Anaphylaxis

Anaphylaxis is a serious allergic reaction

that is rapid in onset and may cause
death.[4][5] It typically causes more than
one of the following: an itchy rash, throat
or tongue swelling, shortness of breath,
vomiting, lightheadedness, and low blood
pressure.[1] These symptoms typically
come on over minutes to hours.[1]
 Anaphylaxis

Angioedema of the face such that the boy

cannot open his eyes. This reaction was caused
by an allergen exposure.

Specialty Allergy and

immunology
Symptoms Itchy rash, throat
swelling, shortness of
breath,
lightheadedness[1]

Usual onset Over minutes to

hours[1]

Causes Insect bites, foods,

medications[1]

Diagnostic method Based on symptomz[2]

Differential diagnosis Allergic reaction,

angioedema, asthma
exacerbation, carcinoid
syndrome[2]

Treatment Epinephrine,
intravenous fluids[1]

Frequency 0.05–2%[3]
Common causes include insect bites and
stings, foods, and medications.[1] Other
causes include latex exposure and
exercise.[1] Additionally, cases may occur
without an obvious reason.[1] The
mechanism involves the release of
mediators from certain types of white
blood cells triggered by either
immunologic or non-immunologic
mechanisms.[6] Diagnosis is based on
the presenting symptoms and signs after
exposure to a potential allergen.[1]

The primary treatment of anaphylaxis is

epinephrine injection into a muscle,
intravenous fluids, and positioning the
person flat.[1][7] Additional doses of
epinephrine may be required.[1] Other
measures, such as antihistamines and
steroids, are complementary.[1] Carrying
an epinephrine autoinjector and
identification regarding the condition is
recommended in people with a history of
anaphylaxis.[1]

Worldwide, 0.05–2% of the population is

estimated to experience anaphylaxis at
some point in life.[3] Rates appear to be
increasing.[3] It occurs most often in
young people and females.[7][8] Of people
who go to a hospital with anaphylaxis in
the United States about 99.7% survive.[9]
The term comes from the Ancient Greek:
ἀνά, romanized: ana, lit. 'against', and the
Ancient Greek: φύλαξις,
romanized: phylaxis, lit. 'protection'.[10]

Signs and symptoms

Signs and symptoms of anaphylaxis

Anaphylaxis typically presents many

different symptoms over minutes or
hours[7][11] with an average onset of 5 to
30 minutes if exposure is intravenous
and 2 hours if from eating food.[12] The
most common areas affected include:
skin (80–90%), respiratory (70%),
gastrointestinal (30–45%), heart and
vasculature (10–45%), and central
nervous system (10–15%)[13] with usually
two or more being involved.[3]

Skin

Urticaria and flushing on the back of a person with

anaphylaxis
Symptoms typically include generalized
hives, itchiness, flushing, or swelling
(angioedema) of the afflicted tissues.[4]
Those with angioedema may describe a
burning sensation of the skin rather than
itchiness.[12] Swelling of the tongue or
throat occurs in up to about 20% of
cases.[14] Other features may include a
runny nose and swelling of the
conjunctiva.[15] The skin may also be blue
tinged because of lack of oxygen.[15]

Respiratory

Respiratory symptoms and signs that

may be present include shortness of
breath, wheezes, or stridor.[4] The
wheezing is typically caused by spasms
of the bronchial muscles[16] while stridor
is related to upper airway obstruction
secondary to swelling.[15] Hoarseness,
pain with swallowing, or a cough may
also occur.[12]

Cardiovascular

While a fast heart rate caused by low

blood pressure is more common,[15] a
Bezold–Jarisch reflex has been
described in 10% of people, where a slow
heart rate is associated with low blood
pressure.[8] A drop in blood pressure or
shock (either distributive or cardiogenic)
may cause the feeling of
lightheadedness or loss of
consciousness.[16] Rarely very low blood
pressure may be the only sign of
anaphylaxis.[14]

Coronary artery spasm may occur with

subsequent myocardial infarction,
dysrhythmia, or cardiac arrest.[3][13]
Those with underlying coronary disease
are at greater risk of cardiac effects from
anaphylaxis.[16] The coronary spasm is
related to the presence of histamine-
releasing cells in the heart.[16]

Other
Gastrointestinal symptoms may include
crampy abdominal pain, diarrhea, and
vomiting.[4] There may be confusion, a
loss of bladder control or pelvic pain
similar to that of uterine cramps.[4][15]
Dilation of blood vessels around the
brain may cause headaches.[12] A feeling
of anxiety or of "impending doom" has
also been described.[3]

Causes
Anaphylaxis can occur in response to
almost any foreign substance.[17]
Common triggers include venom from
insect bites or stings, foods, and
medication.[8][18] Foods are the most
common trigger in children and young
adults while medications and insect bites
and stings are more common in older
adults.[3] Less common causes include:
physical factors, biological agents such
as semen, latex, hormonal changes, food
additives such as monosodium
glutamate and food colors, and topical
medications.[15] Physical factors such as
exercise (known as exercise-induced
anaphylaxis) or temperature (either hot
or cold) may also act as triggers through
their direct effects on mast cells.[3][19]
Events caused by exercise are frequently
associated with the ingestion of certain
foods.[12] During anesthesia,
neuromuscular blocking agents,
antibiotics, and latex are the most
common causes.[20] The cause remains
unknown in 32–50% of cases, referred to
as "idiopathic anaphylaxis."[21] Six
vaccines (MMR, varicella, influenza,
hepatitis B, tetanus, meningococcal) are
recognized as a cause for anaphylaxis,
and HPV may cause anaphylaxis as
well.[22] Physical exercise is an
uncommon cause of anaphylaxis;[23] in
about a third of such cases there is a co-
factor like taking an NSAID or eating a
specific food prior to exercising.[24]

Food
Many foods can trigger anaphylaxis; this
may occur upon the first known
ingestion.[8] Common triggering foods
vary around the world. In Western
cultures, ingestion of or exposure to
peanuts, wheat, nuts, certain types of
seafood like shellfish, milk, and eggs are
the most prevalent causes.[3][13] Sesame
is common in the Middle East, while rice
and chickpeas are frequently
encountered as sources of anaphylaxis
in Asia.[3] Severe cases are usually
caused by ingesting the allergen,[8] but
some people experience a severe
reaction upon contact. Children can
outgrow their allergies. By age 16, 80% of
children with anaphylaxis to milk or eggs
and 20% who experience isolated
anaphylaxis to peanuts can tolerate
these foods.[17]

Medication

Any medication may potentially trigger

anaphylaxis. The most common are β-
lactam antibiotics (such as penicillin)
followed by aspirin and NSAIDs.[13][25]
Other antibiotics are implicated less
frequently.[25] Anaphylactic reactions to
NSAIDs are either agent specific or occur
among those that are structurally similar
meaning that those who are allergic to
one NSAID can typically tolerate a
different one or different group of
NSAIDs.[26] Other relatively common
causes include chemotherapy, vaccines,
protamine and herbal preparations.[3]
Some medications (vancomycin,
morphine, x-ray contrast among others)
cause anaphylaxis by directly triggering
mast cell degranulation.[8]

The frequency of a reaction to an agent

partly depends on the frequency of its
use and partly on its intrinsic
properties.[27] Anaphylaxis to penicillin or
cephalosporins occurs only after it binds
to proteins inside the body with some
agents binding more easily than
others.[12] Anaphylaxis to penicillin
occurs once in every 2,000 to 10,000
courses of treatment, with death
occurring in fewer than one in every
50,000 courses of treatment.[12]
Anaphylaxis to aspirin and NSAIDs
occurs in about one in every 50,000
persons.[12] If someone has a reaction to
penicillins, his or her risk of a reaction to
cephalosporins is greater but still less
than one in 1,000.[12] The old
radiocontrast agents caused reactions in
1% of cases, while the newer lower
osmolar agents cause reactions in 0.04%
of cases.[27]

Venom
Venom from stinging or biting insects
such as Hymenoptera (ants, bees, and
wasps) or Triatominae (kissing bugs)
may cause anaphylaxis in susceptible
people.[7][28][29] Previous reactions, that
are anything more than a local reaction
around the site of the sting, are a risk
factor for future anaphylaxis;[30][31]
however, half of fatalities have had no
previous systemic reaction.[32]

Risk factors

People with atopic diseases such as

asthma, eczema, or allergic rhinitis are at
high risk of anaphylaxis from food, latex,
and radiocontrast agents but not from
injectable medications or stings.[3][8] One
study in children found that 60% had a
history of previous atopic diseases, and
of children who die from anaphylaxis,
more than 90% have asthma.[8] Those
with mastocytosis or of a higher
socioeconomic status are at increased
risk.[3][8] The longer the time since the
last exposure to the agent in question,
the lower the risk.[12]

Pathophysiology
Anaphylaxis is a severe allergic reaction
of rapid onset affecting many body
systems.[5][6] It is due to the release of
inflammatory mediators and cytokines
from mast cells and basophils, typically
due to an immunologic reaction but
sometimes non-immunologic
mechanism.[6]

Immunologic

In the immunologic mechanism,

immunoglobulin E (IgE) binds to the
antigen (the foreign material that
provokes the allergic reaction). Antigen-
bound IgE then activates FcεRI receptors
on mast cells and basophils. This leads
to the release of inflammatory mediators
such as histamine. These mediators
subsequently increase the contraction of
bronchial smooth muscles, trigger
vasodilation, increase the leakage of fluid
from blood vessels, and cause heart
muscle depression.[6][12] There is also an
immunologic mechanism that does not
rely on IgE, but it is not known if this
occurs in humans.[6]

Non-immunologic

Non-immunologic mechanisms involve

substances that directly cause the
degranulation of mast cells and
basophils. These include agents such as
contrast medium, opioids, temperature
(hot or cold), and vibration.[6][19] Sulfites
may cause reactions by both
immunologic and non-immunologic
mechanisms.[33]

Diagnosis
Anaphylaxis is diagnosed on the basis of
a person's signs and symptoms.[3] When
any one of the following three occurs
within minutes or hours of exposure to
an allergen there is a high likelihood of
anaphylaxis:[3]

1. Involvement of the skin or mucosal

tissue plus either respiratory
difficulty or a low blood pressure
causing symptoms
2. Two or more of the following
symptoms after a likely contact with
 an allergen:
a. Involvement of the skin or
mucosa
b. Respiratory difficulties
c. Low blood pressure
d. Gastrointestinal symptoms
3. Low blood pressure after exposure
to a known allergen

Skin involvement may include: hives,

itchiness or a swollen tongue among
others. Respiratory difficulties may
include: shortness of breath, stridor, or
low oxygen levels among others. Low
blood pressure is defined as a greater
than 30% decrease from a person's usual
blood pressure. In adults a systolic blood
pressure of less than 90 mmHg is often
used.[3]

During an attack, blood tests for tryptase

or histamine (released from mast cells)
might be useful in diagnosing
anaphylaxis due to insect stings or
medications. However these tests are of
limited use if the cause is food or if the
person has a normal blood pressure,[3]
and they are not specific for the
diagnosis.[17]

Classification

There are three main classifications of

anaphylaxis. Anaphylactic shock is
associated with systemic vasodilation
that causes low blood pressure which is
by definition 30% lower than the person's
baseline or below standard values.[14]
Biphasic anaphylaxis is the recurrence of
symptoms within 1–72 hours with no
further exposure to the allergen.[3]
Reports of incidence vary, with some
studies claiming as many as 20% of
cases.[34] The recurrence typically occurs
within 8 hours.[8] It is managed in the
same manner as anaphylaxis.[7]
Pseudoanaphylaxis or anaphylactoid
reactions are a type of anaphylaxis that
does not involve an allergic reaction but
is due to direct mast cell
degranulation.[8][35] Non-immune
anaphylaxis is the current term used by
the World Allergy Organization[35] with
some recommending that the old
terminology no longer be used.[8]

Allergy testing

Skin allergy testing being carried out on the right

arm
Patch test

Allergy testing may help in determining

the trigger. Skin allergy testing is
available for certain foods and
venoms.[17] Blood testing for specific IgE
can be useful to confirm milk, egg,
peanut, tree nut and fish allergies.[17]

Skin testing is available to confirm

penicillin allergies, but is not available for
other medications.[17] Non-immune
forms of anaphylaxis can only be
determined by history or exposure to the
allergen in question, and not by skin or
blood testing.[35]

Differential diagnosis

It can sometimes be difficult to

distinguish anaphylaxis from asthma,
syncope, and panic attacks.[3] Asthma
however typically does not entail itching
or gastrointestinal symptoms, syncope
presents with pallor rather than a rash,
and a panic attack may have flushing but
does not have hives.[3] Other conditions
that may present similarly include:
scrombroidosis and anisakiasis.[8]
Post-mortem findings

In a person who died from anaphylaxis,

autopsy may show an "empty heart"
attributed to reduced venous return from
vasodilation and redistribution of
intravascular volume from the central to
the peripheral compartment.[36] Other
signs are laryngeal edema, eosinophilia
in lungs, heart and tissues, and evidence
of myocardial hypoperfusion.[37]
Laboratory findings could detect
increased levels of serum tryptase,
increase in total and specific IgE serum
levels.[37]

Prevention
Avoidance of the trigger of anaphylaxis is
recommended. In cases where this may
not be possible, desensitization may be
an option. Immunotherapy with
Hymenoptera venoms is effective at
desensitizing 80–90% of adults and 98%
of children against allergies to bees,
wasps, hornets, yellowjackets, and fire
ants. Oral immunotherapy may be
effective at desensitizing some people to
certain food including milk, eggs, nuts
and peanuts; however, adverse effects
are common.[3] For example, many
people develop an itchy throat, cough, or
lip swelling during immunotherapy.[38]
Desensitization is also possible for many
medications, however it is advised that
most people simply avoid the agent in
question. In those who react to latex it
may be important to avoid cross-reactive
foods such as avocados, bananas, and
potatoes among others.[3]

Management
Anaphylaxis is a medical emergency that
may require resuscitation measures such
as airway management, supplemental
oxygen, large volumes of intravenous
fluids, and close monitoring.[7]
Administration of epinephrine is the
treatment of choice with antihistamines
and steroids (for example,
dexamethasone) often used as
adjuncts.[7] A period of in-hospital
observation for between 2 and 24 hours
is recommended for people once they
have returned to normal due to concerns
of biphasic anaphylaxis.[8][12][34][39]

Epinephrine

An old version of an EpiPen auto-injector

Epinephrine (adrenaline) is the primary

treatment for anaphylaxis with no
absolute contraindication to its use.[7] It
is recommended that an epinephrine
solution be given intramuscularly into the
mid anterolateral thigh as soon as the
diagnosis is suspected. The injection
may be repeated every 5 to 15 minutes if
there is insufficient response.[7] A second
dose is needed in 16-35% of episodes
with more than two doses rarely
required.[7] The intramuscular route is
preferred over subcutaneous
administration because the latter may
have delayed absorption.[7][40] Minor
adverse effects from epinephrine include
tremors, anxiety, headaches, and
palpitations.[3]

People on β-blockers may be resistant to

the effects of epinephrine.[8] In this
situation if epinephrine is not effective
intravenous glucagon can be
administered which has a mechanism of
action independent of β-receptors.[8]

If necessary, it can also be given

intravenously using a dilute epinephrine
solution. Intravenous epinephrine,
however, has been associated both with
dysrhythmia and myocardial infarction.[7]
Epinephrine autoinjectors used for self-
administration typically come in two
doses, one for adults or children who
weigh more than 25 kg and one for
children who weigh 10 to 25 kg.[41]

Adjuncts
Antihistamines (both H1 and H2), while
commonly used and assumed effective
based on theoretical reasoning, are
poorly supported by evidence.[42][43] A
2007 Cochrane review did not find any
good-quality studies upon which to base
recommendations[43] and they are not
believed to have an effect on airway
edema or spasm.[8] Corticosteroids are
unlikely to make a difference in the
current episode of anaphylaxis, but may
be used in the hope of decreasing the
risk of biphasic anaphylaxis. Their
prophylactic effectiveness in these
situations is uncertain.[34] Nebulized
salbutamol may be effective for
bronchospasm that does not resolve
with epinephrine.[8] Methylene blue has
been used in those not responsive to
other measures due to its presumed
effect of relaxing smooth muscle.[8]

Preparedness

People prone to anaphylaxis are advised

to have an "allergy action plan." Parents
are advised to inform schools of their
children's allergies and what to do in
case of an anaphylactic emergency. The
action plan usually includes use of
epinephrine autoinjectors, the
recommendation to wear a medical alert
bracelet, and counseling on avoidance of
triggers.[44] Immunotherapy is available
for certain triggers to prevent future
episodes of anaphylaxis. A multi-year
course of subcutaneous desensitization
has been found effective against stinging
insects, while oral desensitization is
effective for many foods.[13]

Prognosis
In those in whom the cause is known and
prompt treatment is available, the
prognosis is good.[45] Even if the cause is
unknown, if appropriate preventative
medication is available, the prognosis is
generally good.[12] If death occurs, it is
usually due to either respiratory (typically
asphyxia) or cardiovascular causes
(shock),[6][8] with 0.7–20% of cases
causing death.[12][16] There have been
cases of death occurring within
minutes.[3] Outcomes in those with
exercise-induced anaphylaxis are
typically good, with fewer and less severe
episodes as people get older.[21]

Epidemiology
The number of people who get
anaphylaxis is 4–100 per 100,000
persons per year,[8][46] with a lifetime risk
of 0.05–2%.[47] About 30% of people get
more than one attack.[46] Exercise-
induced anaphylaxis affects about 1 in
2000 young people.[24]
Rates appear to be increasing: with the
numbers in the 1980s being
approximately 20 per 100,000 per year,
while in the 1990s it was 50 per 100,000
per year.[13] The increase appears to be
primarily for food-induced
anaphylaxis.[48] The risk is greatest in
young people and females.[7][8]

Anaphylaxis leads to as many as 500–

1,000 deaths per year (2.7 per million) in
the United States, 20 deaths per year in
the United Kingdom (0.33 per million),
and 15 deaths per year in Australia (0.64
per million).[8] Another estimate from the
United States puts the death rate at 0.7
per million.[49] Mortality rates have
decreased between the 1970s and
2000s.[50] In Australia, death from food-
induced anaphylaxis occur primarily in
women while deaths due to insect bites
primarily occur in males.[8] Death from
anaphylaxis is most commonly triggered
by medications.[8]

History
The term aphylaxis was coined by
Charles Richet in 1902 and later changed
to anaphylaxis due to its nicer quality of
speech.[17] In his experiments, Richet
injected a dog with sea anemone
(Actinia) toxin in an attempt to protect it.
Although the dog had previously