A 42-year-old woman reports to her husband of being stung on her right forearm while working in her

garden. Her husband inspected it and found only localized swelling. Within minutes, she experienced
flushing, sweating, followed by shortness of breath and dyspnea. Her husband immediately brought
her to the hospital. At the ER, she was noted to be confused and in respiratory distress. Vital signs
were T 37.2, P 120, R 39, BP 69/45. She had generalized urticaria and wheezing. Husband claims that
his wife had tolerated insect stings on several occasions in the past without reaction.
GUIDE QUESTIONS:
1. What are the salient features of this case?
2. What are your differentials?
3. What is your final diagnosis? Support your diagnosis.
4. What lab exams can be requested?
5. Explain the pathophysiology of this immunologic process.
6. Differentiate anaphylactic from anaphylactoid reaction.
7. Discuss the structure and function of the immunoglobulin involved.
8. Enumerate the most common triggers of this immunologic process.
9. Explain the clinical presentation of the patient.
10. Discuss the initial treatment algorithm of this medical emergency.
11. What adjunct medications can you give to treat?
12. What advise can you give the patient for long-term care?

A previously healthy 12-year-old boy is brought to the emergency department after being stung by a
bee on his right forearm. He initially complained of localized pain and swelling. Fifteen minutes later,

he began to complain of shortness of breath and was observed by his parents to be wheezing. He
reported feeling weak and dizzy.
In the emergency department, VS: T 37.1 C, P 120, R 39, BP 69/45. Exam: He is drowsy and pale, but
able to answer questions. Generalized urticaria is present. He has no conjunctival edema and his lips
and tongue are not swollen. His voice sounds normal. He is tachycardic and hypotensive. Respiratory
examination reveals mild wheezing, with fair aeration and mild subcostal retractions. Abdomen is soft
and non-tender. His capillary refill time is delayed. The bee sting site on his right forearm shows
moderate swelling without visualization of a foreign body.
A diagnosis of anaphylactic shock is made, and he is given intramuscular epinephrine and albuterol via
nebulizer with subsequent improvement of his symptoms. An IV is started, and he is given
diphenhydramine, ranitidine, methylprednisolone, and a fluid bolus of normal saline. IV epinephrine is
considered but his status has rapidly improved since the IM epinephrine. His urticaria resolves, his
blood pressure normalizes, and his wheezing resolves. After being observed in the ED for six hours, he
feels back to normal. He is subsequently discharged from the ED on oral diphendramine, ranitidine,
and prednisone. His parents are advised of the possibility of a late phase reaction that could result in
worsening, so they are advised to monitor his condition carefully and return to the ED if his conditions
worsens. He is also prescribed an epinephrine autoinjector and instructed in its use.
Anaphylaxis is a clinical syndrome in which there is a systemic reaction following antigen exposure in a
sensitized person. It is rapid in onset and can lead to death. Reflecting the varied and potentially
atypical presentations of anaphylaxis, three diagnostic criteria exist; fulfillment of any one criterion is
diagnostic:
1) Acute onset (minutes to hours) of a reaction involving the skin and/or mucosal tissue (e.g., flushing,
pruritis, hives, swollen lips, tongue, or uvula), and at least one of:
. . . . . Respiratory compromise (e.g., dyspnea, wheeze, hypoxia) or
. . . . . Reduced blood pressure or
. . . . . Symptoms of end-organ dysfunction (e.g., syncope, hypotonia, incontinence)
2) Two or more of the following, occuring rapidly after exposure to a likely allergen for that particular
patient:
. . . . . Involvement of the skin/mucosal tissue (e.g. flushing, pruritis, hives, swollen lips, tongue, or
uvula)
. . . . . Respiratory compromise (e.g., dyspnea, wheeze, hypoxia)
. . . . . Reduced blood pressure or associated symtpoms (syncope, incontinence)
. . . . . Persistent gastrointestinal symptoms (abdominal pain, nausea, emesis)
3) Reduced blood pressure after exposure to a known allergen for that particular patient (using agespecific blood pressure criteria, e.g., less than 70 mmHg for infants 1 to 12 months in age, less than 70
mmHg + 2 times the age in years for 1 to 10 years of age, and less than 90 mmHg for children 11
years of age and up.
Anaphylaxis remains underreported. Current estimates indicate that the incidence of life-threatening
anaphylaxis is about 10 per 100,000 persons. In 2006, a group of international experts estimated the
incidence of anaphylaxis to be as high as 2%, which was based on the number of prescriptions of
automatic epinephrine injectors. A Massachusetts study examining the use of epinephrine for
anaphylaxis in schools found that up to 24% of anaphylaxis episodes occurred in children who did not
have a prior history of life-threatening allergies. According to more recent studies, the incidence is
rising, especially in younger age groups. Those same studies also suggest that anaphylaxis-related
hospitalizations and fatalities are also increasing. Current data estimates that approximately 1500
deaths occur each year from anaphylaxis in the United States.
Most clinical manifestations of anaphylaxis occur within minutes to hours of exposure to an allergen.
On rare occasions, delayed reactions, with symptoms presenting many hours later may occur. The
most common manifestations are cutaneous (pruritus, urticaria, angioedema, flushing), occurring in
80-90% of children. Children may also present with a feeling of impending doom, weakness, dizziness,
confusion, loss of consciousness and seizures. Airway and pulmonary findings include congestion,
sneezing, rhinorrhea, swelling of the lips and tongue, stridor, hoarseness, dyspnea and wheezing.
Cardiovascular findings include light-headedness, syncope, tachycardia, hypotension, pallor,
arrhythmia and complete cardiovascular collapse. Although uncommon, patients may present with
cardiovascular symptoms before cutaneous manifestations. In a retrospective analysis, 15% of patients
presented with chest pain and 7% presented with arrhythmia. Gastrointestinal findings include nausea,

emesis, abdominal cramping and diarrhea. Patients with anaphylaxis may have any combination of
cutaneous, GI or cardiac findings described above. Given the broad range of potentially non-specific
symptoms, diagnostic criteria as described above must be used.
Following initial presentation and treatment, symptoms may recur despite appropriate managment.
This recurrence of symptoms is known as biphasic anaphylaxis, and is defined as symptom recurrence
1 to 72 hours after resolution of the initial symptoms despite no further exposure to the trigger.
Biphasic anaphylactic reactions occur in up to 20% of fatal and near-fatal food reactions. The rates of
biphasic anaphylactic reactions are between 5% and 20% in adults, and about 6% in children. Recent
studies have reported an increased incidence of biphasic reactions, which portends an increased risk of
fatal anaphylaxis.
The differential diagnosis for anaphylaxis includes asthmatic attacks, vasovagal reactions, Scombroid
fish poisoning (a histamine reaction), hereditary angioedema, systemic mastocytosis, vocal cord
dysplasia, shock (secondary to other causes), serum sickness, panic attacks, and less severe acute
allergic reactions.
Etiological agents may potentially include food, arthropod stings, antibiotics, vaccines, latex, or may be
idiopathic and unidentifiable. In the outpatient setting, food remains the most common cause of
anaphylaxis, affecting about 6% of young children in North America. While any food may trigger an
anaphylactic reaction, peanuts and tree nuts (walnuts, pecans, cashews, pistachios, macadamias)
account for the majority of reactions, followed by shellfish. Milk, eggs, and sesame are also common
triggers. Allergies to peanut, tree nuts, fish and shellfish are likely to be life-long, whereas allergies to
milk, egg, soy, and wheat are usually outgrown within the first decade of life. Thus, it is important for
these children to have yearly evaluations by an allergist to determine which patients may be eligible
for oral food challenges and determine if allergies have been outgrown.
Low-molecular-weight medications induce an IgE-mediated reaction after combining with a carrier
protein and producing a complete multivalent antigen. Penicillin is the most common cause of druginduced anaphylaxis. Cephalosporins share the beta-lactam ring, but confer a lower risk of crossreactivity. The degree of cross-reactivity between penicillin and carbapenems also appears to be low.
Non beta-lactam antibiotics, aspirin, nonsteroidal anti-inflammatory drugs, and chemotherapy agents
also may trigger anaphylaxis. Patients with penicillin allergies or cephalosporin allergies should consult
with an allergist to discuss possible interventions such as graded challenge or drug desensitization.
Anaphylaxis to insect stings may be fatal in 1% of children, even on first exposure. The most common
causes of insect anaphylaxis are, wasps, hornets, bumblebees, honeybees, and red fire ants. Most
insults do not require treatment; however large local reactions can still lead to future anaphylaxis.
Children under 16 years of age who experience solely cutaneous symptoms (urticaria, angioedema,
flushing) have about a 5-10% risk for future anaphylaxis, whereas children who have organ-specific
symptoms (cardiovascular, respiratory, gastrointestinal) have a 20-40% risk for future anaphylaxis,
suggesting an allergy to the insect venom. Venom immunotherapy may reduce the risk to less than
5%.
Latex allergy affects a high proportion of those who have spina bifida and 10% to 15% of health-care
workers. In patients with spina bifida it is believed that early and frequent exposure to latex due to
multiple surgeries early in life, frequent bladder catheterizations, and manual rectal disimpactions all
contribute to development of latex allergies.
Anaphylaxis after routine vaccination is rare, with an estimated risk of 0.65 cases per 1 million doses.
Vaccine components that have been implicated include latex in vial stoppers, egg, gelatin, yeast, and
antimicrobial agents, such as neomycin. Inactivated influenza vaccine is grown in the ovalbumin of
chick embryos. However, it should still be administered to all patients except for those who have a
documented history of true anaphylaxis. The measles component of MMR is grown in chick fibroblast
cultures that do not contain egg antigens. Many of those who have reactions to the MMR vaccine do
not have egg allergies and have been shown to be sensitive to other agents, including gelatin or
neomycin. Yellow fever vaccine presents the greatest potential risk for reaction, as it is grown in chick
embryos.
Exercise-induced anaphylaxis (EIA) and food-dependent exercise-induced anaphylaxis (FDEIAn)
generally occur in older children. In FDEIAn, anaphylaxis only occurs when a food allergen is consumed
within hours to minutes prior to exercise. The reaction usually does not occur in the setting of food
consumption without exercise or vice versa. Foods most commonly associated with FDEIAn are wheat,
grains, and nuts in Western populations, and with wheat and shellfish in Asian populations. EIA

typically occurs in the setting of moderate exercise; however, it can occur with minimal exercise, such
as walking.
The pathogenesis of anaphylaxis involves prior exposure to an allergen (such as mentioned above).
Upon first exposure to the offending allergen, a specific IgE antibody is produced against the allergen.
These IgE antibodies become affixed to receptors on tissue mast cells and peripheral blood basophils.
Upon re-exposure, the allergen cross-links specific IgE antibodies on mast cells. This cross linkage
initiates a cascade of biochemical events that leads to degranulation of tissue mast cells and blood
basophils, allowing release of inflammatory mediators such as histamine, proteases and chemotactic
factors (tumor necrosis factor), and production of secondary mediators, such as prostaglandins and
leukotrienes. These potent mediators have the effect of producing the symptoms of anaphylaxis,
having physiologic effects on multiple organ systems. The main inflammatory mediator is histamine,
which causes initial erythema (vasodilatation), edema (vasopermeability), and secondary flare (axon
reflex with arteriolar dilation). The severity of anaphylactic reactions is proportional to the amount of
mediator release and the time for mediator degradation. Other mediator cascades are also responsible
for the symptoms of anaphylaxis. These include, but are not limited to, clotting and complement
cascades and other non-mast cell derived mediators. This was most recently described in studies
where patients, unresponsive to epinephrine, responded to tranexamic acid (in anaphylaxis associated
with intravascular coagulation) or methylene blue (in anaphylaxis associated with hypotension).
Anaphylactoid reactions produce a similar inflammatory response, though these reactions are not IgEmediated and do not require immunologic memory. Thus degranulation of mast cells occurs upon first
exposure to the allergen. Examples of anaphylactoid reactions are those caused by radiocontrast
media, anesthetics, and exercise.
Epinephrine is the first-line of therapy and administration should not be delayed. Frequently caregivers
administer antihistamines first, particularly because children often present initially with cutaneous
symptoms. Any clinical improvement after administration of antihistamines is likely due to endogenous
compensatory mechanism because drug absorption of antihistamines may be slow. Patients with a
previous history of anaphylaxis are usually given epinephrine autoinjectors for home use (EpiPen 0.3
mg, EpiPen Junior 0.15 mg).
Since most anaphylaxis events occur at home or in school, intramuscular administration - typically in
the lateral thigh - is the suggested route and site. The recommended pediatric dosage for
intramuscular epinephrine (1:1000 dilution) is 0.01 mg/kg up to a max dose of 0.5 mg per dose.
Another option is a dose of 0.5 ml of 1:1000 IM every 15 minutes for two doses and then every 4 hours
as needed. Epinephrine auto-injectors come in 0.15 mg in the EpiPen Junior, for children who weigh
between 15 and 30 kg, or 0.3 mg doses in the EpiPen for patients greater than or equal to 30 kg. All
patients receiving epinephrine should immediately go to the emergency department or call 911, as
there is a 20% incidence of biphasic latent reactions after administration of epinephrine.
The adult dosage is 0.2-0.5 ml of a 1:1000 epinephrine solution. IM administration is faster than
subcutaneous (SQ). IV epinephrine is given for severe reactions in which patients are in severe shock.
When in severe shock, the skin and muscle may not be adequately perfused, so SQ or IM epinephrine
will not be absorbed sufficiently unless it is given IV. Additionally IV fluid boluses may be required to
compensate for the marked peripheral vasodilation and third spacing that may occur with anaphylaxis.
IV epinephrine should be given as a dilute infusion calculated as 0.1 to 1.0 mcg/kg/min. Another
practice is to utilize the 1 mg 1:10,000 epinephrine injector (1 mg diluted in 10cc), and inject this VERY
slowly into the IV line (0.5 mL per minute = 50 mcg per minute which would be OK for adult but this
would be too much for a small child), allowing the clinician to titrate the dose, and to prevent
palpitations and/or dysrhythmias associated with rapid administration.
Adjunctive therapy for anaphylaxis includes antihistamines. Diphenhydramine is the most commonly
used drug given parenterally. A combination of H1 (diphenhydramine or hydroxyzine) and H2 blockers
(ranitidine, famotidine, or cimetidine) are commonly given together with the thought that they can be
synergistic in their effect. While corticosteroids are not very effective in the treatment of anaphylaxis
in the acute period, it may be effective in the biphasic phase of anaphylaxis, though this remains
controversial. In fact, in a study by Lee (4), 5 of 6 biphasic cases of anaphylaxis received
corticosteroids at time of presentation. Bronchodilators are effective for patients developing wheezing
and bronchospasm, although epinephrine alone may be sufficient. All patients require at least some
period of observation since one cannot predict which patient will develop the biphasic response of
anaphylaxis. The length of time of observation remains controversial, but periods of up to 8 to 10
hours are often used.

In 2007, the American College of Allergy, Asthma and Immunology and the American College of
Emergency Physicians recommended SAFE: a multidisciplinary approach to anaphylaxis education. The
SAFE system encourages (S) seeking support, (A) allergen identification and avoidance, (F) follow-up
for specialty care, and (E) epinephrine for emergencies. Physicians who identify a patient with a history
of anaphylaxis should encourage their patient to obtain a Medic Alert bracelet or ID. The patient should
be instructed on epinephrine use and dispensed two epinephrine autoinjectors. Physicians should be
responsible for demonstrating and training patients on the use of epinephrine autoinjectors and
making sure to mention the fluid contents should remain at room temperature, with avoidance of
extremes of temperature. Epinephrine autoinjectors have a shelf life of 1-2 years and change color
from clear to brown when they expire. However, considering the practical consideration that this
epinephrine injector is not likely to be available (i.e., the patient won't have it) when their next reaction
occurs, patients should also be taught the best means to obtain medical care depending on the
severity of the reaction. Patients should also be prescribed an oral antihistamine, which should be
taken immediately. Lastly, the management of anaphylaxis should be directed toward avoiding the
offending agent and education of where the offending agent can be hidden (especially if it is a food
item). Allergy testing may be useful to determine the cause of the allergy and desensitization therapy
may be useful for some types of allergies.
Urticaria, also commonly known as hives, are raised erythematous, circumscribed, pruritic lesions.
Urticaria occurs from focal mast cell degranulation, releasing histamine and other mediators. Individual
lesions of urticaria generally do not remain in the same place for greater than 24 hours. Urticaria is
divided into acute and chronic urticaria, with acute lasting less than 6 weeks and chronic lasting longer
than 6 weeks. Acute urticaria is more common in children and young adults, while the peak incidence
of chronic urticaria is during the third and fourth decades.
Urticaria can occur from food allergies, collagen vascular disease, infections, environmental factors
such as heat, cold or pressure, and medications. Despite an extensive workup, most cases of chronic
urticaria are idiopathic. Urticaria is treated with antihistamines. In most instances, the urticaria should
be largely resolved within several hours. Second-generation H1 blockers, such as loratadine, are
considered first-line therapy. This drug class has a better side effect profile (non-sedating) than firstgeneration H1 blockers. First-generation H1 blockers, such as diphenhydramine and hydroxyzine,
should still be provided as a rescue antihistamine for "breakthrough" symptoms. H2 blockers, such as
ranitidine, famotidine, and cimetidine, have variable degrees of success so routine use is controversial.
Avoidance of known triggers of urticaria is probably the most important aspect in chronic
management.
Angioedema is a localized subcutaneous or submucosal swelling, giving rise to non-pitting, stretched,
colorless, well demarcated skin lesions. In contrast, urticaria lesions are typically raised, erythematous
and pruritic. Characteristically, pruritus is absent in angioedema. There are fewer mast cells and
sensory nerve endings in the deeper layers of skin involved. Most frequently, angioedema affects the
scalp, lips, face, eyes, extremities and genitalia. Angioedema is treated similarly as urticaria.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent bouts
of swelling typically affecting the face, extremities, respiratory and GI tract in the absence of pruritis or
urticaria. HAE has a reported prevalence of 1 in 10,000 to 1 in 50,000 individuals. This condition occurs
because of the deficiency or dysfunction of C1 esterase inhibitor. C1 esterase inhibitor prevents
complement activation. If CI esterase is not functioning or absent, then the activation of the classical
complement pathway could be unchecked and allow for excessive bradykinin production, a potent
vasodilatory mediator. The disorder is usually self-limited; however, severe laryngeal edema or GI
involvement may occur. Untreated HAE patients are at risk for laryngeal edema or even death.
Treatment to prevent attacks involves the use of prophylactic oral attenuated androgens in the
postpubertal adolescent or young adult. Androgens cause the production of sufficient amounts of C1
esterase inhibitor to prevent C1 activation. In Europe, purified C1 esterase inhibitor concentrate is used
in acute attacks and for surgery prophylaxis. Studies in the United States have shown similar results.
Fresh frozen plasma has been shown to be safe and effective in acute attacks and prophylaxis.
Erythema multiforme may also resemble urticaria, especially in the early stages. However, erythema
multiforme (EM) does not respond to antihistamines or corticosteroids. The lesions are varying in size
and shape (multiformed) and some lesions have a target appearance with a rim of urticaria
surrounding a central depression (target lesion). The most common presenting complaint is a case of
"hives" which has not responded to an antihistamine. Serum sickness may present a similar clinical
picture. Joint swelling may accompany both conditions. These conditions are generally self-resolving in

about 2 weeks. If the inciting cause is known, then withdrawal of the allergic substance is the key
component of treatment. Group A beta hemolytic streptococci, herpes simplex, and mycoplasma are
known causes of EM, but there are numerous other causes as well. Stevens-Johnson Syndrome is a
severe form of EM (also known as EM major) which requires hospitalization. Treatment is supportive,
but corticosteroids may be beneficial.
Questions
1. What is the primary treatment of severe anaphylaxis and what is the appropriate dose?
2. What are the adjunctive therapies for anaphylaxis?
3. Two weeks after a viral illness, a teenage boy breaks out in an evolving rash that is remarkable for
target lesions. What is the primary treatment?
. . . . . a. Epinephrine
. . . . . b. Glucagon
. . . . . c. Corticosteroids
. . . . . d. Antihistamines
. . . . . e. Symptomatic or supportive therapy depending on severity.
4. A girl is brought to her pediatrician by her mother because of recurrent bouts of non-pitting, nonpruritic facial swelling that have occurred three times prior. Her father also has a history of recurrent
facial swelling. What is the probably diagnosis?
. . . . . a. Environmental allergen
. . . . . b. Hereditary angioedema
. . . . . c. Child abuse
. . . . . d. Anaphylaxis
. . . . . e. Urticaria
5. A 5 year old boy develops shortness of breath and hives after eating lunch at school. His lunch
consisted of a banana, milk, and a peanut butter and jelly sandwich. Which of the foods was the most
likely offending cause of his anaphylaxis?
. . . . . a. Milk
. . . . . b. Banana
. . . . . c. Jelly
. . . . . d. Bread
. . . . . e. Peanut Butter
References
1. Sampson HA, et al. Second symposium on the definition and management of anaphylaxis: summary
report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol 2006;117(2):391-397.
2. Lieberman P, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma
and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol
2006;97(5):596-602.
3. Lieberman P, et al. The diagnosis and management of anaphylaxis practice parameter: 2010
update. J Allergy Clin Immunol 2010;126(3):477-480(e1-42).
4. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106(4):762-766.
5. Waibel KH. Anaphylaxis. Pediatr Rev 2008;29(8):255-263.
6. Langley EW, Gigante J. Anaphylaxis, Urticaria, and Angioedema. Pediatr Rev 2013;34:247.
Answers to questions
1. Epinephrine. Pediatric dosage for epinephrine is 0.01 mg/kg up to a max dose of 0.5 mg per dose or
0.5 ml of 1:1000 SQ/IM every 15 minutes for two doses and then every 4 hours as needed. The adult
dosage is 0.2-0.5 ml of a 1:1000 epinephrine solution.
2. Adjunctive therapies include antihistamines, bronchodilators, and perhaps glucagon and
corticosteroids.
3. e. This is erythema multiforme. There is no good treatment. Treatment is largely symptomatic.
4. b. Hereditary angioedema.
5. e. Peanuts and tree nuts remain the leading causes of food-related anaphylaxis.

2. Differential diagnosis of anaphylaxis in children and adults

INTRODUCTION Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause
death. The diagnosis of anaphylaxis may be readily apparent in patients with a clear history of
exposure to a known or likely allergen in the minutes or few hours preceding onset of characteristic
symptoms in several body systems. However, the symptoms and signs of anaphylaxis overlap with
those of many other disorders, and diagnosis is not always easy to make [ 1-3 ].
Disorders that may present with some similar symptoms and signs to anaphylaxis in children and
adults will be reviewed here. The differential diagnosis of anaphylaxis in infants (ie, children under two
years of age) and in pregnant women during labor and delivery is reviewed elsewhere. The rapid
recognition and acute treatment of anaphylaxis are also presented separately. (See "Unique aspects of
anaphylaxis in infants" and "Anaphylaxis in pregnant and breastfeeding women" and "Anaphylaxis:
Rapid recognition and treatment" .)
CLINICAL DIAGNOSIS OF ANAPHYLAXIS The diagnosis of anaphylaxis is based on recognition of
characteristic symptoms and signs occurring within minutes to a few hours after exposure to potential
triggering agents or events. These symptoms potentially include itching, flushing, urticaria,
angioedema, hoarseness, throat tightness, stridor, wheezing, coughing, shortness of breath, abdominal
pain, vomiting, and/or dizziness, collapse, or hypotension ( table 1). (See "Anaphylaxis: Rapid
recognition and treatment" .)
Involvement of body organ systems varies among patients and even in the same patient from one
episode to another. However, review of anaphylaxis case series reveals some general patterns:

Skin involvement is reported in up to 90 percent of episodes

Respiratory tract involvement (up to 70 percent)

Gastrointestinal tract involvement (up to 45 percent)

Cardiovascular system involvement (up to 45 percent)


Central nervous system (CNS) involvement (up to 15 percent)
If the patient is seen after resolution of the acute anaphylactic episode (eg, in the clinician's office
weeks or months later) the relevant emergency medical services and emergency department records
should be obtained and reviewed [ 1-3 ].
LABORATORY TESTS TO CONFIRM THE DIAGNOSIS OF ANAPHYLAXIS The clinical history is
the most important element in the evaluation. Sometimes, the diagnosis of anaphylaxis can be
confirmed, or anaphylaxis can be distinguished from other disorders with similar symptoms, by
demonstration of an elevated plasma histamine level or an elevated serum or plasma total tryptase
level. Typically, elevations in plasma histamine occur within 5 to 15 minutes of the onset of
anaphylaxis symptoms and then decline to baseline by 60 minutes due to rapid metabolism.
Elevations in serum tryptase are somewhat slower and more prolonged. Serum for tryptase
measurement should be obtained from 15 minutes to 3 hours of symptom onset. Tryptase elevations
are more likely to be detected in anaphylaxis from stinging insect venoms or injected medications, and
following anaphylaxis with hypotension [ 2,4 ]. Proper collection of samples for the measurement of
plasma histamine and serum tryptase is described in the table ( table 2 ).
Elevations of histamine or tryptase levels is not specific for anaphylaxis; for example, elevated
histamine levels are found in scombroid poisoning, and elevated tryptase levels are found in
myocardial infarction, mastocytosis and other clonal mast cell disorders, other hematologic disorders,
and other diseases, but for some of these disorders, levels are chronically elevated whereas in
anaphylaxis, follow-up testing days later will reveal normal levels [ 2,4 ].
Histamine or tryptase levels that are within normal limits cannot be used to exclude or refute the
clinical diagnosis of anaphylaxis. Tryptase levels are seldom elevated in patients with food-induced
anaphylaxis, or in patients who remain normotensive during an anaphylactic episode. The
interpretation of serum tryptase levels is discussed in greater detail separately. (See "Laboratory tests
to support the clinical diagnosis of anaphylaxis" .)
DIFFERENTIAL DIAGNOSIS OF ANAPHYLAXIS Common disorders that mimic anaphylaxis
include acute generalized urticaria, acute angioedema, acute asthma exacerbations, syncope (faint),
and panic attacks or acute anxiety attacks ( table 3 ). Additionally, anaphylaxis may present as sudden
collapse without cutaneous symptoms, and may be misdiagnosed as myocardial infarction or stroke in
adults. Age-related entities in the differential diagnosis, including choking and foreign body aspiration,
are important considerations particularly in infants and young children. (See "Unique aspects of
anaphylaxis in infants" .)
Common disorders
Acute generalized urticaria and/or angioedema Sudden onset of generalized urticaria may be
a symptom of anaphylaxis, or it may occur as an isolated problem. Urticaria, with or without
angioedema, is limited to the skin and subcutaneous tissues. Anaphylaxis is typically characterized by
involvement of one or more body system in addition to the skin. Therefore, the clinician should
determine if symptoms and signs are present in the respiratory, gastrointestinal, or cardiovascular
systems, as well as ascertaining the time elapsed between exposure to a likely or known trigger and
the onset of initial symptoms [ 2,3 ]. (See "New onset urticaria" .)
The various allergic and nonallergic disorders associated with angioedema are reviewed separately.
(See "An overview of angioedema: Pathogenesis and causes" .)
Typically, patients with nonallergic hereditary or acquired angioedema have intermittent episodes of
swelling that are unilateral, not associated with itching or urticaria, and located in the deep cutaneous
or mucosal tissues of the face, extremities, and genitalia. Patients with nonallergic angioedema can
also present with edema of the tongue and larynx, leading to life-threatening asphyxia, or with edema
of the bowel wall, leading to recurrent abdominal pain that varies in severity from mild discomfort to
severe intractable pain accompanied by vomiting, diarrhea, and hypovolemic shock. In hereditary
angioedema, complement (C4 and C2) levels are reduced during acute attacks, and C4 is persistently
low. C1-esterase inhibitor is deficient or functionally absent in most patients with hereditary
angioedema [ 5,6 ]. (See "Hereditary angioedema: Pathogenesis and diagnosis" and "Hereditary
angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" .)
Asthma exacerbation Sudden onset of wheeze, cough, and shortness of breath may occur during
anaphylaxis; or these symptoms may occur as an isolated problem. The diagnosis of anaphylaxis
should be considered in any patient presenting with wheeze, cough, or shortness of breath within
minutes or a few hours after exposure to a likely or known trigger for anaphylaxis; for example, food,
medication, or insect sting [ 2,3 ].

Such patients should be asked about sudden onset of concurrent symptoms such as itching, flushing,
urticaria, angioedema, hoarseness, throat tightness, abdominal pain, vomiting, diarrhea, dizziness,
collapse, or hypotension.
Vasovagal syncope Vasovagal syncope (faint) may be a symptom of anaphylaxis or may occur as
an isolated problem. Typically, vasovagal syncope is associated with pallor, diaphoresis, weakness,
nausea, vomiting, bradycardia, and if severe, by loss of consciousness, and is relieved by recumbency.
Anaphylaxis, in contrast, is usually characterized by sudden onset of flushing rather than pallor, and
other symptoms and signs that are not typically seen with vasovagal syncope, including sudden onset
of itching, urticaria, angioedema, hoarseness, throat tightness, stridor, wheeze, cough, shortness of
breath, crampy abdominal pain, or diarrhea. In anaphylaxis, tachycardia is more common than
bradycardia [ 3 ].
Information about the patient's propensity to syncope may be available. Patients with recurrent
syncope require further evaluation. (See "Causes of syncope in children and
adolescents" and "Approach to the adult patient with syncope in the emergency
department" and "Pathogenesis and etiology of syncope" .)
Panic attack/acute anxiety attack In a panic attack or an acute anxiety attack, symptoms can
include a sense of impending doom, breathlessness, flushing, sweating, trembling, palpitations, globus
sensation (feeling of choking), gastrointestinal symptoms, "feeling faint", chest pain, and numbness or
tingling of the extremities [ 3 ].
In anaphylaxis, associated symptoms can include itching, urticaria, angioedema, hoarseness, throat
tightness, stridor, wheezing, coughing, collapse, and/orhypotension. These symptoms are unlikely
during a panic attack or an acute anxiety attack [ 3,7 ]. (See "Pharmacotherapy for panic
disorder" and "Globus sensation" .)
Other causes of sudden collapse
Myocardial infarction or stroke Anaphylaxis can also present as sudden collapse, without skin
symptoms or signs, especially in middle-aged and older adults, hence the possibility for diagnostic
confusion. To make this situation more complicated, elevated tryptase levels can be found in
myocardial infarction as well as in anaphylaxis, making it difficult to distinguish these two diagnostic
entities in some patients [ 2,4,8 ].
Other causes of acute respiratory distress Other causes of sudden onset of respiratory
distress include vocal cord dysfunction, choking/foreignbody aspiration, and epiglottitis.
Vocal cord dysfunction Vocal cord dysfunction involves the involuntary, paradoxical adduction of
the vocal cords during inspiration. Symptoms and signs include dyspnea, cough, inspiratory stridor, or
expiratory wheezing. This disorder is most common in young women, although it has been reported in
adults and children of both sexes [ 9,10 ]. In a symptomatic patient, direct observation of the adducted
vocal cords by laryngoscopy is diagnostic. (See"Paradoxical vocal cord motion" .)
Useful clues to the diagnosis of vocal cord dysfunction are obstruction to airflow that is present during
both inspiration and expiration, characteristically abnormal inspiratory portions of flow volume loops
on pulmonary function testing suggestive of variable extrathoracic obstruction, and absence of uvular
edema. In anaphylaxis, laryngeal edema is characterized by inspiratory stridor and is often associated
with uvular edema. In asthma, expiratory noises are prominent and are more audible over the chest
than over the neck.
Choking/foreign body aspiration and epiglottitis are discussed separately. (See "Unique aspects of
anaphylaxis in infants" and "Emergent evaluation of acute upper airway obstruction in
children" and "Airway foreign bodies in adults" .)
Other forms of shock Shock is characterized by a significant systemic reduction in tissue
perfusion, resulting in decreased tissue oxygen delivery. There are four broad mechanisms associated
with shock: hypovolemic, cardiogenic, distributive (which can be due to anaphylaxis or spinal cord
injury), and septic (which involves hypovolemic, cardiogenic, and distributive mechanisms). The
approach to a patient presenting with apparent shock is reviewed elsewhere [ 2,3 ]. (See "Shock in
adults: Types, presentation, and diagnostic approach" and "Initial evaluation of shock in children" .)
Flushing disorders Flushing is defined as a sensation of warmth, accompanied by a visible
reddening of the skin. Typically, it is prominent in the classic blush area that includes the face, neck,
upper portion of the chest, and upper limbs. Pathologic flushing is a common symptom of anaphylaxis.
It may also be a prominent symptom during menopause and may occur after the administration of
certain medications, after the ingestion of alcohol (ethanol), and in association with several uncommon
tumors [ 11 ].

Menopause The peri-menopausal state is commonly associated with brief episodes of flushing that
last less than five minutes. Perimenopausal flushing is not associated with urticaria, angioedema,
itching, or significant hypotension [ 3,11 ]. (See "Menopausal hot flashes" .)
Medications Medications associated with flushing are discussed in more detail elsewhere.
(See "Approach to flushing in adults", section on 'Medications' .)
Alcohol (ethanol) Some people are susceptible to flushing after ingestion of alcoholic beverages,
because of genetic variations in the enzyme alcohol dehydrogenase, Hodgkin's disease or other
malignancies, hypereosinophilic syndromes, or adverse reactions to other ingredients in alcoholic
beverages (eg, histamine or metabisulfites). In addition, ethanol can also amplify food-induced
anaphylaxis by increasing the rate of intestinal absorption of food allergens [11-15 ].
Ethanol-induced flushing can be potentiated by certain medications. These
include chlorpropamide , chloramphenicol ,
cephalosporins, disulfiram , griseofulvin, ketoconazole , metronidazole , phentolamine , niacin, and
topical tacrolimus [ 11,16 ].
Tumors Carcinoid tumors, gastrointestinal tumors, medullary carcinoma of the thyroid, renal cell
carcinoma, and pancreatic carcinoma can present with flushing. Some of these tumors will be
described in more detail below:

Carcinoid tumors - Carcinoid syndrome refers to a constellation of symptoms mediated by

the serotonin, substance P, and other vasoactive substances released by some carcinoid
tumors (eg, those in the small bowel, appendix, and colon). Episodic flushing occurs in most
patients, typically affecting the face, neck, and upper chest. The areas become red to
violaceous or purple, and there may be a mild burning sensation in the discolored skin ( picture
1 ). Flushing episodes begin suddenly and last 20 to 30 seconds, although they may become
more prolonged over time. Diarrhea is also a common symptom. Wheezing can occur
[ 11,17 ].
If carcinoid syndrome is suspected, plasma serotonin or 24-hour urinary excretion of the
serotonin metabolite 5-hydroxyindoleacetic acid (HIAA) should be measured while the patient
avoids foods that have high levels of serotonin and tryptophan. (See "Clinical features of the
carcinoid syndrome" and"Diagnosis of the carcinoid syndrome and tumor localization", section
on 'Biochemical testing for the carcinoid syndrome' .)

Gastrointestinal tumors - Gastrointestinal tumors producing vasoactive intestinal

polypeptide (VIPomas) or substance P are extremely rare. Most patients have watery diarrhea,
hypokalemia, and hypochlorhydria, and a minority (20 percent) experience associated flushing
episodes. Measurement of serum VIP or substance P is helpful in diagnosis [ 11 ]. (See "The
VIPoma syndrome" .)

Medullary carcinoma of the thyroid - This carcinoma usually presents as a solitary thyroid
nodule in a middle-aged adult. Facial flushing and diarrhea can occur in advanced disease
[ 11 ]. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging" .)
Post-prandial syndromes
Scombroidosis Scombroid syndrome, also called histamine fish poisoning, occurs within 15 to 90
minutes of eating spoiled fish such as tuna, mackerel, saury, mahi mahi, sardines, anchovies, herring,
and others. It is characterized by acute onset of flushing, headache, nausea, vomiting, diarrhea,
abdominal pain, dysphagia, palpitations, dizziness, and hypotension after ingestion. Urticaria and
itching are uncommon [ 18 ].
Symptoms are due, at least in part, to elevated levels of histamine in the fish. The histamine
production occurs under conditions of inadequate refrigeration or preservation, when bacterial
decomposition in the musculature of the fish leads to decarboxylation of the amino acid L-histidine to
histamine. Additional compounds might be responsible for the symptoms, because ingestion of large
oral doses of histamine does not reproduce the syndrome. Cooking the fish does not reduce the
histamine content. Clustering of cases (ie, several people developing similar symptoms after eating
the same fish meal) is consistent with the diagnosis of scombroidosis [ 2,3 ].
Plasma histamine levels are acutely elevated in scombroidosis but serum tryptase levels are not. Either
plasma histamine or serum tryptase levels, or both, are elevated in some patients with anaphylaxis
triggered by fish. These two disorders can be further distinguished by skin tests and measurement of
serum specific IgE levels to the fish implicated by the history. In fish allergy, these tests are positive,

whereas in scombroidosis, sensitization to fish is not typical [19 ]. (See "Seafood allergies: Fish and
shellfish" .)
Anisakiasis Historically, anisakiasis has been included in the differential diagnosis of anaphylaxis;
however, anaphylaxis can be triggered by an immediate hypersensitivity reaction to the fish parasite
Anisakis simplex. Such patients have typically ingested raw or undercooked saltwater fish, for
example, marinated anchovies, a few hours before symptom onset; however, the delay between
ingestion and symptoms may be as long as 24 hours. They have positive skin tests and elevated
serum IgE levels to the fish parasite Anisakis simplex. The major allergen in this parasite was identified
as Ani s 7 in 2007. Skin prick tests and specific IgE antibody levels to the ingested fish are typically
negative [ 20,21 ]. (See "Seafood allergies: Fish and shellfish" and"Miscellaneous nematodes", section
on 'Anisakiasis' .)
Pollen-food allergy syndrome Pollen food syndrome, also known as oral allergy syndrome, is
elicited by fresh fruits and vegetables containing various plant proteins that cross-react with airborne
allergens, such as birch tree and ragweed pollen. Typical symptoms include itching, tingling, and
angioedema of the lips, tongue, palate, throat, and ears after eating raw, but not cooked, fruits and
vegetables [ 22 ]. (See "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food
allergy syndrome)", section on 'Clinical manifestations' .)
Sulfites Ingestion or food or beverages containing sulfites can cause significant asthmatic
reactions in patients with asthma, and there are rare reports of anaphylaxis [ 23 ]. (See "Allergic and
asthmatic reactions to food additives", section on 'Sulfites' .)
Food poisoning Historically, anaphylaxis was often diagnosed as "food poisoning", for example
"egg poisoning." However, modern use of the term food poisoning refers to a nonallergic acute illness
caused by microorganisms or microbial toxins in food. Food poisoning may present with vomiting,
crampy abdominal pain, and diarrhea within a few hours of ingesting a meal. (See "Food poisoning in
children" and "Differential diagnosis of microbial foodborne disease" .)
Signs and symptoms of food poisoning are usually limited to the gastrointestinal tract. In contrast, the
gastrointestinal symptoms of anaphylaxis are typically accompanied by symptoms in at least one other
body organ system such as itching, flushing, urticaria, angioedema, hoarseness, throat tightness,
stridor, wheeze, cough, shortness of breath, dizziness, collapse, or hypotension.
Excess histamine syndromes Syndromes characterized by excessive endogenous
overproduction of histamine include mast cell disorders, other clonal disorders of mast cells, certain
forms of leukemia, and hydatid cysts.
Mastocytosis Mastocytosis refers to a group of disorders characterized by excessive mast cell
proliferation and accumulation of these cells in one or multiple tissues. In these disorders, anaphylaxis
can result from IgE-dependent mechanisms (eg, insect stings), other immunologic mechanisms that do
not involve IgE, or nonimmunologic mechanisms (eg, direct mast cell stimulation after exposure to
extremely cold air or water) [ 24 ]. Patients with mastocytosis may have both transient elevations and
baseline elevations of serum total tryptase, in addition to histamine elevations. Mast cell disorders are
reviewed in detail elsewhere. (See "Clinical manifestations, pathogenesis, and classification of
mastocytosis (cutaneous and systemic)" .)
Other clonal disorders of mast cells Some patients who do not fully meet diagnostic criteria for
mastocytosis may have an aberrant mast cell population with clonal markers [ 25 ]. (See "Evaluation
and diagnosis of mastocytosis (cutaneous and systemic)", section on 'Disorders with similar clinical
manifestations' .)
Certain forms of leukemia There may be an overproduction of histamine-containing cells in
basophilic leukemia and acute promyelocytic leukemia in patients receiving treatment with tretinoin
[ 26 ].
Hydatid cysts Initial infection with the cestode Echinococcus multilocularis is asymptomatic.
Typically, infections are latent for decades before symptoms develop due to the mass of cystic lesions
within lung, liver, or other organs, leading to obstruction of blood flow or lymphatic flow, or to other
complications. Cyst rupture, either spontaneously or during a surgical procedure to reduce the cystic
mass, can result in fever and symptoms resembling those of an anaphylactic episode; these symptoms
are due to the release of cyst contents [ 3 ]. New case reports [ 27,28 ] (See "Clinical manifestations
and diagnosis of echinococcosis" .)
Rare disorders
Pheochromocytoma Pheochromocytomas are catecholamine-secreting tumors arising from the
adrenal medulla, and associated with the classic symptom triad of episodic headache, sweating, and

tachycardia. Hypertension is characteristic, although paradoxical hypotension has been reported. Pallor
during attacks is more common than flushing. Initial testing in patients with suggestive symptoms
includes 24-hour urine assays for total and fractionated metanephrines, vanillylmandelic acid, and
catecholamines, plasma levels of catecholamines and free metanephrines, and CT and MRI imaging
[ 11,29 ]. (See"Clinical presentation and diagnosis of pheochromocytoma" .)
Capillary leak syndrome Idiopathic systemic capillary leak syndrome is a rare, often fatal
disease, characterized by recurrent episodes of angioedema, gastrointestinal symptoms, and shock
with hemoconcentration, usually associated with a monoclonal gammopathy. The diagnosis is
suggested by an elevated hematocrit during an episode of hypotension and treatment involves
aggressive fluid resuscitation and supportive care [ 30,31 ]. (See"Idiopathic systemic capillary leak
syndrome" .)
Other nonorganic disease
Munchausen stridor Some individuals with Munchausen syndrome (in which the patient
consciously and voluntarily produces physical symptoms of illness for secondary gain) have a similar
presentation to those with vocal cord dysfunction; however, they are usually able to adduct their vocal
cords voluntarily and they can be distracted by requests to perform maneuvers such as coughing.
(See "Paradoxical vocal cord motion", section on 'Presentation' .)
Munchausen anaphylaxis is induced when the patient consciously self-triggers anaphylaxis; for
example, by knowingly ingesting a food or medication to which he or she is sensitized [ 23 ].
(See "Factitious disorder and Munchausen syndrome" .)
Undifferentiated somatiform anaphylaxis Patients with this disorder present with symptoms,
such as throat closure, shortness of breath, and syncope; however, there are no objective signs of
anaphylaxis; for example, no evidence of upper or lower airway obstruction or hypotension [ 3 ].
SUMMARY

Anaphylaxis can potentially present with different permutations and combinations of more than
40 symptoms and signs. The presentation can vary from patient to patient, and in the same
patient from one episode to another ( table 1 ). (See 'Clinical diagnosis of anaphylaxis' above.)

The clinical diagnosis of anaphylaxis is sometimes supported by the demonstration of typically

transiently elevated levels of mast cell mediators such as histamine or tryptase. These
elevated levels are not specific for anaphylaxis, and test results that are within normal limits
cannot be used to exclude or refute the clinical diagnosis of anaphylaxis. (See "Laboratory
tests to support the clinical diagnosis of anaphylaxis" .)

The symptoms and signs of anaphylaxis overlap with those of many other disorders ( table 3 ).
(See 'Differential diagnosis of anaphylaxis' above.)

Common disorders that mimic anaphylaxis include acute generalized urticaria, acute
angioedema, acute asthma, syncope (faint), and panic attacks or acute anxiety attacks.
(See 'Common disorders' above.)

Age-related disorders that are important in the differential diagnosis include myocardial
infarction or stroke, especially in middle-aged or elderly adults, and choking from aspiration of
a foreign body, especially in children. (See 'Other causes of sudden collapse' above and 'Other
causes of acute respiratory distress' above.)

In the patient presenting with hypotension and shock, anaphylaxis must be differentiated from
other forms of shock (hypovolemic, cardiogenic, distributive, and septic). (See 'Other forms of
shock' above.)

Flushing can be seen with a variety of medications, as well as in response to alcohol ingestion
or the combination of alcohol and certain medications. Several uncommon tumors are also
associated with flushing. (See 'Flushing disorders' above.)

Post-prandial reactions include scombroidosis, anisakiasis, pollen-food allergy syndrome,

reactions to sulfites, and microbial food poisoning. (See 'Post-prandial syndromes' above.)

Patients with disorders that involve excessive production of endogenous histamine can
experience episodic symptoms that resemble allergic reactions and anaphylaxis. Such
disorders include mastocytosis and other mast cell disorders, certain forms of leukemia, and
rupture of hydatid cysts. (See'Excess histamine syndromes' above.