http://emedicine.medscape.

com/article/135065-overview#showall
Practice Essentials
Anaphylaxis is an acute, potentially fatal, multiorgan system reaction caused by the release of
chemical mediators from mast cells and basophils.[1, 2] The classic form involves prior sensitization to
an allergen with later reexposure, producing symptoms via an immunologic mechanism.

Signs and symptoms

Anaphylaxis most commonly affects the cutaneous, respiratory, cardiovascular, and gastrointestinal
systems. The skin or mucous membranes are almost always involved. A majority of adult patients
have some combination of urticaria, erythema, pruritus, or angioedema. However, for poorly
understood reasons, children may present more commonly with respiratory symptoms followed by
cutaneous symptoms.[3]
Initially, patients often describe a sense of impending doom, accompanied by pruritus and flushing.
Other symptoms can evolve rapidly, such as the following:

Dermatologic/ocular: Flushing, urticaria, angioedema, cutaneous and/or conjunctival injection

or pruritus, warmth, and swelling
Respiratory: Nasal congestion, coryza, rhinorrhea, sneezing, throat tightness, wheezing,
shortness of breath, cough, hoarseness, dyspnea
Cardiovascular: Dizziness, weakness, syncope, chest pain, palpitations
Gastrointestinal: Dysphagia, nausea, vomiting, diarrhea, bloating, cramps
Neurologic: Headache, dizziness, blurred vision, and seizure (very rare and often associated
with hypotension)
Other: Metallic taste, feeling of impending doom
See Clinical Presentation for more detail.

Diagnosis
Anaphylaxis is primarily a clinical diagnosis. The first priority in the physical examination should be to
assess the patients airway, breathing, circulation, and adequacy of mentation (eg, alertness,
orientation, coherence of thought).
Examination may reveal the following findings:

General appearance and vital signs: Vary according to the severity of the anaphylactic
episode and the organ system(s) affected; patients are commonly restless and anxious
Respiratory findings: Severe angioedema of the tongue and lips; tachypnea; stridor or severe
air hunger; loss of voice, hoarseness, and/or dysphonia; wheezing
Cardiovascular: Tachycardia, hypotension; cardiovascular collapse and shock can occur
immediately, without any other findings
Neurologic: Altered mentation; depressed level of consciousness or may be agitated and/or
combative
Dermatologic: Classic skin manifestation is urticaria (ie, hives) anywhere on the body;
angioedema (soft-tissue swelling); generalized (whole-body) erythema (or flushing) without urticaria
or angioedema
Gastrointestinal: Vomiting, diarrhea, and abdominal distention
Testing
Laboratory studies are not usually required and are rarely helpful. However, if the diagnosis is unclear,
especially with a recurrent syndrome, or if other diseases need to be excluded, the following
laboratory studies may be ordered in specific situations:

Plasma/urinary histamine and serum tryptase assessment: May help confirm diagnosis of
anaphylaxis[2]

Urinary 24-hour 5-hydroxyindoleacetic acid levels: If carcinoid syndrome is a consideration

Skin testing, in vitro immunoglobulin E (IgE) tests, or both may be used to determine the stimulus
causing the anaphylactic reaction. Such studies may include the following:

Testing for food allergy(ies)

Testing for medication allergy(ies)
Testing for causes of IgE-independent reactions
See Workup for more detail.

Management
Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Patient
management and disposition are dependent on the severity of the initial reaction and the treatment
response. Measures beyond basic life support are not necessary for patients with purely local
reactions. Patients with refractory or very severe anaphylaxis (with cardiovascular and/or severe
respiratory symptoms) should be admitted or treated and observed for a longer period in the
emergency department or an observation area.
Nonpharmacotherapy
Supportive care for patients with suspected anaphylaxis includes the following:

Airway management (eg, ventilator support with bag/valve/mask, endotracheal intubation)

High-flow oxygen
Cardiac monitoring and/or pulse oximetry
Intravenous access (large bore)
Fluid resuscitation with isotonic crystalloid solution
Supine position (or position of comfort if dyspneic or vomiting) with legs elevated
Pharmacotherapy
The primary drug treatments for acute anaphylactic reactions are epinephrine and H1 antihistamines.
Medications used in patients with anaphylaxis include the following:

Adrenergic agonists (eg, epinephrine)

Antihistamines (eg, diphenhydramine, hydroxyzine)
H2 receptor antagonists (eg, cimetidine, ranitidine, famotidine)
Bronchodilators (eg, albuterol)
Corticosteroids (eg, methylprednisolone, prednisone)
Positive inotropic agents (eg, glucagon)
Vasopressors (eg, dopamine)
Surgical option
In extreme circumstances, cricothyrotomy or catheter jet ventilation may be lifesaving when
orotracheal intubation or bag/valve/mask ventilation is not effective. Cricothyrotomy is easier to
perform than emergency tracheostomy.
See Treatment and Medication for more detail.

Background
Portier and Richet first coined the term anaphylaxis in 1902 when a second vaccinating dose of sea
anemone toxin caused a dogs death. The term is derived from the Greek words ana - (up, back,
again) and phylaxis (guarding, protection, immunity).
Anaphylaxis is an acute, potentially fatal, multiorgan system reaction caused by the release of
chemical mediators from mast cells and basophils.[1, 2] The classic form involves prior sensitization to
an allergen with later re-exposure, producing symptoms via an immunologic mechanism. (See
Pathophysiology and Etiology.)
The most common organ systems involved include the cutaneous, respiratory, cardiovascular, and
gastrointestinal systems. The full-blown syndrome includes urticaria (hives) and/or angioedema with
hypotension and bronchospasm. (See Clinical Presentation.)
Anaphylaxis has no universally accepted clinical definition. It is a clinical diagnosis based on typical
systemic manifestations, often with a history of acute exposure to a causative agent. (See Diagnosis.)

Because anaphylaxis is primarily a clinical diagnosis, laboratory studies are not usually required and
are rarely helpful. However, if the diagnosis is unclear, especially with a recurrent syndrome, or if
other diseases need to be excluded, some limited laboratory studies are indicated. Skin testing and in
vitro IgE tests may be helpful. (See Workup.)
Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Disposition
of patients with anaphylaxis depends on the severity of the initial reaction and the response to
treatment. Note that guidelines for the emergency medical treatment of anaphylaxis vary
internationally.[4] (See Treatment and Management.)
Go to Pediatric Anaphylaxis and Pediatric Exercise-Induced Anaphylaxis for complete information on
these topics.

Pathophysiology
The traditional nomenclature for anaphylaxis reserves the term anaphylactic for reactions mediated by
immunoglobulin E (IgE) and the term anaphylactoid for IgE-independent events, which are clinically
indistinguishable. The World Allergy Organization has recommended replacing this terminology with
immunologic (IgE-mediated and nonIgE-mediated [eg, IgG and immune complex complement
mediated]) and nonimmunologic anaphylaxis (events resulting in sudden mast cell and basophil
degranulation in the absence of immunoglobulins).[5]
The physiologic responses to the release of anaphylaxis mediators include smooth muscle spasm in
the respiratory and gastrointestinal (GI) tracts, vasodilation, increased vascular permeability, and
stimulation of sensory nerve endings. Increased mucous secretion and increased bronchial smooth
muscle tone, as well as airway edema, contribute to the respiratory symptoms observed in
anaphylaxis.
Cardiovascular effects result from decreased vascular tone and capillary leakage. Hypotension,
cardiac arrhythmias, syncope, and shock can result from intravascular volume loss, vasodilation, and
myocardial dysfunction. Increased vascular permeability can produce a shift of 35% of vascular
volume to the extravascular space within 10 minutes.
These physiologic events lead to some or all of the classic symptoms of anaphylaxis:
flushing; urticaria/angioedema; pruritus; bronchospasm; laryngeal edema; abdominal cramping with
nausea, vomiting, and diarrhea; and feeling of impending doom. Concomitant signs and symptoms
can include rhinorrhea, dysphonia, metallic taste, uterine cramps, light-headedness, and headache.
Additional mediators activate other pathways of inflammation: the neutral proteases, tryptase and
chymase; proteoglycans such as heparin and chondroitin sulfate; and chemokines and cytokines.
These mediators can activate the kallikrein-kinin contact system, the complement cascade, and
coagulation pathways. The development and severity of anaphylaxis also depend on the
responsiveness of cells targeted by these mediators.
Interleukin (IL)4 and IL-13 are cytokines important in the initial generation of antibody and
inflammatory cell responses to anaphylaxis. No comparable studies have been conducted in humans,
but anaphylactic effects in mice depend on IL-4R-dependent IL-4/IL-13 activation of the transcription
factor, STAT-6 (signal transducer and activator of transcription 6). [6] Eosinophils may be inflammatory
(release cytotoxic granule-associated proteins, for example) or anti-inflammatory (metabolize
vasoactive mediators, for example).
Additional mediators include newly generated lipid-derived mediators such as prostaglandin D2,
leukotriene B4, and platelet-activating factor (PAF), as well as the cysteinyl leukotrienes, such as
LTC4, LTD4, and LTE4. These mediators further contribute to the proinflammatory cascade seen in
anaphylaxis.
Under rigid experimental conditions, histamine infusion alone is sufficient to produce most of the
symptoms of anaphylaxis. Histamine mediates its effects through activation of histamine 1 (H 1) and
histamine 2 (H2) receptors.
Vasodilation, hypotension, and flushing are mediated by both H 1 receptors and H1receptors.
H1 receptors alone mediate coronary artery vasoconstriction,tachycardia, vascular permeability,
pruritus, bronchospasm, and rhinorrhea. H2receptors increase atrial and ventricular contractility, atrial

chronotropy, and coronary artery vasodilation. H3 receptors in experimental models of canine

anaphylaxis appear to influence cardiovascular responses to norepinephrine. The importance of
H3 receptors in humans is unknown.

Processes inducing cardiovascular changes

Anaphylaxis has been associated clinically with myocardial ischemia, atrial and ventricular
arrhythmias, conduction defects, and T-wave abnormalities. Whether such changes are related to
direct mediator effects on the myocardium, to exacerbation of preexisting myocardial insufficiency by
the adverse hemodynamic effects of anaphylaxis, to epinephrine released endogenously by the
adrenals in response to stress, or to therapeutically injected epinephrine is unclear.
Since mast cells accumulate at sites of coronary atherosclerotic plaques, and immunoglobulins bound
to mast cells can trigger mast cell degranulation, some investigators have suggested that anaphylaxis
may promote plaque rupture, thus risking myocardial ischemia. Stimulation of the H 1 histamine
receptor may also produce coronary artery vasospasm. PAF also delays atrioventricular conduction,
decreases coronary artery blood flow, and has negative inotropic effects.
Calcitonin gene-related peptide (CGRP), a sensory neurotransmitter that is widely distributed in
cardiovascular tissues, may help to counteract coronary artery vasoconstriction during anaphylaxis.
CGRP relaxes vascular smooth muscle and has cardioprotective effects in animal models of
anaphylaxis.
Two distinct physiologic responses occur in mammals experiencing hypovolemia. [7] The initial
response to hypovolemia is a baroreceptor-mediated increase in overall cardiac sympathetic drive
and a concomitant withdrawal of resting vagal drive, which together produce peripheral
vasoconstriction and tachycardia.
When effective blood volume decreases by 20-30%, a second phase follows, which is characterized
by withdrawal of vasoconstrictor drive, relative or absolute bradycardia, increased vasopressin, further
catecholamine release as the adrenals become more active, and hypotension. Hypotension in this
hypovolemic setting is independent of the bradycardia, since it persists when the bradycardia
reverses with atropine administration.
Conduction defects and sympatholytic medications may also produce bradycardia. Excessive venous
pooling with decreased venous return (also seen in vasodepressor reactions) may activate tensionsensitive sensory receptors in the inferoposterior portions of the left ventricle, thus resulting in a
cardio-inhibitory (Bezold-Jarisch) reflex that stimulates the vagus nerve and causes bradycardia.
The implications of relative or absolute bradycardia in human anaphylaxis andhypovolemic
shock have not been studied.
However, one retrospective review of approximately 11,000 trauma patients found that mortality was
lower with the 29 percent of hypotensive patients who were bradycardic when they were compared to
the group of hypotensive individuals who were tachycardic, after adjustment for other mortality factors.
[8]
Thus, bradycardia may have a specific compensatory role in these settings.

Etiology
IgE-mediated anaphylaxis is the classic form of anaphylaxis, whereby a sensitizing antigen elicits an
IgE antibody response in a susceptible individual. The antigen-specific IgE antibodies then bind to
mast cells and basophils. Subsequent exposure to the sensitizing antigen causes cross-linking of cellbound IgE, resulting in mast cell (and/or basophil) degranulation.
Other types of immunologic anaphylaxis do not involve IgE. For example, anaphylaxis resulting from
administration of blood products, including intravenous immunoglobulin, or animal antiserum is due, at
least in part, to complement activation. Immune complexes formed in vivo or in vitro can activate the
complement cascade. Certain byproducts of the cascadeplasma-activated complement 3 (C3a),
plasma-activated complement 4 (C4a), and plasma-activated complement 5 (C5a)are called
anaphylatoxins and can cause mast cell/basophil degranulation.
When mast cells and basophils degranulate, whether by IgE- or nonIgE-mediated mechanisms,
preformed histamine and newly generated leukotrienes, prostaglandins, and platelet-activating factor

(PAF) are released. In the classic form, mediator release occurs when the antigen (allergen) binds to
antigen-specific IgE attached to previously sensitized basophils and mast cells. The mediators are
released almost immediately when the antigen binds.
Certain agents are thought to cause direct nonimmunologic release of mediators from mast cells, a
process not mediated by IgE. These include opioids, dextrans, protamine, and vancomycin.
Mechanisms underlying these reactions are poorly understood but may involve specific receptors (eg,
opioids) or nonreceptor-mediated mast cell activation (eg, hyperosmolarity).

Inciting agents
The most common inciting agents in anaphylaxis are foods, Hymenoptera stings, and intravenous (IV)
contrast materials. Anaphylaxis may also be idiopathic.

Immunologic IgE-mediated reactions

Typical examples of IgE-mediated anaphylaxis include the reactions to many foods, drugs, and insect
stings.
Hypersensitivity to foods is a problem encountered throughout the industrialized world. [9] In the United
States, an estimated 4 million Americans have well-substantiated food allergies. A study from Australia
showed that more than 10% of 12-month-old children had challenge-proven IgE-mediated food
allergies.[10] In Montreal, 1.5% of early elementary school students were found to be sensitized to
peanuts. Reactions to foods are thought to be the most common prehospital (outpatient) cause of
anaphylaxis and are estimated to cause 125 deaths per year in the United States.
Certain foods are more likely than others to elicit an IgE antibody response and lead to anaphylaxis.
Foods likely to elicit an IgE antibody response in all age groups include peanuts, tree nuts, fish, and
shellfish. Those likely to elicit an IgE antibody response in children also include cows milk, eggs,
wheat, and soy.
An analysis of 32 fatalities thought to be due to food-induced anaphylaxis revealed that peanuts likely
were the responsible food in 62% of the cases. In placebo-controlled food challenges, peanutsensitive patients can react to as little as 100 g of peanut protein. [11] The Rochester Epidemiology
Project, in agreement with earlier studies, found that food ingestion was the leading cause of
anaphylaxis, accounting for as many as one third of all cases. [12]
In the past, a history of IgE-mediated egg allergy has been a contraindication to receiving the annual
influenza vaccination. Recently, egg-allergic individuals have been safely receiving the influenza
vaccination, but routinely with a graded multidose protocol or based on skin prick testing to the
vaccine itself. Given a dearth of recent evidence that egg-allergic individuals can safely receive the
influenza vaccine with no increased risk of systemic reaction as compared to the general population,
the most recent guidelines now recommend that all egg-allergic individuals should be vaccinated with
a single dose of influenza vaccine. Furthermore, skin testing has no role because no evidence
suggests this reliably identifies individuals at risk of a systemic reaction. [13, 14]
Scombroid fish poisoning can occasionally mimic food-induced anaphylaxis. Bacteria in spoiled fish
produce enzymes capable of decarboxylating histidine to produce biogenic amines, including
histamine and cis-urocanic acid, which is also capable of mast cell degranulation.
Most cases of IgE-mediated drug anaphylaxis in the United States are due to penicillin and other
beta-lactam antibiotics. Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or
cephalosporin antibiotic causes anaphylaxis.
Penicillin is metabolized to a major determinant, benzylpenicilloyl, and multiple minor determinants.
Penicillin and its metabolites are haptens, small molecules that only elicit an immune response when
conjugated with carrier proteins. Other beta-lactam antibiotics may cross-react with penicillins or may
have unique structures that also act as haptens.
Reactions to cephalosporins may occur in penicillin-allergic patients. In these patients, older agents
such as cephalothin, cephalexin, cefadroxil, and cephazolin are more likely to precipitate an allergic
reaction than newer agents such as cefprozil, cefuroxime, ceftazidime, or ceftriaxone. This increased

reactivity with the older agents is due to greater antigenic similarity of the side chain not present with
the newer second- and third-generation agents.
One report suggested that the actual incidence of anaphylaxis to cephalosporins in penicillinanaphylactic patients is much lower than the 10% frequently quotedperhaps 1%, with most
reactions considered mild.[15] A retrospective study evaluated 606 hospitalized patients with a history of
penicillin allergy who were given a cephalosporin. Only one patient (0.17%) had a reaction, and it was
minor.[16]
Another paper indicated that patients with a history of allergy to penicillin seem to have a higher risk
(by a factor of about 3) of subsequent reaction to any drug and that the risk of an allergic reaction to
cephalosporins in patients with a history of penicillin allergy may be up to 8 times as high as the risk in
those with no history of penicillin allergy (ie, at least part of the observed cross-reactivity may
represent a general state of immune hyperresponsiveness, rather than true cross-reactivity). [17]
Pichichero reviewed the complicated literature and offered specific guidance for the use of
cephalosporins in patients who have a history of IgE-mediated reactions to penicillin. [18]
Patients with a history of positive skin tests for penicillin allergy are at high risk of subsequent
reactions to penicillins. However, approximately 85% of patients with a history of penicillin allergy
have negative skin tests and a low risk of reactions. Patients with less well-defined reactions to
penicillin have a very low risk (1-2%) of developing anaphylaxis to cephalosporins. The rate of skintest reactivity to imipenem in patients with a known penicillin allergy is almost 50%. In contrast, no
known in vitro or clinical cross-reactivity exists between penicillins and aztreonam.
When either a penicillin or a cephalosporin is the drug of choice for a patient with a life-threatening
emergency, a number of options exist. When the history is indefinite, the drug may be administered
under close observation; however, when possible, obtain the patients informed consent. Immediate
treatment measures for anaphylaxis should be available. Alternatively, when the history is more
convincing, an alternative agent should be chosen if it provides similar efficacy or one must pursue a
desensitization protocol.
Many other drugs have been implicated in IgE-mediated anaphylaxis, albeit less frequently. In the
surgical setting, anaphylactic reactions are most often due to muscle relaxants but can also be due to
hypnotics, antibiotics, opioids, colloids, and other agents. The prevalence of latex allergy was higher
during the 1980s (due to the HIV and hepatitis B and C epidemics and the institution of universal
precautions), but the incidence has decreased significantly since the widespread use of latex-free
materials. If latex is responsible for anaphylaxis in the perioperative setting, reactions tend to occur
during maintenance anesthesia, whereas other agents tend to cause reactions during the induction of
anesthesia. Volatile anesthetic agents can cause immune-mediated hepatic toxicity but have not been
implicated in anaphylactic reactions.[19]
Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. From 0.5%-3% of the
US population experiences a systemic reaction after being stung. [20] In the United States, Hymenoptera
envenomations result in fewer than 100 reported deaths per year. Local reaction and urticaria without
other manifestations of anaphylaxis are much more common than full-blown anaphylaxis after
Hymenoptera stings. Adults with generalized urticaria are at increased risk for anaphylaxis with future
stings, but a local reaction, regardless of severity, is not a risk factor for anaphylaxis.
Caution patients treated and released from the emergency department (ED) after an episode of
anaphylaxis or generalized urticaria from Hymenoptera envenomation to avoid future exposure when
possible. Consider referral to an allergist for desensitization, particularly when further exposure is
likely. Additionally, consider prescribing a treatment kit with an epinephrine autoinjector and oral
antihistamine. Both are effective measures in preventing or ameliorating future reactions.
Allergen-specific subcutaneous immunotherapy (SCIT) can cause IgE-mediated anaphylaxis. Allergy
injections are a common trigger for anaphylaxis. This is not unexpected, because the treatment is
based on injecting an allergen to which the patient is sensitive. However, life-threatening reactions are
rare. Three studies suggest that fatalities from SCIT occur at a rate of approximately 1 death per
2,500,000 injections.[21, 22, 23] A total of 104 fatalities due to SCIT and skin testing were reported from
1945-2001.

Risk factors for severe anaphylaxis due to immunotherapy include poorly controlled asthma,
concurrent use of beta-blockers, high allergen dose, errors in administration, and lack of a sufficient
observation period following the injection.
Near-fatal reactions (NFRs) to subcutaneous immunotherapy also have been examined
retrospectively. Of 646 allergist-immunologists who responded to a survey on reactions, 273 reported
NFRs. The investigators defined an NFR as respiratory compromise, hypotension, or both, requiring
emergency epinephrine. Hypotension was reported in 80% and respiratory failure occurred in 10% of
NFRs, exclusively in subjects with asthma. Epinephrine was delayed or not administered in 6% of
these cases.

Immunologic reactions to aspirin, NSAIDs, and ACE inhibitors

Reactions to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) in the past have been
classified as IgE-independent because they were thought to occur from aberrant metabolism of
arachidonic acid.
Isolated cutaneous reactions to aspirin/NSAIDs and bronchospasm in aspirin-sensitive asthmatics
(often in association with nasal polyposis) are indeed mediated through IgE-independent
mechanisms. Blockade of cyclooxygenase by these drugs causes the prostanoid pathway to shut
down, resulting in an overproduction of leukotrienes via the 5-lipoxygenase pathway. These patients
have marked cross-reactivity between aspirin and most NSAIDs.
Anaphylaxis after taking these drugs, however, apparently occurs via a different mechanism that is
more consistent with IgE-mediated anaphylaxis. With true anaphylaxis, the different cyclooxygenase
inhibitors do not appear to cross-react. Anaphylaxis occurs only after 2 or more exposures to the
implicated drug, suggesting a need for prior sensitization. Finally, patients with true anaphylaxis do not
usually have underlying asthma, nasal polyposis, or urticaria.
In one study of nearly 52,000 people taking NSAIDs, 35 developed anaphylactic shock.
Angiotensin-converting enzyme (ACE) inhibitors, widely used in the treatment of hypertension, are
associated with angioedema in 0.5-1.0% of patients who take them. Systemic anaphylaxis is rarely
associated with these agents.

Immunologic IgE-independent reactions

Anaphylaxis may result from administration of blood products, including IV immunoglobulin, or animal
antiserum, at least partly as a consequence of activation of the complement cascade. Certain
byproducts of the cascade are capable of causing mast cell/basophil degranulation. (See
Pathophysiology.)
Exercise-induced anaphylaxis is a rare syndrome that can take 1 of 2 forms. The first form is food
dependent, requiring exercise and the recent ingestion of particular foods (eg, wheat, celery) or
medications (eg, NSAIDs) to cause an episode of anaphylaxis. In these patients, exercise alone does
not produce an episode, and, similarly, ingesting the culprit food or medication alone does not cause
an episode.
The second form is characterized by intermittent episodes of anaphylaxis during exercise,
independent of any food ingestion. Anaphylaxis does not necessarily occur during every episode of
physical exertion.
Anaphylaxis can be a manifestation of systemic mastocytosis, a disease characterized by excessive
mast cell burden in multiple organs. Such patients appear to be at increased risk for food and venom
reactions. Alcohol, vancomycin, opioids, radiocontrast media, and other biologic agents that can
directly degranulate mast cells are generally discouraged in these patients.

Nonimmunologic reactions
Certain agents, including opioids, dextrans, protamine, and vancomycin, are thought to cause direct,
nonimmunologic release of mediators from mast cells. Evidence also exists that dextrans and
protamine can activate several inflammatory pathways, including complement, coagulation, and
vasoactive (kallikrein-kinin) systems.

Intravenously administered radiocontrast media cause an anaphylactoid reaction that is clinically

similar to true anaphylaxis and is treated in the same way. The reaction is not related to prior
exposure. Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a
reaction. Reactions to radiocontrast media usually are mild (most commonly urticarial), with only rare
fatalities reported. Risk of a fatal reaction has been estimated at 0.9 cases per 100,000 exposures.
Pretreatment with antihistamines or corticosteroids and use of low-molecular-weight (LMW) contrast
agents lead to lower rates of anaphylactoid reactions to IV radiocontrast media (approximately 0.5%).
Consider these measures for patients who have prior history of reaction, since rate of recurrence is
estimated at 17-60%. Some institutions use only LMW agents. Personnel, medications, and
equipment needed for treatment of allergic reactions always should be available when these agents
are administered. Obtain consent before administration.
Patients who are atopic and/or asthmatic also are at increased risk of reaction. In addition, allergic
reaction is more difficult to treat in those taking beta-blockers.
Shellfish or iodine allergy is not a contraindication to use of IV contrast and does not mandate a
pretreatment regimen. As with any allergic patient, give consideration to use of LMW contrast agents.
In fact, the term iodine allergy is a misnomer. Iodine is an essential trace element present throughout
the body. No one is allergic to iodine. Patients who report iodine allergy usually have had either a prior
contrast reaction, a shellfish allergy, or a contact reaction to povidone-iodine (Betadine).
Mucosal exposure (eg, GI, genitourinary [GU]) to radiocontrast agents has not been reported to cause
anaphylaxis; therefore, a history of prior reaction is not a contraindication to GI or GU use of these
agents.

Idiopathic anaphylaxis
Idiopathic anaphylaxis is a syndrome of recurrent anaphylaxis for which no consistent triggers can be
determined despite an exhaustive search.[24] This recurrent syndrome should be distinguished from a
single episode of anaphylaxis for which the etiology may be unclear.
Idiopathic anaphylaxis can be categorized as infrequent (< 6 episodes per year) or frequent (6
episodes per year or 2 or more episodes within the last 2 months). [24]One approach is expectant
treatment with epinephrine, antihistamines, and prednisone for individuals who have infrequent
episodes and a prolonged taper of prednisone for those with frequent episodes.
Most of these patients are female, and atopy appears to be an underlying risk factor. Two thirds of
patients have 5 or fewer episodes per year, while one third have more than 5 episodes per year.
A subpopulation of women develops anaphylaxis in relationship to their menstrual cycle; this
phenomenon is known as catamenial anaphylaxis.[25, 26] In severe cases, these patients require
manipulation of their hormonal levels by medical pituitary suppression and even oophorectomy. Most
of these patients react to shifts in progesterone levels, and the diagnosis can be confirmed by
provoking an anaphylactic event through administration of low doses of progesterone.

Biphasic and persistent anaphylaxis

The reported incidence of biphasic (recurrent) anaphylaxis varies from less than 1% to a maximum of
23%. Additionally, the reported time of onset of the late phase may vary from 1 to 72 hours (most
occur within 8-10 h). Potential risk factors include severity of the initial phase, delayed or suboptimal
doses of epinephrine during initial treatment, laryngeal edema or hypotension during the initial phase,
delayed onset of symptoms after exposure to the culprit antigen (often a food or insect sting), or prior
history of biphasic anaphylaxis.[27]
Persistent anaphylaxis, anaphylaxis that may last from 5-32 hours, occurred in 7 of 25 subjects (28%)
in the Stark and Sullivan report, with 2 fatalities. [28] Of 13 subjects analyzed in a report on fatal or nearfatal anaphylaxis to foods, 3 (23%) similarly experienced persistent anaphylaxis. [29] Retrospective data
from other investigators, however, suggest that persistent anaphylaxis is uncommon.
Neither biphasic nor persistent anaphylaxis can be predicted from the severity of the initial phase of
an anaphylactic reaction. Since life-threatening manifestations of anaphylaxis may recur, it may be

necessary to monitor patients 24 hours or more after apparent recovery from the initial phase. [27] When
prescribing epinephrine, all patients should be instructed to have 2 injectors on hand at all times.

Risk factors
As mentioned above, atopy is a risk factor for anaphylaxis. In the Rochester Epidemiology Project,
53% of the patients with anaphylaxis had a history of atopic diseases (eg, allergic
rhinitis, asthma, atopic dermatitis).[12] The Memphis study detected atopy in 37% of the patients.
[30]
Other studies have shown atopy to be a risk factor for anaphylaxis from foods, exercise-induced
anaphylaxis, idiopathic anaphylaxis, radiocontrast reactions, and latex reactions. Underlying atopy
does not appear to be a risk factor for reactions to penicillin or insect stings.
Route and timing of administration affect anaphylactic potential. The oral route of administration is
less likely to cause a reaction, and such reactions are usually less severe, although fatal reactions
occur following ingestions of foods by someone who is allergic. The longer the interval between
exposures, the less likely that an IgE-mediated reaction will recur. This is thought to be due to
catabolism and decreased synthesis of allergen-specific IgE over time. This does not appear to be the
case for IgE-independent reactions.
A retrospective emergency department study of 302 patients presenting with anaphylaxis, 87 (29%) of
whom were taking at least 1 antihypertensive medication, found that antihypertensive
pharmacotherapy increased the risk of organ system involvement and hospitalization. [31, 32] There was a
more than 2-fold increased risk of involvement in 3 or more organ systems when ACE inhibitors, beta
blockers, diuretics, or any antihypertensive medications were used. Most of these agents were also
associated with an increased risk for inpatient admission. [31, 32]

Epidemiology
The true incidence of anaphylaxis is unknown. Some clinicians reserve the term for the full-blown
syndrome, whereas others use it to describe milder cases. The frequency of anaphylaxis is
increasing, and this has been attributed to the increased number of potential allergens to which
people are exposed.
A review concluded that the lifetime prevalence of anaphylaxis is 1-2% of the population as a whole. [33]

United States statistics

Neugut et al estimated that 1-15% of the US population is at risk of experiencing an anaphylactic or
anaphylactoid reaction.[34] They estimated that the rate of actual anaphylaxis to food was 0.0004%,
0.7-10% for penicillin, 0.22-1% for radiocontrast media (RCM), and 0.5-5% after insect stings.
A population-based study from Rochester, Minnesota, found an average annual incidence of
anaphylaxis of 58.9 cases per 100,000 person-years, which had increased from 46.9 cases per
100,000 in 1990.[12] Of identified causes, ingestion of a specific food was responsible for 33%, insect
stings for 18.5%, and medications for 13.7%. Twenty-five percent of cases were considered
idiopathic. Episodes of anaphylaxis occurred more frequently from July through September, a
difference that is attributable to insect stings.
In a study of patients referred to a university-affiliated allergy-immunology practice in Memphis,
Tennessee, food was the cause of anaphylaxis in 34% of patients, medications in 20%, and exercise
in 7% (anaphylaxis due to insect stings or SCIT was excluded from the study). [30] The cause could not
be determined in 59% (ie, they were diagnosed with idiopathic anaphylaxis). A separate study
estimated that there are 20,000-47,000 cases of idiopathic anaphylaxis in the United States per year
(approximately 8-19 episodes per 100,000 person-years).
Reactions to insects and other venomous plants and animals are more prevalent in tropical areas
because of the greater biodiversity in these areas. Exposure and therefore reactions to medications
are more common in industrialized areas.

International statistics
The incidence of anaphylaxis does not appear to vary significantly between countries. Two European
studies detected a lower average annual incidence than found in the Rochester study (3.2 cases of
anaphylactic shock per 100,000 person-years in Denmark; 9.8 cases of out-of-hospital anaphylaxis

per 100,000 person-years in Munich, Germany[35] ). Rates in Europe range from 1-3 cases per 10,000.
[36, 35]
However, the incidence of anaphylaxis may be increasing.[37]
Simons and colleagues examined the rate of epinephrine prescriptions for a population of 1.15 million
patients in Manitoba, Canada, and found that 0.95% of this population was prescribed epinephrine, an
indicator of perceived risk that future anaphylaxis may occur.[38] Moneret-Vautrin et al reviewed the
published literature and stated that severe anaphylaxis affects at least 1-3 persons per 10,000
population.[39]

Age distribution for anaphylaxis

Anaphylaxis can occur at any age. In the Rochester study, the mean age was 29.3 years (range, 0.8
to 78.2 years). Age-specific rates were highest for ages 0-19 years (70 cases per 100,000 personyears).[12] The Memphis study had an age range of 1-79 years, with a mean of 37 years. [30] Simons and
colleagues noted the highest frequency of epinephrine prescriptions for boys aged 12-17 months
(5.3%).[38] The rate was 1.4% for those younger than 17 years, 0.9% for those aged 17-64 years, and
0.3% for those aged 65 years or older.
Severe food allergy is more common in children than in adults. However, the frequency in adults may
be increasing, since severe food allergy often persists into adulthood. Anaphylaxis to radiocontrast
media, insect stings, and anesthetics has been reported to be more common in adults than in
children. Whether this is a function of exposure frequency or increased sensitivity is unclear.
Go to Pediatric Anaphylaxis and Pediatric Exercise-Induced Anaphylaxis for more complete
information on these topics.

Sex distribution for anaphylaxis

The Rochester and Memphis studies both showed a slight female predominance. [12, 30] Earlier studies
have suggested that episodes of anaphylaxis to IV muscle relaxants, aspirin, and latex are more
common in women, whereas insect sting anaphylaxis is more common in men. These sex
discrepancies are likely a function of exposure frequency.

Prognosis
Fatal anaphylaxis is infrequent but not rare; milder forms occur much more frequently. Up to 500-1000
fatal cases of anaphylaxis per year are estimated to occur in the United States. Estimated mortality
rates range from 0.65-2% of patients with anaphylaxis. [40, 41]
Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside
of the hospital and are estimated to cause 125 deaths per year in the United States. Severe reactions
to penicillin occur with a frequency of 1-5 cases per 10,000 patient courses, with fatalities in 1 case
per 50,000-100,000 courses. Fewer than 100 fatal reactions to Hymenoptera stings are reported each
year in the United States, but this is considered to be an underestimate.
Anaphylaxis to conventional radiocontrast media (RCM) was estimated to have caused up to 900
fatalities in 1975, or 0.009% of patients receiving RCM. [42] In one series, the reported risk of adverse
reactions (mild or severe) in patients receiving lower osmolar RCM agents is 3.13% compared with
12.66% for patients receiving conventional RCM. [43] The study also reported premedication did not
lower the risk of nonionic reactions further. The rate of fatal anaphylaxis is also reduced significantly
by lower-osmolar RCM, approximately 1 in 168,000 administrations. [44]
In the United Kingdom, half of fatal anaphylaxis episodes are of iatrogenic origin (eg, anesthesia,
antibiotics, radiocontrast media), while foods and insect stings each account for a quarter of the fatal
episodes.
The most common causes of death are cardiovascular collapse and respiratory compromise. One
report examined 214 anaphylactic fatalities for which the mode of death could be surmised in 196, 98
of which were due to asphyxia (49 lower airways [bronchospasm], 26 both upper and lower airways,
and 23 upper airways [angioedema]). The fatalities from acute bronchospasm occurred almost
exclusively in those with preexisting asthma.

Another analysis of 23 unselected cases of fatal anaphylaxis determined that 16 of 20 immediate

deaths (death occurring within one hour of symptom onset) and 16 of the 23 cases that underwent
autopsy were due to upper airway edema.
Death can occur rapidly. An analysis of anaphylaxis fatalities occurring in the United Kingdom from
1992 to 2001 revealed the interval between initial onset of food anaphylaxis symptoms and fatal
cardiopulmonary arrest averaged 25-35 minutes, which was longer than for drugs (mean, 10-20
minutes pre-hospital; 5 minutes in-hospital) or for insect stings (10-15 minutes).
Asthma is a risk factor for fatal anaphylaxis. Delayed administration of epinephrine is also a risk factor
for fatal outcomes.[9]
Posture also influences anaphylaxis outcomes. In a retrospective review of prehospital anaphylactic
fatalities in the United Kingdom, the postural history was known for 10 individuals. [45] Four of the 10
fatalities were associated with the assumption of an upright or sitting posture during anaphylaxis.
Postmortem findings were consistent with pulseless electrical activity and an empty heart attributed
to reduced venous return from vasodilation and redistribution of intravascular volume from the central
to the peripheral compartment.
Patients may experience multiple anaphylactic episodes. The Rochester study detected a total of 154
anaphylactic episodes involving 133 people in a 5-year period. [12] Most patients (116) had only 1
episode in those 5 years. Thirteen people had 2 episodes, and 4 people had 3 episodes.
In contrast, in the Memphis study, 48% of patients had 3 or more anaphylactic episodes. [30] Of the 112
patients who responded to survey, however, 38 patients (34%) reported a recurrence of symptoms
and the remaining 74 patients (66%) reported remission of symptoms. Overall, 85% of patients either
were in remission or reported diminished symptom severity in a subsequent episode or episodes. The
Memphis study evaluated a referral population and also deliberately excluded patients with
anaphylaxis due to insect stings or SCIT.[30]

Patient Education
Avoidance education is crucial, especially in younger patients with food anaphylaxis. Important issues
include cross-contamination and inadequate labeling of foods. The Food Allergy & Anaphylaxis
Network is an excellent resource for families, as well as physicians. A study of children with food
allergy visiting a subspecialty allergy clinic found 59% had an epinephrine autoinjector with them,
although 71% of parents reported keeping the autoinjector available at all times. The only variable
positively associated with having an autoinjector available was epinephrine autoinjector instruction. [46]
Patients with sensitivity to multiple antibiotics should be provided a list of alternative antibiotics. They
can present this list to their primary care physicians when antibiotic therapy is required.
Avoidance education is also important for persons who are hypersensitive to insect stings. Caution
patients to avoid use of perfumes or hygiene products that include perfumes, particularly floral scents,
as these attract flying Hymenoptera. Brightly colored clothing attracts bees and other pollinating
insects. Avoid locations of known hives or nests, and avoid using equipment that disturbs the hive.
Persons who are sensitive to Hymenoptera and who must be outdoors should carry an epinephrine
autoinjector (see below). Inform patients who react to Hymenoptera venom of the availability of
desensitization therapy. On discharge, warn patients of the possibility of recurrent symptoms, and
instruct them to seek further care if this occurs.
In 2011, the Joint Task Force on Practice Parameters, representing the American Academy of Allergy,
Asthma & Immunology, the American College of Allergy, Asthma & Immunology, and the Joint Council
of Allergy, Asthma and Immunology, issued an updated practice parameter on insect sting
hypersensitivity. The practice parameter states that patients with a possible systemic reaction should
be referred to an allergist or immunologist, where they should be educated about their risk of another
reaction, their options for preventative treatment, and the benefits of wearing a medical identification
necklace or bracelet. Avoiding insect stings and dealing with an emergency should be discussed.
[47]
The 2010 Joint Task Force updated anaphylaxis parameter and the 2011 World Allergy Organization
guidelines are generally in accordance with these recommendations. [48, 49]

For patient education information, see eMedicineHealths Allergies Center. Also, see
eMedicineHealth's patient education articles Severe Allergic Reaction (Anaphylactic Shock), Food
Allergy, and Drug Allergy.

Epinephrine autoinjector instruction

Good evidence suggests that physicians underprescribe epinephrine and that patients (or their
parents) fail to use epinephrine as quickly as possible.[50, 51, 52]Accordingly, at discharge, all patients
should be provided an epinephrine autoinjector and should receive proper instruction on how to selfadminister it in case of a subsequent episode.[51]
Patients should be instructed to keep an epinephrine autoinjector with them at all times; they should
also carry diphenhydramine and take this in conjunction with use of the epinephrine autoinjector. They
should be instructed to keep the device from extremes of temperature. Epinephrine is sensitive to
both light and temperature and therefore should not be stored, for example, in a refrigerator or in a
motor vehicle glove compartment. They also should be instructed to replace any epinephrine
autoinjector before its expiration date.
Patients should be instructed to have ready and prompt access to emergency medical services for
transportation to the closest ED for treatment. They should also be instructed to obtain emergency
medical care immediately after injecting the epinephrine because the effect is short lived (< 15 min)
and biphasic reactions can occur.
An EpiPen (Dey Pharma, Napa, Calif) autoinjector for adults is available with a single 0.3-mg (1:1,000
v/v) dose. Similarly, an EpiPen Jr., with a 0.15-mg (1:2,000 v/v) dose, is available for children who
weigh less than 30 kg. The Adrenaclick (Schionogi USA, Inc., Florham Park, NJ) is also available as a
single-dose autoinjector of either 0.15 mg or 0.3 mg. The Twinject (Schionogi USA, Inc., Florham
Park, NJ) is a pen-sized device containing 2 doses of epinephrine available either as a 0.15- or 0.3mg formulation. In both cases, the first of the 2 doses is delivered by autoinjector, and the second is
injected manually.
Placebo syringes are recommended as educational tools. Live demonstrations of injections might be
considered on a case-by-case basis when the patient or parent expresses a fear of injection. [51]

http://emedicine.medscape.com/article/135065-clinical#showall
History
Anaphylaxis is an acute multiorgan system reaction. The most common organ systems involved
include the cutaneous, respiratory, cardiovascular, and gastrointestinal (GI) systems. In most studies,
the frequency of signs and symptoms of anaphylaxis is grouped by organ system.
Anaphylactic reactions almost always involve the skin or mucous membranes. Greater than 90% of
patients have some combination of urticaria, erythema, pruritus, or angioedema. In the Memphis
study, for example, 87% of patients had urticaria and/or angioedema. [30] Other retrospective studies
have reported similar rates of mucocutaneous involvement.
Children, however, may be different. An Australian study evaluated 57 children under age 16 years
who presented to a pediatric emergency department (ED) over a three-year period. Cutaneous
features were noted in 82.5%, whereas 95% had respiratory symptoms. The reasons why a lack of
dermal findings would be more common in children than in adults are not well understood.
The upper respiratory tract commonly is involved, with complaints of nasal congestion, sneezing, or
coryza. Cough, hoarseness, or a sensation of tightness in the throat may presage significant airway
obstruction. Eyes may itch and tearing may be noted. Conjunctival injection may occur.
Dyspnea is present when patients have bronchospasm or upper airway edema. Hypoxia and
hypotension may cause weakness, dizziness, or syncope. Chest pain may occur due to
bronchospasm or myocardial ischemia (secondary to hypotension and hypoxia). GI symptoms of
cramplike abdominal pain with nausea, vomiting, or diarrhea also occur but are less common, except
in the case of food allergy.
The Memphis study reported dyspnea in 59%, syncope or lightheadedness in 33%, and diarrhea or
abdominal cramps in 29%.[30] Other studies have reported similar findings.
Initially, patients often describe a sense of impending doom, accompanied by pruritus and flushing.
This can evolve rapidly into the following symptoms, broken down by organ system:

Cutaneous/ocular - Flushing, urticaria, angioedema, cutaneous and/or conjunctival pruritus,

warmth, and swelling
Respiratory - Nasal congestion, rhinorrhea, throat tightness, wheezing, shortness of breath,
cough, hoarseness
Cardiovascular - Dizziness, weakness, syncope, chest pain, palpitations
Gastrointestinal - Dysphagia, nausea, vomiting, diarrhea, bloating, cramps
Neurologic - Headache, dizziness, blurred vision, and seizure (very rare and often associated
with hypotension)
Other - Metallic taste, feeling of impending doom
Symptoms usually begin within 5-30 minutes from the time the culprit antigen is injected but can occur
within seconds. If the antigen is ingested, symptoms usually occur within minutes to 2 hours. In rare
cases, symptoms can be delayed in onset for several hours. Parenteral administration of monoclonal
antibodies and oral ingestion of mammalian meat (eg, beef, pork, lamb) have recently been reported
to be potential causes for anaphylaxis characterized by delayed onset. [53, 54, 55, 56, 57] It must be
remembered that anaphylaxis can begin with relatively minor cutaneous symptoms and rapidly
progress to life-threatening respiratory or cardiovascular manifestations. In general, the more rapidly
anaphylaxis develops after exposure to an offending stimulus, the more likely the reaction is to be
severe.
A thorough history remains the best test to determine a causative agent. For recurrent idiopathic
episodes, a patient diary may be helpful to implicate specific foods or medications, including over-thecounter (OTC) products.

Physical Examination
The first priority in the physical examination should be to assess the patients airway, breathing,
circulation, and adequacy of mentation (eg, alertness, orientation, coherence of thought).

General appearance and vital signs vary according to the severity of the anaphylactic episode and the
organ system(s) affected. Vital signs may be normal or significantly disordered with tachypnea,
tachycardia, and/or hypotension.
Patients commonly are restless due to severe pruritus from urticaria. Anxiety, tremor, and a sensation
of cold may result from compensatory endogenous catecholamine release. Anxiety is common unless
hypotension or hypoxia causes obtundation. Frank cardiovascular collapse or respiratory arrest may
occur in severe cases.

Respiratory findings
Severe angioedema of the tongue and lips (as may occur with the use of angiotensin-converting
enzyme [ACE] inhibitors) may obstruct airflow. Laryngeal edema may manifest as stridor or severe air
hunger. Loss of voice, hoarseness, and/or dysphonia may occur. Bronchospasm, airway edema, and
mucus hypersecretion may manifest as wheezing. In the surgical setting, increased pressure of
ventilation can be the only manifestation of bronchospasm. Complete airway obstruction is the most
common cause of death in anaphylaxis.

Cardiovascular findings
Tachycardia is present in one fourth of patients, usually as a compensatory response to reduced
intravascular volume or to stress from compensatory catecholamine release.
Bradycardia, in contrast, is more suggestive of a vasodepressor (vasovagal) reaction. Although
tachycardia is the rule, bradycardia has also been observed in anaphylaxis (see Pathophysiology).
Thus, bradycardia may not be as useful for distinguishing anaphylaxis from a vasodepressor reaction
as was previously thought. Relative bradycardia (initial tachycardia followed by diminished heart rate
despite worsening hypotension) has been reported previously in experimental settings of insect sting
anaphylaxis, as well as in trauma patients.[7, 8, 58, 59, 60]
Hypotension (and resultant loss of consciousness) may be observed secondary to capillary leak,
vasodilation, and hypoxic myocardial depression. Cardiovascular collapse and shock can occur
immediately, without any other findings. This is an especially important consideration in the surgical
setting. Because shock may develop without prominent skin manifestations or history of exposure,
anaphylaxis is part of the differential diagnosis for patients who present with shock and no obvious
cause.

Cognitive findings
If hypoperfusion or hypoxia occurs, it can cause altered mentation. The patient may exhibit a
depressed level of consciousness or may be agitated and/or combative.

Cutaneous findings
The classic skin manifestation is urticaria (ie, hives). Urticaria can occur anywhere on the body, often
localizing to the superficial dermal layers of the palms, soles, and inner thighs. Lesions are red and
raised, and they sometimes have central blanching. Intense pruritus occurs with the lesions. Lesion
borders are usually irregular and sizes vary markedly. Only a few small or large lesions may become
confluent, forming giant urticaria. At times, the entire dermis is involved with diffuse erythema and
edema.
In a local reaction, lesions occur near the site of a cutaneous exposure (eg, insect bite). The involved
area is erythematous, edematous, and pruritic. If only a local skin reaction (as opposed to generalized
urticaria) is present, systemic manifestations (eg, respiratory distress) are less likely. Local reactions,
even if severe, are not predictive of systemic anaphylaxis on reexposure.
Angioedema (soft-tissue swelling) is also commonly observed. These lesions involve the deeper
dermal layers of skin. It is usually nonpruritic and nonpitting. Common areas of involvement are the
larynx, lips, eyelids, hands, feet, and genitalia.
Generalized (whole-body) erythema (or flushing) without urticaria or angioedema is also occasionally
observed.
Cutaneous findings may be delayed or absent in rapidly progressive anaphylaxis.

Gastrointestinal findings
Vomiting, diarrhea, and abdominal distension are frequently observed.

Complications
Complications from anaphylaxis are rare, and most patients completely recover. Myocardial ischemia
may result from hypotension and hypoxia, particularly when underlying coronary artery disease exists.
Ischemia or arrhythmias may result from treatment with pressors. Prolonged hypoxia also may cause
brain injury. At times, a fall or other injury may occur when anaphylaxis leads to syncope.
Respiratory failure from severe bronchospasm or laryngeal edema can cause hypoxia, which could
lead to brain injury if prolonged.