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Pathophysiology of anaphylaxis - UpToDate

Official reprint from UpToDate 2016 UpToDate

Pathophysiology of anaphylaxis

Author: Stephen F Kemp, MD

Section Editor: John M Kelso, MD
Deputy Editor: Anna M Feldweg, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2016. | This topic last updated: Jun 09, 2015.

INTRODUCTION Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the
sudden release of mast cell- and basophil-derived mediators into the circulation [1]. 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 [2].

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 [3]. 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

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 [4].

Immunologic anaphylaxis Immunologic anaphylaxis includes the following:

IgE-mediated reactions

IgG-mediated reactions (which have not been identified in humans, as discussed below)

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

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'Nonimmunologic anaphylaxis' below.)

Immunologic anaphylaxis

IgE-mediated The classical mechanism associated with human-allergic disease is initiated by an

antigen (allergen) interacting with allergen-specific 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 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 [1]. 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 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) [5-7,9-11]. 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 [12].

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

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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 [13]. 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 [5,14] and PAF can activate mast cells in
vitro [15], so PAF potentially may contribute to human anaphylaxis [16]. 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) [17,18]. Omalizumab blocks the binding of IgE to Fc-epsilon-RI receptors and does
not bind Fc-epsilon-RI-associated IgE (figure 3) [5,19]. 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 [5]. IgE-independent anaphylaxis has also been reported in some patients receiving another
monoclonal antibody preparation, infliximab [20,21]. 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 [22]. 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 [23,24].

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 "Immediate hypersensitivity reactions to radiocontrast media: Clinical
manifestations, diagnosis, and treatment".)

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 [25-27]. It has been proposed that under physiologic conditions, Cremophor
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

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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 "red man syndrome." This reaction can involve hypotension and present similarly to
anaphylaxis in up to 15 percent of patients. The mechanism is unknown. (See "Vancomycin

Opiate medications, such as meperidine and codeine, can cause nonimmunologic histamine release via
direct mast cell degranulation [28]. Mild reactions, such as urticaria, are common, although anaphylactic
reactions are occasionally reported [29]. In the past, some allergy specialists used opiates 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 [30]. (See "Cold urticaria" and
"Overview of cryoglobulins and cryoglobulinemia" and "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 [31,32]. (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 [5].
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 [2]:

Histamine, tryptase, chymase, and heparin, which are preformed substances associated with intracellular

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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, 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

A mutation of c-kit, a tyrosine kinase receptor expressed on the membrane surfaces of all mast cells has been
associated with anaphylaxis [33]. 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".)

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 [34,35].

The systemic effects of histamine are dose-dependent. Histamine was administered to normal volunteers
over 30 minutes at doses ranging from 0.05 to 1.0 micrograms/kg/minute, to determine the plasma levels
required to elicit symptoms of anaphylaxis [36]:

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 [36].

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 [37].

Murine models suggest H4 receptors might be involved in chemotaxis and mast cell cytokine release, and
they might also help to mediate pruritus [38,39]. Their role (if any) in human anaphylaxis has not been

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.

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Tryptase can activate the complement and coagulation pathways, as well as the kallikrein-kinin contact
system [40]. 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 [41]. (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 [40,42]. 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 [43,44]. 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 [43].
Overall, tryptase levels generally correlate with the clinical severity of anaphylaxis, with the notable exception
of food allergens previously described.

Postmortem measurements of serum tryptase may be useful in establishing anaphylaxis as the cause of

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

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 [45-47]. 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 [46,47]. (See "Mast cell
disorders: An overview".)

Platelet-activating factor PAF-receptor antagonists are effective in rodent models of anaphylaxis

[5,48]. 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 [49]. PAF
receptors have been identified in some subsets of human mast cells [15]. 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 [16]. 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 [50]. (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 accounts for the bioactivity of
endothelium-derived relaxing factor [51]. Under normal circumstances, NO participates in the homeostatic
control of vascular tone and regional blood pressure [52]. NO is also involved in the complex interaction of
regulatory and counter-regulatory mediators in mast cell activation, and has been implicated in the

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hypotension of sepsis and anaphylaxis [53,54].

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 [54].

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 antiinflammatory 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 [55]. 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 [56]. 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 [57,58], and one report
describes its successful use in a normotensive subject with refractory anaphylaxis [59]. Methylene blue may
exert its favorable effects by blocking NO-mediated vascular smooth muscle relaxation [60]. However,
methylene blue itself is capable of causing anaphylaxis in some subjects [61,62].

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 [40].

Leukotriene B4 is a chemotactic agent that theoretically may contribute to biphasic and protracted

Overproduction of leukotriene C4 enhances mast cell degranulation [40].

Leukotrienes D4 and E4 increase microvascular permeability and are potent bronchoconstrictors [63-65].

Prostaglandin D2 (PGD2) causes vasodilation, increased vasopermeability, and airway smooth muscle
bronchoconstriction in various experimental models [66-68]. It is also chemotactic for neutrophils and
activates eosinophils [69,70].

Modulatory mediators Other mediators may have antiinflammatory 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 [35,40].

Eosinophils Eosinophils may be proinflammatory (eg, through release of cytotoxic granule-associated

proteins) or antiinflammatory (eg, through metabolism of vasoactive mediators) [40,71]. 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

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allergic response [72]. 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 [35,73]. 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 [73]. Successful treatment with
tranexamic acid has been reported [74].

Decreased high molecular weight kininogen and the formation of kallikrein C1 inhibitor and factor XIIa C1
inhibitor complexes indicate contact system activation [35,75,76]. 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 [77]. (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 [5]. 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 [1]. (See "Anaphylaxis: Acute diagnosis", section on 'Time

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 an 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

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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 develops

following the apparent resolution of the initial anaphylactic event without additional exposure to the trigger.
Biphasic anaphylaxis occurs up to one-fifth of anaphylaxis cases and the mechanisms underlying the
recurrence of symptoms is 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 [2,78]:

In the human, the predominant shock organs are the heart, vasculature, and lungs, and fatalities are
divided between circulatory collapse and respiratory arrest [73].

Anaphylaxis in rabbits produces fatal pulmonary artery vasoconstriction with right ventricular failure [2].

In the guinea pig, there is bronchial smooth muscle constriction, which leads to bronchospasm,
hypoxemia, and death [2].

The primary shock organ in the dog is the hepatic venous system, which contracts and produces severe
hepatic congestion [2].

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 [79].

The clinical manifestations and diagnosis of anaphylaxis is discussed elsewhere. (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 [80]. Echocardiography, nuclear imaging, and hemodynamic measurements confirmed
myocardial dysfunction. Intra-aortic balloon counter-pulsation 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 [81,82].

It is unclear whether such changes are related to direct mediator effects on the myocardium, exacerbation of
preexisting myocardial insufficiency by the hemodynamic stress of anaphylaxis, endogenous epinephrine
released from the adrenal medulla in response to stress, or exogenously-injected epinephrine [35,80,81,83].

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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, as previously mentioned. The interaction of H1 and H2
receptor stimulation results in decreased diastolic pressure and increased pulse pressure [87]. (See
'Histamine' above.)

Platelet-activating factor (PAF) decreases coronary blood flow, delays atrioventricular conduction, and
has negative inotropic effects on the heart [81].

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 [88,89]. CGRP relaxed vascular smooth muscle and had cardioprotective effects in animal
models of anaphylaxis [90].

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 [91]. Of these 122,
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 [92].

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 [2]. 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 [93]. 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 elsewhere. (See "Fatal anaphylaxis",
section on 'Upright posture during anaphylaxis'.)

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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 [35,94-96].

The etiology of this bradycardia has been studied in animal models of hypovolemia. Two distinct phases of
physiologic response are apparent [97]:

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

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 [98]. In this setting, release of the anaphylatoxin, C5a, and adenosine acting via A1 adenosine
receptors, are believed responsible.

Conduction defects and sympatholytic medications, such as beta-blockers, may also produce bradycardia in
patients with anaphylaxis [2]. 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 [87].

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 [96]. 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 [84]. Mast cells
accumulate at sites of coronary atherosclerotic plaques, and mast cell degranulation may promote plaque
rupture during both acute myocardial events and anaphylaxis [84,99]. 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

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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 [87].

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 [73]. 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 preexisting 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 [100].

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" [101].

One study compared rats with ovalbumin-induced anaphylaxis to a parallel group with severe hypotension
induced experimentally by nicardipine [102]. 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 [102]. This may partly explain why end-organ injury and irreversible shock
can develop so quickly.

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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 [103]. 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 [73]. (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 preexisting
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 preexisting
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'

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

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cerebral edema. Cutaneous findings, such as urticaria or angioedema, are uncommon. (See 'Autopsy
findings' above and "Fatal anaphylaxis".)

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99. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary
atheromatous erosion or rupture in myocardial infarction. Circulation 1995; 92:1084.
100. Greenberger PA, Rotskoff BD, Lifschultz B. Fatal anaphylaxis: postmortem findings and associated
comorbid diseases. Ann Allergy Asthma Immunol 2007; 98:252.
101. Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care 2002; 6:491.
102. Dewachter P, Jouan-Hureaux V, Franck P, et al. Anaphylactic shock: a form of distributive shock without
inhibition of oxygen consumption. Anesthesiology 2005; 103:40.
103. Pumphrey RS, Roberts IS. Postmortem findings after fatal anaphylactic reactions. J Clin Pathol 2000;

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Allergen-specific IgE production and dissemination

Allergens (in this figure, aeroallergens) enter the tonsils within which they are taken
up and degraded by antigen-presenting cells (APCs). APCs then interact with T helper
type 2 (Th2) cells and B cells in the lymph nodes, leading to allergen-specific IgE
production. The IgE enters the blood stream and then diffuses through tissues
(especially the skin and mucosal tissues of the respiratory and gastrointestinal
tracts). The IgE binds to high affinity Fc receptors (Fc-epsilon-RI) on the surface of
the tissue mast cells and circulating basophils. When these IgE-coated cells encounter
that specific aeroallergen subsequently, they become activated, leading to the release
of inflammatory mediators, which results in the signs and symptoms of IgE-mediated

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allergic reactions.

IgE: immunoglobulin E.

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IgG-mediated anaphylaxis in mice

In a mouse model of anaphylaxis, allergen interacts with allergen-specific IgG

on the surface of macrophages, through the IgG receptor Fc-gamma-RIII.
Cross-linking of multiple IgG molecules by allergen initiates intracellular
signaling and macrophage activation. In mice, macrophage-derived platelet-
activating factor and other inflammatory mediators trigger signs and symptoms
similar to those of IgE-mediated anaphylaxis in humans.

IgG: immunoglobulin G; IgE: immunoglobulin E.

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Omalizumab mechanism of action

Omalizumab binds free IgE in the serum, forming trimers and hexamers. The drug binds to IgE
at the same site that the high-affinity IgE receptor (Fc-epsilon-RI) binds, so IgE bound to drug
cannot bind its receptor on mast cells and basophils. Omalizumab does not bind IgE that is
already bound to Fc-epsilon-RI, and so should not result in cross-linking of receptors. As a
result of the binding of free IgE, the number of IgE receptors on the surface of mast cells and
basophils declines over time, which is believed to be a critical component of the clinical effect
of the drug. Omalizumab also blocks binding of IgE to the low affinity IgE receptor
(Fc-epsilon-RII or CD23, not shown) although the therapeutic relevance of this is not known.

IgE: immunoglobulin E.

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Symptoms and signs of anaphylaxis

Feeling of warmth, flushing (erythema), itching, urticaria, angioedema, and "hair standing on end" (pilor erection)

Itching or tingling of lips, tongue, or palate

Edema of lips, tongue, uvula, metallic taste

Nose - Itching, congestion, rhinorrhea, and sneezing

Laryngeal - Itching and "tightness" in the throat, dysphonia, hoarseness, stridor

Lower airways - Shortness of breath (dyspnea), chest tightness, cough, wheezing, and cyanosis

Nausea, abdominal pain, vomiting, diarrhea, and dysphagia (difficulty swallowing)

Feeling of faintness or dizziness; syncope, altered mental status, chest pain, palpitations, tachycardia,
bradycardia or other dysrhythmia, hypotension, tunnel vision, difficulty hearing, urinary or fecal incontinence, and
cardiac arrest

Anxiety, apprehension, sense of impending doom, seizures, headache and confusion; young children may have
sudden behavioral changes (cling, cry, become irritable, cease to play)

Periorbital itching, erythema and edema, tearing, and conjunctival erythema

Uterine cramps in women and girls

Original figure modified for this publication. Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010; 125:S161. Table used
with the permission of Elsevier Inc. All rights reserved.

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Contributor Disclosures
Stephen F Kemp, MD Nothing to disclose John M Kelso, MD Nothing to disclose Anna M Feldweg,
MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.

Conflict of interest policy


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