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Anaphylaxis (Pathophysiology)
INTRODUCTION
1.
2.
Anaphylaxis is acute, potentially lethal, multisystem syndrome resulting from sudden release
of mast cell- and basophil-derived mediators into circulation. It most often results from
immunologic reactions to foods, medications, and insect stings, although it can also be
induced through non-immunologic mechanisms by any agent capable of producing sudden,
systemic degranulation of mast cells or basophils.
The phenomenon of anaphylaxis was first described in 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 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).
3. 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.
PROPOSED MECHANISM
1. The mechanism responsible for most cases of human anaphylaxis involves 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.
2. Terminology
A.
The term "anaphylaxis" has traditionally been reserved for IgE-dependent events, and
term "anaphylactoid reaction" has been used to describe IgE-independent events,
although two reactions are often clinically indistinguishable. The World Allergy
Organization (WAO), international umbrella organization representing large number of
regional and national professional societies dedicated to allergy and clinical immunology,
has proposed discarding this nomenclature. WAO categorizes anaphylaxis as either
immunologic or non-immunologic, and this is terminology used in this review.
B. Immunologic anaphylaxis
i.
IgE-mediated reactions
ii.
IgG-mediated reactions (which have not been identified in humans, as discussed
below)
iii.
Immune complex/complement-mediated reactions
C. Non-immunologic anaphylaxis
i.
Non-immunologic anaphylaxis is caused by agents or events that induce sudden,
massive mast cell or basophil degranulation in absence of immunoglobulins.
3.
Immunologic anaphylaxis
A. IgE-mediated
i.
ii.
iii.
iv.
v.
B.
The classical mechanism associated with human-allergic disease is initiated by
antigen (allergen) interacting with allergen-specific IgE bound to receptor
Fc-epsilon-RI on mast cells and/or basophils.
The events leading to allergen-specific IgE production in atopic individual are
complex. In brief, B cells are driven to differentiate into IgE-producing cells via
activity of type 2 subset of CD4-bearing helper T cells (Th2 cells). This process
largely takes place in peripheral lymphoid tissues. IL-4 and its receptors (IL-4R-α/γ-c
and IL-4R-α/IL-13R-α-1) and IL-13 and its receptor (IL-4R-α/IL-13R-α-1) contribute to
IgE responses in humans.
Once produced, allergen-specific IgE diffuses through 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.
When allergen diffuses into proximity of 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 cell surface to cause
cross-linking, which in turn causes 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, mast cell (or basophil) becomes activated and degranulates, releasing
preformed mediators, enzymes, and cytokines (such as histamine, tryptase, and
TNF) and initiating additional mediator, cytokine, and enzyme production. Mast cell
biology is discussed in more depth elsewhere.
These mediators either act directly on tissues to cause allergic symptoms or recruit
and activate additional inflammatory cells, particularly eosinophils. The recruited
cells, in turn, release more mediators and propagate fulminant "chain reaction" of
allergic inflammation. The various mediators and cytokines involved are reviewed
below.
IgG-mediated (in animal models)
i.
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
example, murine anaphylaxis is characterized by dramatic reductions in core body
temperature and subtle cardiopulmonary differences, compared with human
anaphylaxis.
ii.
In mouse models, at least two IgG-mediated pathways have been identified.
1. In one model, allergen interacts with allergen-specific IgG bound to Fc-γ-RIII
on macrophages and basophils. This IgG-dependent pathway requires
proportionately more antibody and antigen than murine IgE-mediated
pathway, and macrophage activation results primarily in release of PAF, rather
than histamine. PAF causes platelet aggregation and release of potent
vasoconstrictors TxA2 and serotonin, and can act directly on vascular
endothelial cells to increase vascular permeability.
2.
3.
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 antigen before it can
cross-link mast cell- and basophil-associated IgE, and by activating inhibitory
receptor, Fc-γ-RIIb. Low doses of IgG are insufficient to induce IgG-mediated
anaphylaxis, presumably because Fc-γ-RIII has much lower affinity than Fc-ε-RI.
In comparison, high doses of allergen can precipitate IgG-dependent
anaphylaxis by forming complexes that activate macrophages and basophils
through Fc-γ-RIII.
Another mouse model found evidence of above mechanism in concert with
activation of neutrophils resulting from interaction of allergen-specific IgG2
with Fc-γ-RIV on those cells. PAF was predominant mediator in this model also.
iii.
iv.
IgG-dependent anaphylaxis has not been demonstrated in humans. However,
human IgG receptors are capable of activating macrophages and neutrophils to
secrete PAF and PAF can activate mast cells in vitro, so PAF potentially may
contribute to human anaphylaxis. 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). Omalizumab blocks binding
of IgE to Fc-ε-RI receptors and does not bind Fc-ε-RI-associated IgE. These
anaphylactic reactions could conceivably be IgG-mediated, with patient's IgE acting
as antigen, and IgG of drug acting as causative antibody. IgE-independent
anaphylaxis has also been reported in some patients receiving another monoclonal
antibody preparation, infliximab. More human data are needed to clarify
mechanism underlying these clinical events.
v.
On basis of previous observations and preliminary studies, one group of
investigators has hypothesized that decreased blood neutrophil Fc-γ-RIII expression
without increased IL-4R-α expression by T lymphocytes might be used in humans to
distinguish IgG- from IgE-dependent anaphylaxis. If observed, decreased neutrophil
Fc-γ-RIII expression would be associated with IgG-dependent anaphylaxis, whereas
increased IL-4R-α expression would be associated with IgE-dependent events.
C. Immune complex/complement-mediated
i.
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 culprit drug and IgG
or other isotypes has been proposed for some of these drugs, such as protamine.
D.
4.
Other proposed mechanism
i.
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 with Fc portions of IgE or IgG already bound to mast cell or
basophil surface, causing cross-linking and activation.
Non-immunologic anaphylaxis
A. 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.
i.
Activation of complement, in absence of immune complex formation, has been
ii.
iii.
proposed to account for reactions to drugs that were solubilized in diluent
Cremophor EL, such as older preparations of propofol and paclitaxel. 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 "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
significance of this in human anaphylaxis has not been demonstrated.
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 HoTN and present similarly to anaphylaxis in up to 15% of patients. The
mechanism is unknown.
Opiate, such as meperidine and codeine, can cause non-immunologic 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 opiates as positive controls in skin testing, because
these agents induce characteristic wheal-and-flare response due to direct
degranulation of mast cells in skin.
iv.
v.
Cold urticaria is reproducible disorder that is characterized by rapid onset of
erythema, pruritus, and edema after exposure to cold (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 HoTN. Some
episodes are characterized by presence of abnormal proteins (cryoglobulins or
cryofibrinogens), which may agglutinate or precipitate at lower temperatures.
However, most instances of cold urticaria/anaphylaxis are idiopathic and lack
abnormal circulating protein.
Oversulfated chondroitin sulfate (OSCS), compound contaminating worldwide
heparin supplies in 2007 to 2008, caused anaphylaxis by directly activating
kinin-kallikrein pathway, which generated bradykinin, C3a, and C5a. Anaphylactic
reactions consisted of HoTN and abdominal pain, and variably included dyspnea,
diarrhea, flushing, and angioedema. However, these reactions consistently lacked
urticaria or pruritus.
5. Regulation of mast cell activation in anaphylaxis
A. 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.
CHEMICAL MEDIATORS OF ANAPHYLAXIS
1. The chemical mediators of IgE-mediated anaphylaxis in humans include biologically active
2.
products of mast cells, basophils, and eosinophils, as well as serum components of
complement, coagulation, and kallikrein-kinin pathways. In addition, cytokines that alter
sensitivity of various target cells to these mediators are believed to influence severity of
anaphylaxis.
Mast cells and basophils
A. The degranulation of mast cells and basophils results in systemic release of various
biochemical mediators and chemotactic substances.
i.
Histamine, tryptase, chymase, and heparin, which are preformed substances
associated with intracellular granules.
ii.
Histamine-releasing factor and other cytokines (TNF, IL-4, IL-13).
iii.
B.
C.
Newly-generated lipid-derived mediators such as prostaglandin D2, leukotriene B4,
PAF, and cysteinyl leukotrienes, LTC4, LTD4, and LTE4.
The functions of these mediators specifically in anaphylaxis have not been extensively
studied, although available data are reviewed here. A more complete description of
mediators, cytokines, and chemokines produced by mast cells is found elsewhere.
A mutation of c-kit, tyrosine kinase receptor expressed on membrane surfaces of all
mast cells has been associated with anaphylaxis. Subjects with D816V c-kit mutation
present with normal numbers of mast cells in BM but abnormal expression of CD25 and
symptoms of severe anaphylaxis.
D.
Histamine
i.
Localized histamine release in skin causes urticaria. Systemic release of histamine,
ii.
iii.
iv.
v.
however, causes hemodynamic and CV changes, and is not associated with
presence of urticaria. Serum histamine levels correlated with severity and
persistence of cardiopulmonary manifestations in studies of human anaphylaxis.
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 μg/kg/min,
to determine plasma levels required to elicit symptoms of anaphylaxis.
1. At low plasma levels, histamine was associated with 30% increase in HR.
2. At moderate plasma levels, histamine precipitated flushing and headache.
3. Higher plasma histamine levels elicited 30% increase in pulse pressure (systolic
pressure minus diastolic pressure).
The actions of histamine in anaphylaxis are mediated by binding to H1 and H2
receptors on target cells. In study above, pretreatment with H1 antihistamines, H2
antihistamines, or both, suggested that both H1 and H2 receptors mediated
flushing, HoTN, and headache, whereas H1 receptors alone mediated tachycardia,
pruritus, rhinorrhea, and bronchospasm.
H3 receptors have been implicated in canine model of anaphylaxis and appear to
influence CV 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. Their role (if any) in
human anaphylaxis has not been studied.
vi.
The specific effects of histamine on CV system are discussed below.
E. Tryptase
i.
Tryptase is protease that is abundant in human mast cells. Tryptase is relatively
specific for mast cells, although basophils and myeloid precursors contain small
amount. There are different forms of tryptases. Beta tryptase is enzymatically
active, concentrated in mast cell secretory granules, and released upon
degranulation.
ii.
Tryptase can activate complement and coagulation pathways, as well as
iii.
kallikrein-kinin contact system. Potential clinical consequences include HoTN,
angioedema, clotting, and clot lysis, with the latter two explaining variable
development of DIC in severe anaphylaxis.
The route of allergen exposure appears to influence 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.
iv.
v.
In 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. This difference in tryptase levels may be related to subtype of mast cell first
encountered by culprit antigen. Mast cells that predominate in mucosa of small
intestine and lung contain much less tryptase per cell than those in connective
tissues. Overall, tryptase levels generally correlate with clinical severity of
anaphylaxis, with notable exception of food allergens previously described.
Postmortem measurements of serum tryptase may be useful in establishing
anaphylaxis as the cause of death.
1.
vi.
F.
The measurement of tryptase in anaphylaxis and differential diagnosis of
elevated tryptase level are presented in more detail elsewhere.
2. Technical aspects of collecting and measuring tryptase in postmortem setting
are reviewed separately.
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. Higher baseline tryptase concentrations (> 11.4 mcg/L) might
indicate mastocytosis or monoclonal mast cell disorder (c-kit mutation) and require
bone marrow biopsy and cytogenetic analysis for further evaluation.
Platelet-activating factor
i.
PAF-receptor antagonists are effective in rodent models of anaphylaxis. In contrast,
roles of PAF and PAF acetylhydrolase, 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 prospective study of 41 subjects (ages 15 to 74 years) and 23
non-allergic adult controls, serum PAF levels correlated directly and PAF
acetylhydrolase levels correlated inversely with severity of anaphylaxis. In
companion retrospective analysis, PAF acetylhydrolase activity was significantly
lower in nine individuals who experienced fatal peanut-induced anaphylaxis
compared with patients in 5 different control groups. Similarly, PAF levels in this
study population of 41 subjects correlated better with severity of acute allergic
reactions than did serum levels of histamine or tryptase.
G. Nitric oxide
i.
NO acts as messenger molecule in most human organ systems. Within blood vessel
walls it has potent vasodilator and accounts for bioactivity of EDRF. Under normal
circumstances, NO participates in homeostatic control of vascular tone and regional
BP. NO is also involved in complex interaction of regulatory and counter-regulatory
mediators in mast cell activation, and has been implicated in HoTN of anaphylaxis.
ii.
iii.
iv.
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 activity of NOS. Various
isoforms of NOS have been identified, depending on tissue in which they were first
isolated. Constitutively expressed isoforms, ie, eNOS and nNOS, are presumed to
produce low amounts of NO for physiologic and/or anti-inflammatory functions. In
contrast, 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 CV 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 absence of iNOS, and that in PAF-associated anaphylaxis, eNOS is 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 use of methylene blue for treatment of anaphylactic
shock refractory to epinephrine, IVF, vasoconstrictors, and IABP, and one report
describes its successful use in 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.
H. Arachidonic acid metabolites
i.
Arachidonic acid is fatty acid derived from membrane phospholipids that can be
metabolized via lipoxygenase and cyclooxygenase pathways to generate
proinflammatory mediators, such as leukotrienes, prostaglandins, and PAF. Effects
of these AA metabolites include bronchospasm, HoTN, and erythema.
1. LTB4 is chemotactic agent that theoretically may contribute to biphasic and
2.
3.
4.
protracted reactions.
Overproduction of LTC4 enhances mast cell degranulation.
LTD4 and E4 increase microvascular permeability and are potent
bronchoconstrictors.
PGD2 causes vasodilation, increased vasopermeability, and airway smooth
muscle bronchoconstriction in various experimental models. It is also
chemotactic for neutrophils and activates eosinophils.
I.
3.
4.
5.
Modulatory mediator
i.
Other mediators may have anti-inflammatory and modulatory effects that limit
anaphylaxis. As examples, chymase may facilitate conversion of angiotensin I to
angiotensin II, theoretically helping to counteract HoTN during anaphylaxis. Heparin
opposes complement activation, modulates tryptase activity, and inhibits clotting,
plasmin, and kallikrein.
Eosinophils
A. Eosinophils may be proinflammatory (through release of cytotoxic granule-associated
proteins) or anti-inflammatory (through metabolism of vasoactive mediators). A guinea
pig anaphylaxis model suggests that eosinophils already present in chronically-inflamed
airways may participate in immediate-phase response to allergen exposure, as well as
their traditional role in late-phase allergic response. These mechanisms have not been
studied in human anaphylaxis.
Serum factors and other inflammatory pathways
A. During severe episodes of anaphylaxis, there is concomitant activation of complement,
coagulation pathways, and kallikrein-kinin contact system. Much of 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. An analysis of 202
anaphylaxis fatalities over 10-year period in the UK determined that 8% of deaths were
attributable to DIC. Successful treatment with tranexamic acid has been reported.
B. Decreased high molecular weight kininogen and formation of kallikrein C1 inhibitor and
factor XIIa C1 inhibitor complexes indicate contact system activation. 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 important mediator in development of
DIC.
Changes in target cells
A. The development and severity of anaphylaxis also depend upon responsiveness of cells
targeted by these mediators. As example, IL-4 and IL-13 are cytokines important in initial
generation of antibody and inflammatory cell responses to anaphylaxis in both mice and
humans. In murine anaphylaxis, however, IL-4 also induces 3- to 6-fold 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 alpha chain of IL-4 receptor, resulting in activation of transcription factor
signal transducer and activator of transcription 6 (STAT-6). Comparable mechanisms
have not been demonstrated in humans.
TEMPORAL COURSE
1. Anaphylaxis is usually characterized by rapid onset of symptoms over period of minutes to
2.
hours following exposure to trigger.
Factors affecting time course
A. The variables that determine temporal course of anaphylaxis are not entirely defined.
However, several factors appear to be involved.
i.
The route through which allergen enters body is one factor in determining 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 1 hour or two. However, these are generalizations to which
exceptions are well-reported.
ii.
3.
The type of allergen responsible for reaction also affects timing of symptom onset.
In IgE-mediated anaphylaxis triggered by protein allergens (the best-characterized
type of allergen), symptoms usually begin within 2 hours of trigger exposure. In
contrast, IgE-mediated anaphylaxis to carbohydrate allergens, such as those
responsible for some anaphylaxis to mammalian meats and to monoclonal drug
cetuximab, results in symptoms that typically appears 4 to 6 hours after exposure.
B. These factors have been examined in cases of fatal and near-fatal anaphylaxis, and are
reviewed in more detail elsewhere.
Temporal pattern
A. Anaphylaxis symptoms most commonly appear, build, peak, and subside in 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.
B. Biphasic anaphylaxis
i.
Biphasic anaphylaxis is defined as recurrence of symptoms that develops following
apparent resolution of initial anaphylactic event without additional exposure to
trigger. Biphasic anaphylaxis occurs up to 20% of anaphylaxis cases and
mechanisms underlying recurrence of symptoms is unclear.
C. Protracted anaphylaxis
i.
Protracted anaphylaxis is defined as anaphylactic reaction that lasts for hours, days,
or even weeks in extreme cases.
ORGAN SYSTEMS IN ANAPHYLAXIS
1. Organ system involvement in anaphylaxis varies from species to species and determines
clinical manifestations observed. Factors that determine specific "shock organ" include
variations in immune response, location of smooth muscle, and distribution, rate of
degradation, and responsiveness to chemical mediators.
A. In human, predominant shock organs are heart, vasculature, and lungs, and fatalities
are divided between circulatory collapse and respiratory arrest.
B.
Anaphylaxis in rabbits produces fatal pulmonary artery vasoconstriction with right
ventricular failure.
C.
2.
3.
4.
In guinea pig, there is bronchial smooth muscle constriction, which leads to
bronchospasm, hypoxemia, and death.
D. The primary shock organ in dog is hepatic venous system, which contracts and produces
severe hepatic congestion.
Human anaphylaxis was traditionally considered form of distributive shock characterized by
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 is discussed elsewhere.
Cardiovascular system
A. The human heart may be profoundly affected during anaphylaxis, independently of
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.
IABP 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.
B.
Anaphylaxis has been associated clinically with myocardial ischemia, as well as
conduction defects, including atrial and ventricular arrhythmias and T-wave
abnormalities.
C. It is unclear whether such changes are related to direct mediator effects on myocardium,
exacerbation of preexisting myocardial insufficiency by hemodynamic stress of
anaphylaxis, endogenous epinephrine released from adrenal medulla in response to
stress, or exogenously-injected epinephrine.
D. Effects of mediator
i.
Histamine, acting at H1 receptors, mediates coronary artery vasoconstriction and
possibly vasospasm, and increases vascular permeability. H2 receptors increase
ii.
iii.
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.
PAF decreases coronary blood flow, delays AV conduction, and has negative
inotropic effects on heart.
CGRP, sensory neurotransmitter widely distributed in CV 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.
iv.
Levels of enzymes involved in bradykinin metabolism, serum ACE, and
aminopeptidase P (APP) were measured in 122 patients with peanut and tree nut
allergy who presented to regional allergy center with acute allergic reactions after
ingestion of these agents. 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 clinical scenario in which some patients who experience
angioedema during anaphylaxis might be more resistant to treatment with
epinephrine and 2nd-line therapeutic agents (antihistamines, glucocorticoids)
commonly recommended for use after epinephrine.
E. Responses to fluid shift
i.
Massive fluid shifts occur during anaphylaxis due to increased vascular
permeability. Up to 35% of intravascular volume can shift to extravascular space
within 10 minutes during anaphylaxis.
ii.
F.
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 SVR
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.
Body posture
i.
The patient's posture during anaphylaxis may impact clinical outcome. In
retrospective review of 10 prehospital anaphylactic fatalities in the UK, 4 of the 10
fatalities were associated with assumption of upright or sitting posture.
Postmortem findings were consistent with PEA and "empty ventricle," attributed to
inadequate venous return secondary to vasodilation and loss of intravascular
volume. This is discussed further elsewhere.
G.
Bradycardia
i.
Tachycardia is the most common arrhythmia observed during anaphylaxis and is
ii.
iii.
iv.
v.
believed to develop in response to HoTN, intravascular depletion, and endogenous
catecholamines, as in other forms of shock. However, some patients present with
bradycardia or with relative bradycardia (initial tachycardia followed by reduction in
HR despite worsening HoTN). This has been reported in setting of
experimentally-induced insect sting anaphylaxis, as well as in trauma patients.
The etiology of this bradycardia has been studied in animal models of hypovolemia.
Two distinct phases of physiologic response are apparent.
1. The initial response to hypovolemia is baroreceptor-mediated increase in
cardiac sympathetic drive and concomitant withdrawal of resting vagal drive,
which together produce tachycardia and peripheral vasoconstriction.
2. A second phase follows when EAV falls by 20 to 30%, which is characterized by
withdrawal of vasoconstrictor drive, relative or absolute bradycardia,
increased vasopressin, further catecholamine release as adrenal axis becomes
more active, and HoTN. HoTN in this setting is independent of bradycardia,
since it persists even if bradycardia is reversed with atropine.
Bradycardia has also been observed in porcine anaphylaxis precipitated
experimentally by various liposomal medications. In this setting, release of
anaphylatoxin, C5a, and adenosine acting via A1 adenosine receptors, are believed
responsible.
Conduction defects and sympatholytic medications, such as βB, 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 inferoposterior portions of LV, thus resulting in
cardioinhibitory (Bezold-Jarisch) reflex that stimulates 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% 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.
H. Exacerbation of underlying cardiac disease
i.
The concurrence of acute coronary events and anaphylaxis has been noted,
although 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.
ii.
5.
Coronary artery vasoconstriction and decreased intravascular volume could
conceivably also precipitate ACS in 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
A. Anaphylaxis may have adverse effects on any part of 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).
B. In retrospective series of acute nonfatal anaphylaxis, respiratory signs and symptoms
were observed in 40 to 60% of subjects, with rhinitis, dyspnea/wheeze, and upper
airway angioedema in up to 20, 50, and 60%.
C. Similar observations have been made in cases of fatal anaphylaxis.
i.
One report examined 214 anaphylactic fatalities, among which mode of death could
be surmised in 196. Asphyxia was cause of death in approximately 50% (98 cases),
with involvement of 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.
ii.
Another postmortem analysis of 23 unselected cases of fatal anaphylaxis
6.
determined that 16 of 20 "immediate" deaths (deaths occurring within one hour of
symptom onset) were due to upper airway edema.
Anaerobic metabolism
A. Anaerobic metabolism complicates anaphylaxis. Blood flow to periphery is decreased, to
preserve perfusion of central organs, such as brain, heart, and kidneys.
B. Preliminary evidence suggests that anaerobic metabolism occurs within peripheral
tissues during anaphylaxis, similar to other forms of distributive shock, although
mechanism may be distinct. In septic shock, paradigm of distributive shock, HoTN results
from decreased SVR. Oxygen consumption by skeletal muscle is impaired despite
increased partial pressure of oxygen, leading to anaerobic metabolism. This impairment
C.
in cellular respiration has been attributed to unregulated inflammatory process called
"cytopathic hypoxia".
One study compared rats with ovalbumin-induced anaphylaxis to parallel group with
severe HoTN induced experimentally by nicardipine. The time course and magnitude of
HoTN were similar, and both groups experienced decreased perfusion of skeletal muscle.
There were metabolic differences.
i.
ii.
iii.
The anaphylactic animals showed greater activation of sympathetic nervous system,
with higher plasma catecholamine levels beginning at 20 minutes, which were
maintained throughout 60-minute protocol. Plasma epinephrine increased 15-fold
and norepinephrine levels increased 10-fold over baseline values in anaphylactic
animals.
Skeletal muscle blood flow was decreased in both nicardipine- and
anaphylaxis-induced hypotensive rats initially, which was followed by further
decrease in anaphylaxis group beginning at 20 minutes and persisting for duration
of observation period.
A higher gradient between plasma and interstitial epinephrine indicated more
impaired skeletal muscle blood flow in anaphylactic animals, possibly due to greater
skeletal muscle vasoconstriction.
iv.
The anaphylactic animals experienced more rapid increase in interstitial lactate
levels and 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.
D. 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 FINDING
1.
2.
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 1 hour in 39 cases. This is in keeping with 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 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.
SUMMARY
1. Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden
release of mast cell-, basophil- and macrophage-derived mediators into the circulation.
2. Anaphylaxis can be classified as "immunologic" or "nonimmunologic." Immunologic
anaphylaxis includes both IgE-mediated and IgG-mediated reactions (which have not been
identified in humans), as well as immune complex/complement-mediated mechanisms.
Non-immunologic anaphylaxis is caused by agents or events that induce sudden, massive
mast cell or basophil degranulation, without involvement of antibodies.
3.
4.
5.
6.
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 PAF. Cellular activation also stimulates the
production of lipid-derived mediators such as prostaglandins and cysteinyl leukotrienes.
In humans, predominant shock organs are heart, lung, and vasculature, and fatalities are
divided between circulatory collapse and respiratory arrest.
A. 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.
B. 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.
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.
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 lungs, and cerebral edema. Cutaneous findings, such as urticaria or
angioedema, are uncommon.