INTRODUCTION — Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation . It most often results from immunologic reactions to foods, medications, and insect stings, although it can also be induced through nonimmunologic mechanisms by any agent capable of producing a sudden, systemic degranulation of mast cells or basophils .
The phenomenon of anaphylaxis was first described in the modern medical literature in 1902 in a study involving protocols for immunizing dogs with jellyfish toxin. The injection of small amounts of toxin in some animals rather than generating protection precipitated the rapid onset of fatal or near-fatal symptoms . The authors named this response "l'anaphylaxie," which is derived from the Greek words a- (against) and phylaxis (immunity or protection).
The pathophysiology of anaphylaxis will be reviewed here. The clinical manifestations, diagnosis, and management of anaphylaxis and the epidemiology and etiology of fatal anaphylaxis are discussed separately. (See "Anaphylaxis: Emergency treatment" and "Fatal anaphylaxis".)
PROPOSED MECHANISMS — The mechanism responsible for most cases of human anaphylaxis involves immunoglobulin E (IgE). Possible alternative mechanisms remain incompletely understood. Environmental exposures and complex genetic factors may also have important roles, although these are not explored in this review.
Terminology — The term "anaphylaxis" has traditionally been reserved for IgE-dependent events, and the term "anaphylactoid reaction" has been used to describe IgE-independent events, although the two reactions are often clinically indistinguishable. The World Allergy Organization (WAO), an international umbrella organization representing a large number of regional and national professional societies dedicated to allergy and clinical immunology, has proposed discarding this nomenclature. The WAO categorizes anaphylaxis as either immunologic or nonimmunologic, and this is the terminology used in this review .
●Immunologic anaphylaxis – Immunologic anaphylaxis includes the following:
•Immunoglobulin G (IgG)-mediated reactions (which have not been identified in humans)
•Immune complex/complement-mediated reactions
●Nonimmunologic anaphylaxis – Nonimmunologic anaphylaxis is caused by agents or events that induce sudden, massive mast cell or basophil degranulation in the absence of immunoglobulins. (See 'Nonimmunologic anaphylaxis' below.)
IgE-mediated — The classical mechanism associated with human-allergic disease is initiated by an antigen (allergen) interacting with allergen-specific immunoglobulin E (IgE) bound to the receptor Fc-epsilon-RI on mast cells and/or basophils.
The events leading to allergen-specific IgE production in an atopic individual are complex. In brief, B cells are driven to differentiate into IgE-producing cells via the activity of the type 2 subset of CD4-bearing helper T cells (Th2 cells). This process largely takes place in the peripheral lymphoid tissues. The cytokines interleukin-4 (IL-4) and its receptors (IL-4R-alpha/gamma-c and IL-4R-alpha/IL-13R-alpha-1) and interleukin-13 (IL-13) and its receptor (IL-4R-alpha/IL-13R-alpha-1) contribute to IgE responses in humans.
Once produced, allergen-specific IgE diffuses through the tissues and vasculature and constitutively occupies high-affinity IgE receptors (Fc-epsilon-RI) on mast cells and basophils (figure 1). The generation of allergen-specific IgE is reviewed in more detail separately. (See "The biology of IgE".)
When allergen diffuses into the proximity of a mast cell or basophil, it interacts with any surface-bound IgE that is specific for that allergen. Certain allergens are able to interact with IgE molecules on two or more receptors of the cell surface to cause cross-linking, which in turn causes the receptors to become aggregated and initiate intracellular signaling. Allergens that are capable of cross-linking are either multivalent (having multiple identical sites for IgE antibody binding) or univalent (having multiple different sites for IgE antibody binding). If signaling is sufficiently robust, the mast cell (or basophil) becomes activated and degranulates, releasing preformed mediators, enzymes, and cytokines (such as histamine, tryptase, and tumor necrosis factor [TNF], respectively) and initiating additional mediator, cytokine, and enzyme production. Mast cell biology is discussed in more depth elsewhere. (See "Mast cells: Surface receptors and signal transduction" and "Mast cell-derived mediators".)
These mediators either act directly on tissues to cause allergic symptoms or recruit and activate additional inflammatory cells, particularly eosinophils [5,6]. The recruited cells, in turn, release more mediators and propagate a fulminant "chain reaction" of allergic inflammation. The various mediators and cytokines involved are reviewed below. (See 'Chemical mediators of anaphylaxis' below.)
IgG-mediated (in animal models) — Animal models that appear analogous to human anaphylaxis have been established in mice, pigs, and dogs . Clinically, each has some distinctive signs and symptoms. As an example, murine anaphylaxis is characterized by dramatic reductions in core body temperature and subtle cardiopulmonary differences, compared with human anaphylaxis [7,8].
In mouse models, at least two immunoglobulin G (IgG)-mediated pathways have been identified:
●In one model, allergen interacts with allergen-specific IgG bound to Fc-gamma-RIII on macrophages and basophils (figure 2) [5-7]. This IgG-dependent pathway requires proportionately more antibody and antigen than the murine IgE-mediated pathway, and macrophage activation results primarily in the release of platelet-activating factor (PAF), rather than histamine [5,6]. PAF causes platelet aggregation and the release of the potent vasoconstrictors thromboxane A2 and serotonin and can act directly on vascular endothelial cells to increase vascular permeability .
There is evidence in mice that pathways of IgG- and IgE-mediated anaphylaxis are interrelated. When low doses of allergen are administered, IgG antibody can block IgE-dependent anaphylaxis by intercepting the antigen before it can cross-link mast cell- and basophil-associated IgE and by activating the inhibitory receptor, Fc-gamma-RIIb. Low doses of IgG are insufficient to induce IgG-mediated anaphylaxis, presumably because Fc-gamma-RIII has a much lower affinity than Fc-epsilon-RI [5,6]. In comparison, high doses of allergen can precipitate IgG-dependent anaphylaxis by forming complexes that activate macrophages and basophils through Fc-gamma-RIII.
●Another mouse model found evidence of the above mechanism in concert with activation of neutrophils resulting from the interaction of allergen-specific IgG2 with Fc-gamma-RIV on those cells . PAF was the predominant mediator in this model also.
IgG-dependent anaphylaxis has not been demonstrated in humans. However, human IgG receptors are capable of activating macrophages and neutrophils to secrete PAF [5,11], and PAF can activate mast cells in vitro , so PAF potentially may contribute to human anaphylaxis [13,14]. Additionally, anaphylaxis has been reported to be more severe in individuals who catabolize PAF slowly.
Rare individuals have experienced anaphylaxis after receiving therapeutic preparations of IgG anti-IgE antibodies (omalizumab) [15,16]. Omalizumab blocks the binding of IgE to Fc-epsilon-RI receptors and does not bind Fc-epsilon-RI-associated IgE (figure 3) [5,17]. These anaphylactic reactions could conceivably be IgG-mediated, with the patient's IgE acting as the antigen and the IgG of the drug acting as the causative antibody . IgE-independent anaphylaxis has also been reported in some patients receiving another monoclonal antibody preparation, infliximab [18,19]. More human data are needed to clarify the mechanism underlying these clinical events. (See "Anti-IgE therapy", section on 'Adverse effects'.)
On the basis of previous observations and preliminary studies, one group of investigators has hypothesized that decreased blood neutrophil Fc-gamma-RIII expression without increased IL-4R-alpha expression by T lymphocytes might be used in humans to distinguish IgG- from IgE-dependent anaphylaxis . If observed, decreased neutrophil Fc-gamma-RIII expression would be associated with IgG-dependent anaphylaxis, whereas increased IL-4R-alpha expression would be associated with IgE-dependent events.
Immune complex/complement-mediated — Several drugs have been implicated in immediate life-threatening reactions that are clinically similar to anaphylaxis except that drug-specific IgE could not be identified. Activation of complement by immune complexes composed of the culprit drug and IgG or other isotypes has been proposed for some of these drugs, such as protamine .
Other proposed mechanisms — A number of non-IgE-mediated mechanisms have been proposed to explain anaphylaxis caused by radiocontrast media (RCM). One of these involves the interaction of RCM molecules with the Fc portions of IgE or IgG already bound to the mast cell or basophil surface, causing cross-linking and activation. (See "Diagnosis and treatment of an acute reaction to a radiologic contrast agent".)
Nonimmunologic anaphylaxis — Anaphylactic reactions to various drugs have revealed potential mechanisms by which mast cells and basophils could be activated without evidence of involvement of IgE, other antibodies, or immune complexes.
These potential mechanisms include the following:
●Activation of complement, in the absence of immune complex formation, has been proposed to account for reactions to drugs that were solubilized in the diluent Cremophor EL, such as older preparations of propofol and paclitaxel [22,23]. It has been proposed that under physiologic conditions, Cremophor EL formed large micelles with serum lipids and cholesterol, stimulating complement activation. Some human mast cells express receptors for the "anaphylatoxins" C3a and C5a and release histamine in response to exposure to these complement fragments. Macrophages and basophils also have C3a receptors and can produce PAF in response to their activation. This mechanism has been implicated in peanut-induced anaphylaxis in mice, although the significance of this in human anaphylaxis has not been demonstrated. (See "Mast cells: Development, identification, and physiologic roles" and "Complement pathways" and "Infusion reactions to systemic chemotherapy".)
●Direct activation of mast cells and/or basophils by vancomycin, leading to histamine release, has been implicated in vancomycin flushing syndrome. This reaction can involve hypotension and present similarly to anaphylaxis in up to 15 percent of patients. The mechanism is unknown. (See "Vancomycin hypersensitivity".)
●Opioid medications, such as meperidine and codeine, can cause nonimmunologic histamine release via direct mast cell degranulation . Mild reactions, such as urticaria, are common, although anaphylactic reactions are occasionally reported . In the past, some allergy specialists used opioids as positive controls in skin testing because these agents induce a characteristic wheal-and-flare response due to the direct degranulation of mast cells in the skin. (See "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Opioids'.)
●Cold urticaria is a reproducible disorder that is characterized by the rapid onset of erythema, pruritus, and edema after exposure to cold (eg, water, air, food/beverage, or other source of cold temperature). In patients with this disorder, systemic cold exposure, as might occur with swimming or total body exposure to cold air, can cause massive release of histamine and other mediators and lead to hypotension. Some episodes are characterized by the presence of abnormal proteins (ie, cryoglobulins or cryofibrinogens), which may agglutinate or precipitate at lower temperatures. However, most instances of cold urticaria/anaphylaxis are idiopathic and lack abnormal circulating proteins . (See "Cold urticaria" and "Overview of cryoglobulins and cryoglobulinemia" and "Disorders of fibrinogen", section on 'Cryofibrinogenemia'.)
●Oversulfated chondroitin sulfate (OSCS), a compound contaminating worldwide heparin supplies in 2007 to 2008, caused anaphylaxis by directly activating the kinin-kallikrein pathway, which generated bradykinin, C3a, and C5a. Anaphylactic reactions consisted of hypotension and abdominal pain and variably included dyspnea, diarrhea, flushing, and angioedema. However, these reactions consistently lacked urticaria or pruritus [27,28]. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Systemic allergic reactions'.)
Regulation of mast cell activation in anaphylaxis — Multiple additional protein motifs, receptors, channels, and molecular signals act at various levels to modulate the reactivity and responsiveness of mast cells . These are discussed separately. (See "Mast cells: Surface receptors and signal transduction".)
CHEMICAL MEDIATORS OF ANAPHYLAXIS — The chemical mediators of immunoglobulin E (IgE)-mediated anaphylaxis in humans include biologically active products of mast cells, basophils, and eosinophils, as well as serum components of the complement, coagulation, and kallikrein-kinin pathways. In addition, cytokines that alter the sensitivity of various target cells to these mediators are believed to influence the severity of anaphylaxis.
Mast cells and basophils — The degranulation of mast cells and basophils results in the systemic release of various biochemical mediators and chemotactic substances, including the following :
●Histamine, tryptase, chymase, and heparin, which are preformed substances associated with intracellular granules.
●Histamine-releasing factor and other cytokines (tumor necrosis factor [TNF], interleukin-4 [IL-4], interleukin-13 [IL-13]).
●Newly-generated lipid-derived mediators, such as prostaglandin D2 (PGD2), leukotriene B4, platelet-activating factor (PAF), and the cysteinyl leukotrienes, LTC4, LTD4, and LTE4.
The functions of these mediators specifically in anaphylaxis have not been extensively studied, although the available data are reviewed here. A more complete description of the mediators, cytokines, and chemokines produced by mast cells is found elsewhere. (See "Mast cells: Development, identification, and physiologic roles".)
A mutation of c-kit, a tyrosine kinase receptor expressed on the membrane surfaces of all mast cells, has been associated with anaphylaxis [29,30]. Subjects with the D816V c-kit mutation present with normal numbers of mast cells in the bone marrow but abnormal expression of CD25 and symptoms of severe anaphylaxis. (See "Mast cell disorders: An overview".)
Basophils might have a role in human anaphylaxis, although its clinical significance is not well-differentiated from that of mast cells, which are activated concomitantly in most instances of anaphylaxis. One prospective study of patients presenting to an emergency department with anaphylaxis (mostly insect sting-induced) observed that the number of circulating basophils dropped, the expression of high-affinity IgE receptors decreased, and levels of serum chemokine C-C ligand 2 (CCL2, a basophil chemotactic factor) increased when compared with convalescent samples obtained later and to those in Hymenoptera venom-allergic controls and healthy controls . Similar changes were observed in patients experiencing food-allergic reactions during double-blind, placebo-controlled challenges. These findings may open new lines of investigation.
Histamine — Localized histamine release in the skin causes urticaria. Systemic release of histamine, however, causes hemodynamic and cardiovascular changes and is not associated with the presence of urticaria. Serum histamine levels correlated with the severity and persistence of cardiopulmonary manifestations in studies of human anaphylaxis [32,33].
The systemic effects of histamine are dose-dependent. Histamine was administered to normal volunteers over 30 minutes at doses ranging from 0.05 to 1 micrograms/kg/minute to determine the plasma levels required to elicit symptoms of anaphylaxis :
●At low plasma levels, histamine was associated with a 30 percent increase in heart rate.
●At moderate plasma levels, histamine precipitated flushing and headache.
●Higher plasma histamine levels elicited a 30 percent increase in pulse pressure (ie, systolic pressure minus diastolic pressure).
The actions of histamine in anaphylaxis are mediated by binding to H1 and H2 receptors on target cells. In the study above, pretreatment with H1 antihistamines, H2 antihistamines, or both, suggested that both H1 and H2 receptors mediated flushing, hypotension, and headache, whereas H1 receptors alone mediated tachycardia, pruritus, rhinorrhea, and bronchospasm .
H3 receptors have been implicated in the canine model of anaphylaxis and appear to influence cardiovascular responses to norepinephrine, although this has not been studied in human anaphylaxis .
Murine models suggest H4 receptors might be involved in chemotaxis and mast cell cytokine release, and they might also help to mediate pruritus [36,37]. Their role (if any) in human anaphylaxis has not been studied.
The specific effects of histamine on the cardiovascular system are discussed below. (See 'Cardiovascular system' below.)
Tryptase — Tryptase is a protease that is abundant in human mast cells. Tryptase is relatively specific for mast cells, although basophils and myeloid precursors contain a small amount. There are different forms of tryptases. Beta tryptase (mature tryptase) is enzymatically active, concentrated in mast cell secretory granules, and released upon degranulation.
Tryptase can activate the complement and coagulation pathways, as well as the kallikrein-kinin contact system . Potential clinical consequences include hypotension, angioedema, clotting, and clot lysis, respectively, with the latter two explaining the variable development of disseminated intravascular coagulation (DIC) in severe anaphylaxis . (See 'Serum factors and other inflammatory pathways' below.)
The route of allergen exposure appears to influence the resultant tryptase levels for reasons that have not been fully explained. Specifically, anaphylaxis triggered by ingested food may have minimal or no elevation in serum tryptase [38,40]. In an analysis of anaphylaxis fatalities, parenterally-administered triggers (injected medications, insect venoms) were associated with higher serum levels of tryptase and lower levels of antigen-specific IgE, whereas orally-administered allergens were associated with low tryptase levels and comparatively high levels of antigen-specific IgE [41,42]. This difference in tryptase levels may be related to the subtype of mast cell first encountered by the culprit antigen. Mast cells that predominate in the mucosa of the small intestine and lung contain much less tryptase per cell than those in the connective tissues . Overall, tryptase levels generally correlate with the clinical severity of anaphylaxis, with the notable exception of food allergens.
Postmortem measurements of serum tryptase may be useful in establishing anaphylaxis as the cause of death:
●The measurement of tryptase in anaphylaxis and the differential diagnosis of an elevated tryptase level are presented in more detail elsewhere. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)
●Technical aspects of collecting and measuring tryptase in the postmortem setting are reviewed separately. (See "Fatal anaphylaxis", section on 'Postmortem diagnosis'.)
There is mounting evidence to suggest that closer scrutiny to baseline total tryptase levels might be appropriate, especially in patients who experienced hypotension during anaphylaxis. Most studies have evaluated patients with severe anaphylaxis to insect stings [43-45]. Higher baseline tryptase concentrations (greater than 11.4 mcg/L) might indicate mastocytosis or a monoclonal mast cell disorder (eg, c-kit mutation) and require bone marrow biopsy and cytogenetic analysis for further evaluation [44,45]. (See "Mast cell disorders: An overview".)
Platelet-activating factor — Platelet-activating factor (PAF)-receptor antagonists are effective in rodent models of anaphylaxis [5,46]. In contrast, the roles of PAF and PAF acetylhydrolase, the enzyme that inactivates PAF, are not well-defined in human anaphylaxis, although available data suggest that PAF may be important . PAF receptors have been identified in some subsets of human mast cells . In addition, in a prospective study of 41 subjects (ages 15 to 74 years) and 23 nonallergic adult controls, serum PAF levels correlated directly and PAF acetylhydrolase levels correlated inversely with the severity of anaphylaxis . In a companion retrospective analysis, PAF acetylhydrolase activity was significantly lower in nine individuals who experienced fatal peanut-induced anaphylaxis compared with patients in five different control groups. Similarly, PAF levels in this study population of 41 subjects correlated better with the severity of the acute allergic reactions than did serum levels of histamine or tryptase . (See "Mast cells: Surface receptors and signal transduction".)
Nitric oxide — Nitric oxide (NO), a molecular gas, acts as a messenger molecule in most human organ systems. Within blood vessel walls, it has potent vasodilator activity and, under normal circumstances, NO participates in the homeostatic control of vascular tone and regional blood pressure . NO is also involved in the complex interaction of regulatory and counter-regulatory mediators in mast cell activation and has been implicated in the hypotension of sepsis and anaphylaxis [49,50].
NO promotes protective responses, such as bronchodilation, coronary artery vasodilation, and decreased histamine release, as evidenced by experiments with NO inhibitors in mice, rabbits, and dogs. However, its net effects in anaphylaxis appear to be detrimental through vascular smooth muscle relaxation and enhanced vascular permeability .
The binding of histamine to H1 receptors initiates phospholipase C-dependent calcium mobilization, converting L-arginine to NO through the activity of nitric oxide synthase (NOS). Various isoforms of NOS have been identified, depending on the tissue in which they were first isolated. Constitutively expressed isoforms (ie, endothelial NOS [eNOS] and neuronal NOS [nNOS]) are presumed to produce low amounts of NO for physiologic and/or anti-inflammatory functions. In contrast, inducible NOS (iNOS) expression is associated with inflammation. Increased expression of iNOS results in overproduction of NO and activation of guanylate cyclase. This mechanism may be responsible for the cardiovascular morbidity and mortality associated with septic shock and has widely been presumed also to apply to anaphylaxis . However, subsequent studies in knockout mice have demonstrated that anaphylaxis can occur in the absence of iNOS and that in PAF-associated anaphylaxis, eNOS is the critical mediator . Similar data in humans are not available, although these murine findings suggest that NOS involvement in anaphylaxis may be more complex than previously thought.
Seven case reports describe the use of methylene blue for the treatment of anaphylactic shock refractory to epinephrine, intravenous fluids, vasoconstrictors, and intra-aortic balloon pump [53,54], and one report describes its successful use in a normotensive subject with refractory anaphylaxis . Methylene blue may exert its favorable effects by blocking NO-mediated vascular smooth muscle relaxation . However, methylene blue itself is capable of causing anaphylaxis in some subjects [57,58].
Arachidonic acid metabolites — Arachidonic acid is a fatty acid derived from membrane phospholipids that can be metabolized via the lipoxygenase and cyclooxygenase pathways to generate proinflammatory mediators, such as leukotrienes, prostaglandins, and PAF. Effects of these arachidonic acid metabolites include bronchospasm, hypotension, and erythema .
●Leukotriene B4 is a chemotactic agent that theoretically may contribute to biphasic and protracted reactions.
●Overproduction of leukotriene C4 enhances mast cell degranulation .
●Leukotrienes D4 and E4 increase microvascular permeability and are potent bronchoconstrictors [37,59,60].
●Prostaglandin D2 (PGD2) causes vasodilation, increased vasopermeability, and airway smooth muscle bronchoconstriction in various experimental models [61-63]. It is also chemotactic for neutrophils and activates eosinophils [64,65]. Serum levels of 9 alpha, 11 beta-prostaglandin F2 (9α,11β-PGF2), the metabolite of PGD2, were reported to have a greater correlation with clinical severity of anaphylaxis than tryptase levels in a cohort of 18 patients . Another study of plasma levels of 9 alpha, 11 beta-prostaglandin F2 observed them to be increased in 16 insect venom-allergic patients after venom provocation testing .
Modulatory mediators — Other mediators may have anti-inflammatory and modulatory effects that limit anaphylaxis. As examples, chymase may facilitate the conversion of angiotensin I to angiotensin II, theoretically helping to counteract hypotension during anaphylaxis. Heparin opposes complement activation, modulates tryptase activity, and inhibits clotting, plasmin, and kallikrein [33,38].
Eosinophils — Eosinophils may be proinflammatory (eg, through release of cytotoxic granule-associated proteins) or anti-inflammatory (eg, through metabolism of vasoactive mediators) [38,68]. A guinea pig anaphylaxis model suggests that eosinophils already present in chronically-inflamed airways may participate in the immediate-phase response to allergen exposure, as well as their traditional role in the late-phase allergic response . These mechanisms have not been studied in human anaphylaxis.
Serum factors and other inflammatory pathways — During severe episodes of anaphylaxis, there is concomitant activation of complement, coagulation pathways, and the kallikrein-kinin contact system. Much of the evidence for this was obtained during experimental insect sting challenges. Decreases in C4 and C3 and generation of C3a have been observed in anaphylaxis. Demonstrable evidence for coagulation pathway activation during severe anaphylaxis includes decreases in factor V, factor VIII, and fibrinogen and fatal DIC in some instances [33,70]. An analysis of 202 anaphylaxis fatalities over a 10-year period in the United Kingdom determined that 8 percent of deaths were attributable to DIC . Successful treatment with tranexamic acid has been reported .
Decreased high-molecular weight kininogen and the formation of kallikrein C1 inhibitor and factor XIIa C1 inhibitor complexes indicate contact system activation [33,72]. Kallikrein activation not only generates bradykinin but also activates factor XII. Factor XII itself can cause clotting and clot lysis via plasmin formation, leading to complement activation. In mouse models of anaphylaxis, PAF appears to be an important mediator in the development of DIC . (See "Complement pathways" and "Overview of hemostasis".)
Changes in target cells — The development and severity of anaphylaxis also depend upon the responsiveness of cells targeted by these mediators. As an example, interleukin-4 (IL-4) and interleukin-13 (IL-13) are cytokines important in the initial generation of antibody and inflammatory cell responses to anaphylaxis in both mice and humans. In murine anaphylaxis, however, IL-4 also induces a three- to sixfold increase in responsiveness of target cells to inflammatory and vasoactive mediators, including histamine, cysteinyl leukotrienes, serotonin, and PAF . This action of IL-4 appears to take place through the alpha chain of the IL-4 receptor, resulting in the activation of the transcription factor, signal transducer and activator of transcription 6 (STAT-6). Comparable mechanisms have not been demonstrated in humans.
TEMPORAL COURSE — Anaphylaxis is usually characterized by the rapid onset of symptoms over a period of minutes to hours following exposure to a trigger . (See "Anaphylaxis: Acute diagnosis", section on 'Temporal patterns'.)
Factors affecting the time course — The variables that determine the temporal course of anaphylaxis are not entirely defined. However, several factors appear to be involved:
●The route through which the allergen enters the body is one factor in determining the rapidity of onset of symptoms. Specifically, injected or intravenously-administered allergens tend to precipitate symptoms in seconds to minutes, while ingested allergens cause symptoms in minutes to one hour or two. However, these are generalizations to which exceptions are well-reported.
●The type of allergen responsible for the reaction also affects the timing of symptom onset. In immunoglobulin E (IgE)-mediated anaphylaxis triggered by protein allergens (the best characterized type of allergen), symptoms usually begin within two hours of trigger exposure. In contrast, IgE-mediated anaphylaxis to carbohydrate allergens, such as those responsible for some anaphylaxis to mammalian meats and to the monoclonal drug cetuximab, results in symptoms that typically appear four to six hours after exposure.
These factors have been examined in cases of fatal and near-fatal anaphylaxis and are reviewed in more detail elsewhere. (See "Fatal anaphylaxis", section on 'Clinical characteristics of fatal reactions' and "Fatal anaphylaxis", section on 'Possible risk factors'.)
Temporal patterns — Anaphylaxis symptoms most commonly appear, build, peak, and subside in a unimodal manner, although biphasic and protracted anaphylaxis are other recognized patterns of anaphylaxis. The other patterns are mentioned briefly here and reviewed in greater detail separately. (See "Biphasic and protracted anaphylaxis".)
Biphasic anaphylaxis — Biphasic anaphylaxis is defined as a recurrence of symptoms that develop following the apparent resolution of the initial anaphylactic event without additional exposure to the trigger. Biphasic anaphylaxis occurs in up to one-fifth of anaphylaxis cases, and the mechanisms underlying the recurrence of symptoms are unclear.
Protracted anaphylaxis — Protracted anaphylaxis is defined as an anaphylactic reaction that lasts for hours, days, or even weeks in extreme cases.
ORGAN SYSTEMS IN ANAPHYLAXIS — Organ system involvement in anaphylaxis varies from species to species and determines the clinical manifestations observed. Factors that determine a specific "shock organ" include variations in the immune response, the location of smooth muscle, and the distribution, rate of degradation, and responsiveness to chemical mediators [2,74]:
●In the human, the predominant shock organs are the heart, vasculature, and lungs, and fatalities are divided between circulatory collapse and respiratory arrest .
●Anaphylaxis in the rabbit produces fatal pulmonary artery vasoconstriction with right ventricular failure .
●In the guinea pig, there is bronchial smooth muscle constriction, which leads to bronchospasm, hypoxemia, and death .
●The primary shock organ in the dog is the hepatic venous system, which contracts and produces severe hepatic congestion .
Human anaphylaxis was traditionally considered a form of distributive shock characterized by a profound reduction in venous tone, with similarities to septic shock and toxic shock syndrome. An emerging view, however, is that anaphylaxis has features of hypovolemic shock also, with fluid extravasation causing reduced venous return, as well as depressed myocardial function .
The clinical manifestations and diagnosis of anaphylaxis are discussed separately. (See "Anaphylaxis: Emergency treatment".)
Cardiovascular system — The human heart may be profoundly affected during anaphylaxis, independently of the effects of pharmacologic agents administered during treatment. One report described two previously healthy patients without apparent underlying heart disease, who developed profound myocardial depression during anaphylaxis . Echocardiography, nuclear imaging, and hemodynamic measurements confirmed myocardial dysfunction. Intra-aortic balloon counterpulsation was used to provide hemodynamic support, in addition to standard anaphylaxis treatment. This intervention was required for up to 72 hours because of persistent myocardial depression, even though other clinical signs of anaphylaxis had resolved. Both patients recovered with no subsequent evidence of myocardial dysfunction.
Anaphylaxis has been associated clinically with myocardial ischemia, as well as conduction defects, including atrial and ventricular arrhythmias and T-wave abnormalities [77,78]. Angiography has documented coronary artery vasospasm, which can be severe enough to cause myocardial infarction (Kounis syndrome) [79,80]. Stress cardiomyopathy (Takotsubo syndrome), which predominantly affects post-menopausal women, may also occur in anaphylaxis where transient ventricular dysfunction associated with regional ventricular wall abnormalities extending beyond the regions of coronary blood supply ensues [81,82]. (See "Vasospastic angina", section on 'Possible mechanisms'.)
It is unclear whether such changes are related to direct mediator effects on the myocardium, exacerbation of pre-existing myocardial insufficiency by the hemodynamic stress of anaphylaxis, endogenous epinephrine released from the adrenal medulla in response to stress, or exogenously-injected epinephrine [33,76,77,83].
Effects of mediators — The cardiac effects of some of the mediators of anaphylaxis have been studied:
●Histamine, acting at H1 receptors, mediates coronary artery vasoconstriction and possibly vasospasm and increases vascular permeability [84-86]. H2 receptors increase atrial and ventricular inotropy, atrial chronotropy, and coronary artery vasodilation. The interaction of H1 and H2 receptor stimulation results in decreased diastolic pressure and increased pulse pressure . (See 'Histamine' above.)
●Platelet-activating factor (PAF) decreases coronary blood flow, delays atrioventricular conduction, and has negative inotropic effects on the heart .
●Calcitonin gene-related peptide (CGRP), a sensory neurotransmitter widely distributed in cardiovascular tissues and released during anaphylaxis, may help to counteract coronary artery vasoconstriction during anaphylaxis . CGRP relaxed vascular smooth muscle and had cardioprotective effects in animal models of anaphylaxis .
●Levels of enzymes involved in bradykinin metabolism, serum angiotensin-converting enzyme (ACE), and aminopeptidase P (APP) were measured in 122 patients with peanut and tree nut allergy who presented to a regional allergy center with acute allergic reactions after ingestion of these agents . Of these 122 patients, 46 had moderate-to-severe pharyngeal edema, 36 had moderate-to-severe bronchospasm, and the rest lacked these symptoms. Patients clinically deemed to have severe pharyngeal edema had significantly lower serum ACE levels than those with no pharyngeal edema. Multivariate analysis indicated that patients with serum ACE concentrations in the lowest quartile were almost 10 times more likely to have severe pharyngeal edema than those with higher ACE concentrations. However, patients with serum ACE levels in the lowest quartile were no more likely than others to have reduced consciousness, bronchospasm, or urticaria. Serum APP levels did not correlate with clinical severity or show any statistical trends. More studies are needed, but these findings suggest a clinical scenario in which some patients who experience angioedema during anaphylaxis might be more resistant to treatment with epinephrine and second-line therapeutic agents (eg, antihistamines, glucocorticoids) commonly recommended for use after epinephrine.
Responses to fluid shifts — Massive fluid shifts occur during anaphylaxis due to increased vascular permeability. Up to 35 percent of intravascular volume can shift to the extravascular space within 10 minutes during anaphylaxis .
Compensatory responses include release of endogenous catecholamines, angiotensin II, and endothelins. When adequate, these responses may be life-saving, independent of any medical intervention. Some patients, however, experience abnormal elevations of peripheral vascular resistance (maximal vasoconstriction), yet shock persists due to reduced intravascular volume . Others have decreased systemic vascular resistance despite elevated levels of catecholamines. These differences have important clinical implications, since the latter scenario may respond to treatment with vasoconstrictor agents, while the former is vasoconstrictor-unresponsive and requires large-volume fluid resuscitation. (See "Anaphylaxis: Emergency treatment".)
Body posture — The patient's posture during anaphylaxis may impact the clinical outcome. In a retrospective review of 10 prehospital anaphylactic fatalities in the United Kingdom, 4 of the 10 fatalities were associated with the assumption of an upright or sitting posture . Postmortem findings were consistent with pulseless electrical activity and an "empty ventricle" attributed to inadequate venous return secondary to vasodilation and loss of intravascular volume. This is discussed further separately. (See "Fatal anaphylaxis", section on 'Upright posture during anaphylaxis'.)
Bradycardia — Tachycardia is the most common arrhythmia observed during anaphylaxis and is believed to develop in response to decreasing blood pressure, intravascular depletion, and endogenous catecholamines, as in other forms of shock. However, some patients present with bradycardia or with relative bradycardia (ie, initial tachycardia followed by a reduction in heart rate despite worsening hypotension). This has been reported in the setting of experimentally-induced insect sting anaphylaxis, as well as in trauma patients [33,92-94].
The etiology of this bradycardia has been studied in animal models of hypovolemia. Two distinct phases of physiologic response are apparent :
●The initial response to hypovolemia is a baroreceptor-mediated increase in cardiac sympathetic drive and concomitant withdrawal of resting vagal drive, which together produce tachycardia and peripheral vasoconstriction.
●A second phase follows when the effective arterial blood volume falls by 20 to 30 percent, which is characterized by withdrawal of vasoconstrictor drive, relative or absolute bradycardia, increased vasopressin, further catecholamine release as the adrenal axis becomes more active, and hypotension. Hypotension in this setting is independent of the bradycardia, since it persists even if the bradycardia is reversed with atropine.
Bradycardia has also been observed in porcine anaphylaxis precipitated experimentally by various liposomal medications . In this setting, release of the anaphylatoxin C5a and adenosine acting via A1 adenosine receptors are believed to be responsible.
Conduction defects and sympatholytic medications, such as beta-blockers, may also produce bradycardia in patients with anaphylaxis . Excessive venous pooling with decreased venous return (also seen in vasodepressor reactions) may activate tension-sensitive sensory receptors in the inferoposterior portions of the left ventricle, thus resulting in a cardioinhibitory (Bezold-Jarisch) reflex that stimulates the vagus nerve and causes bradycardia .
The implications of relative or absolute bradycardia in human anaphylaxis and hypovolemic shock have not been studied, although one retrospective review of approximately 11,000 trauma patients found that 29 percent of hypotensive patients were bradycardic, and mortality was lower in this group compared with those who were tachycardic after adjustment for other mortality factors . Thus, there may be a specific compensatory role of bradycardia in these settings.
Exacerbation of underlying cardiac disease — The concurrence of acute coronary events and anaphylaxis has been noted, although the causal relationship between them is unclear . Mast cells accumulate at sites of coronary atherosclerotic plaques, and mast cell degranulation may promote plaque rupture during both acute myocardial events and anaphylaxis [84,97]. Coronary artery vasoconstriction and decreased intravascular volume could conceivably also precipitate an acute coronary syndrome in a patient who already had atherosclerotic cardiovascular disease. PAF induction of platelet aggregation and activation of coagulation pathways might additionally predispose to coronary artery thrombosis.
Respiratory system — Anaphylaxis may have adverse effects on any part of the respiratory tract. Upper airway symptoms include sneezing, rhinorrhea, dysphonia, laryngeal edema, laryngeal obstruction, or oropharyngeal angioedema. Lower airway manifestations of anaphylaxis include cough, wheeze, pulmonary hyperinflation, edema, hemorrhage, petechiae, mucus plugging, respiratory failure, or respiratory arrest (table 1).
In retrospective series of acute nonfatal anaphylaxis, respiratory signs and symptoms were observed in 40 to 60 percent of subjects, with rhinitis, dyspnea/wheeze, and upper airway angioedema in up to 20, 50, and 60 percent, respectively .
Similar observations have been made in cases of fatal anaphylaxis:
●One report examined 214 anaphylactic fatalities, among which the mode of death could be surmised in 196 . Asphyxia was the cause of death in approximately one-half (98 cases), with involvement of the lower airways (bronchospasm) in 49, upper airway angioedema in 23, and both upper and lower airway involvement in 26. The fatalities from acute bronchospasm during anaphylaxis occurred almost exclusively in those with pre-existing asthma.
●Another postmortem analysis of 23 unselected cases of fatal anaphylaxis determined that 16 of 20 "immediate" deaths (deaths occurring within one hour of symptom onset) were due to upper airway edema .
Anaerobic metabolism — Anaerobic metabolism complicates anaphylaxis. Blood flow to the periphery is decreased to preserve perfusion of central organs, such as the brain, heart, and kidneys.
Preliminary evidence suggests that anaerobic metabolism occurs within the peripheral tissues during anaphylaxis, similar to other forms of distributive shock, although the mechanism may be distinct. In septic shock, the paradigm of distributive shock, hypotension results from decreased systemic vascular resistance. Oxygen consumption by skeletal muscle is impaired despite an increased partial pressure of oxygen, leading to anaerobic metabolism. This impairment in cellular respiration has been attributed to an unregulated inflammatory process called "cytopathic hypoxia" .
One study compared rats with ovalbumin-induced anaphylaxis with a parallel group with severe hypotension induced experimentally by nicardipine . The time course and magnitude of hypotension were similar, and both groups experienced decreased perfusion of skeletal muscle. There were metabolic differences, however:
●The anaphylactic animals showed greater activation of the sympathetic nervous system, with higher plasma catecholamine levels beginning at 20 minutes, which were maintained throughout the 60-minute protocol. Plasma epinephrine levels increased 15-fold and norepinephrine levels increased 10-fold over baseline values in the anaphylactic animals.
●Skeletal muscle blood flow was decreased in both nicardipine- and anaphylaxis-induced hypotensive rats initially, which was followed by a further decrease in the anaphylaxis group beginning at 20 minutes and persisting for the duration of the observation period.
●A higher gradient between plasma and interstitial epinephrine indicated more impaired skeletal muscle blood flow in the anaphylactic animals, possibly due to greater skeletal muscle vasoconstriction.
●The anaphylactic animals experienced a more rapid increase in interstitial lactate levels and a corresponding decrease in interstitial pyruvate levels, indicating depletion of cellular energy stores. This latter finding was not observed in the rats with nicardipine-induced hypotension.
These findings suggest that skeletal muscle maintains high rates of oxygen utilization during anaphylaxis compared with other forms of distributive shock and that this combined with decreased perfusion leads rapidly to anaerobic metabolism . This may partly explain why end-organ injury and irreversible shock can develop so quickly.
AUTOPSY FINDINGS — Victims of fatal anaphylaxis may show no distinguishing gross pathologic features at autopsy, possibly because anaphylaxis can progress to death so rapidly. A retrospective review included 56 cases of fatal anaphylaxis in which autopsy information was available. Death occurred within one hour in 39 cases . This is in keeping with the clinical observation that in patients in whom shock develops rapidly, there may be essentially no other physical signs or symptoms.
When present however, other findings include upper airway edema and petechial hemorrhages in airway mucosa, mucus plugging and hyperinflation of the lungs, and cerebral edema. Cutaneous findings, such as urticaria or angioedema, are present in only a minority of fatal cases. Autopsy findings are described in more detail elsewhere. (See "Fatal anaphylaxis".)
●Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell-, basophil-, and macrophage-derived mediators into the circulation. (See "Anaphylaxis: Emergency treatment".)
●Anaphylaxis can be classified as "immunologic" or "nonimmunologic." Immunologic anaphylaxis includes both immunoglobulin E (IgE)-mediated and immunoglobulin G (IgG)-mediated reactions (which have not been identified in humans), as well as immune complex/complement-mediated mechanisms. Nonimmunologic anaphylaxis is caused by agents or events that induce sudden, massive mast cell or basophil degranulation, without the involvement of antibodies. (See 'Proposed mechanisms' above.)
●In IgE-mediated anaphylaxis, the activation of mast cells, basophils, and eosinophils results in the release of preformed inflammatory mediators, including histamine, tryptase, chymase, heparin, histamine-releasing factor, and platelet-activating factor (PAF). Cellular activation also stimulates the production of lipid-derived mediators, such as prostaglandins and cysteinyl leukotrienes. (See 'Chemical mediators of anaphylaxis' above.)
●In humans, the predominant shock organs are the heart, lung, and vasculature, and fatalities are divided between circulatory collapse and respiratory arrest . (See 'Organ systems in anaphylaxis' above.)
•Anaphylaxis is associated with myocardial depression, arrhythmias, and myocardial ischemia. Contributing factors include direct mediator effects on the myocardium, exacerbation of pre-existing myocardial insufficiency by the hemodynamic stress of anaphylaxis, and exogenous or endogenous epinephrine. (See 'Cardiovascular system' above.)
•Anaphylaxis may affect any part of the respiratory tract, causing bronchospasm and mucus plugging in the smaller airways and laryngeal edema and asphyxiation in the upper airway. Asphyxiation typically occurs rapidly after allergen exposure, with death occurring within one hour in many cases. Severe bronchospasm during anaphylaxis characteristically develops in individuals with pre-existing asthma. (See 'Respiratory system' above.)
●Preliminary evidence suggests that during anaphylaxis, peripheral tissues continue to consume oxygen at relatively high rates and that this in combination with peripheral vasoconstriction and decreased perfusion leads rapidly to anaerobic metabolism and end-organ damage. (See 'Anaerobic metabolism' above.)
●Victims of fatal anaphylaxis may show no distinguishing gross pathologic features at autopsy, possibly because death can ensue so rapidly. However, when present, findings may include upper airway edema and petechial hemorrhages in airway mucosa, mucus plugging and hyperinflation of the lungs, and cerebral edema. Cutaneous findings, such as urticaria or angioedema, are uncommon. (See 'Autopsy findings' above and "Fatal anaphylaxis".)
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