation have potential for plaque disruption (58). Flushing, headache, increased pulse pressure, and reduced diastolic pressure are better controlled with both H1 and H2 antagonists. Pruritus may be from brain H3 receptor stimulation (59). Other mast cell preformed mediators include neutral proteases (tryptase, chymase, carboxypeptidase A3), acid hydrolase (arylsulphatase), oxidative enzymes (superoxide, peroxidase), chemotactic factors (eosinophils, neutrophils), and proteoglycans (heparin). Circulating tryptase levels increase only after massive mast cell activation as seen in anaphylaxis or mastocytosis.

Along with tryptase, mast cell kininogenase and basophil kallikrein activation of multiple inflammatory cascades occur which are involved in anaphylaxis. These include the contact system, clotting system, and complement system. Tryptase activation of the contact (kallikrein-kinin) system decreases high molecular weight kininogen, formation of activation complexes, and bradykinin production, causing angioedema (60). Tryptase can also inactivate procoagulant proteins promoting fibrin clot lysis and may lead to DIC (60). Chymase can activate the angiotensin system converting angiotensin I to angiotensin II to compensate intravascular volume loss from increased vascular permeability (61). Released heparin (a proteoglycan) also may play a compensatory role by binding to antithrombin III inhibiting the clotting cascade as well as inhibiting the arachidonic acid cascade’s generated chemoattractants for eosinophils.

Mast cells generate and release eicosanoid lipid mediators such as prostaglandins and leukotrienes. Prostaglandin PGD2 causes bronchoconstriction, peripheral vasodilation, and coronary and pulmonary artery vasoconstriction and inhibits platelet aggregation. PGD2 is chemotactic for basophils, eosinophils, dendritic cells, and T_H2 cells, and enhances histamine release from basophils. Skin mast cells mainly produce PG2, whereas mast cells from the lung, heart, and GI tract secrete predominately PGD2 and LTC4. Cysteinyl leukotrienes are synthesized by mast cells, basophils, and eosinophils. The cysteinyl leukotrienes stimulate smooth muscle contraction independent of histamine. They also cause smooth muscle contraction and mucous secretion, increase vascular permeability, cause arteriolar constriction, recruit inflammatory cells, modulate cytokine production, influence neural transmission, and contribute to structural changes in the airway. LTB4 is chemotactic and may possibly contribute to the late phase of protracted anaphylaxis. PAF synthesized from membrane phospholipids causes bronchoconstriction (1,000 times more potent then histamine), increased vascular permeability, chemotaxis, and degranulation of eosinophils and neutrophils. Mast cells also release chemokines and cytokines which contribute to anaphylaxis. These mediators contribute predominately to the late phase of biphasic anaphylaxis. TNF-α is released activating neutrophls, monocyte chemotaxis, and enhances other cytokine production by T cells. Other cytokines released include G-CSF, M-CSF, GM-CSF, IL-1, IL-3, IL-4, IL-6, IL-8, IL-10, IL-16, IL-18, IL-22, and TNF-α Basophils are a major source of IL-4, IL-13, and chemokines (46,52,61–63).

Large quantities of nitric oxide are produced during anaphylaxis. Nitric oxide is synthesized from L-arginine through the action of nitric oxide synthase (NOS). Three isoforms of NOS exist, two constituitive (cNOS), and one inducible (iNOS). cNOS is found in endothelium, myocardium, endocardium, skeletal muscle, platelets, and neural tissue. iNOS is in macrophages, fibroblasts, neutrophils, and smooth muscle. Mediators which enhance cNOS are the same mediators of anaphylaxis: histamine, PAF, several leukotrienes, and bradykinin. Synthesis is further enhanced by hypoxia within minutes and protracted synthesis may occur over hours. Nitric oxide has the potential to be both protective
(relax bronchial smooth muscle) and harmful (enhancing vascular permeability). The sum affect is detrimental with vasodilation and enhanced permeability contributing to shock (14, 64). Nitric oxide has the potential to be both protective (relax bronchial smooth muscle) and harmful (enhances vascular permeability). The sum effect is detrimental with the molecule causing vasodilation, enhancing vascular permeability contributing further to shock (14, 64).

The biphasic response, especially characterized by severe hypotension and shock, follows initial mast cell degranulation resulting in activation of other inflammatory cascades including the complement system and clotting and clot lysis pathways. This is supported by falls in complement and activation of clotting and clot lysis in human episodes of severe anaphylaxis (45, 49).