Urticaria, Angioedema, and Anaphylaxis

Jennifer Pier, MD,* Theresa A. Bingemann, MD*†

*University of Rochester, Rochester, NY
†
Department of Allergy, Immunology, and Rheumatology, Rochester Regional Health, Rochester, NY

Practice Gaps
1. Recognize that chronic urticaria is not likely to be food related. Food
testing is not indicated.
2. Understand the possible causes of urticaria.
3. Know the appropriate treatment of allergic and anaphylactic reactions.

Abstract
Urticaria and, to a lesser extent, angioedema are common occurrences in
the pediatric population. There are multiple causes of acute and chronic
urticaria and angioedema. Most causes are benign, although they can be
worrisome for patients and their parents. An allergist should evaluate
acute urticaria and/or angioedema if there are concerns of an external
cause, such as foods or medications. Chronic urticaria and angioedema
can severely affect quality of life and should be managed aggressively
with antihistamines and immunomodulators if poorly controlled. Chronic
symptoms are unlikely to be due to an external cause. Anaphylaxis is a
more serious allergic condition characterized by a systemic reaction
involving at least 2 organ systems. Anaphylaxis should be initially
managed with intramuscular epinephrine. Patients who experience
AUTHOR DISCLOSURE Drs Pier and
Bingemann have disclosed no financial anaphylaxis should be evaluated by an allergist for possible causes; if
relationships relevant to this article. This found, avoidance of the inciting antigen is the best management. All
commentary does contain a discussion of an
patients should also be given an epinephrine autoinjector and an action
unapproved/investigative use of a
commercial product/device in that there is no plan. Foods are a common cause of anaphylaxis in the pediatric
Food and Drug Administration (FDA) approval population. New evidence suggests that the introduction of highly
for cyclosporine in chronic urticaria. Also,
antihistamines are recommended for use in allergic foods is safe in infancy and should not be delayed. In addition, the
non–FDA-approved doses in accordance with early introduction of foods such as peanuts may help prevent the
the literature for chronic urticaria and
development of food allergies.
angioedema. Off-label use of agents for
hereditary angioedema prophylaxis is also
discussed.

ABBREVIATIONS Objectives After completing this article, readers should be able to:
AAP American Academy of Pediatrics
EIA exercise-induced anaphylaxis 1. Identify the causes of urticaria, angioedema, and anaphylaxis.
FDA Food and Drug Administration
2. Understand how to treat acute and chronic urticaria.
FDEIA food-dependent exercise-induced
anaphylaxis
Ig immunoglobulin

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 3. Understand when and how epinephrine should be administered in the
treatment of allergic reactions.

URTICARIA and 95% of peanut/tree nut–allergic patients developed

symptoms within 20 minutes of exposure. (6)(7) This can
Urticaria presents as raised, erythematous, and generally
help determine the potential trigger. Acute urticaria is
intensely pruritic wheals. Individual lesions usually last
treated with long-acting, nonsedating antihistamines, such
less than 24 hours but can migrate throughout the body
as cetirizine or fexofenadine, until there is resolution. If a
and do not leave skin changes after resolution. Acute
triggering antigen is found, avoidance is the definitive
urticaria, which is most common in the pediatric popula-
treatment (Table 2).
tion, occurs for less than 6 weeks, whereas chronic urti-
caria occurs most days of the week for more than 6 weeks.
Chronic urticaria can be further delineated as spontaneous Chronic Urticaria
or inducible. The prevalence of chronic urticaria is estimated to be 0.5%
Urticaria is caused by the activation of dermal mast cells. to 5% in all ages, with the prevalence in children estimated
Mast cells have the high-affinity receptor for immunoglob- to be 0.1% to 0.3%. (8)(9) The mean age at presentation is
ulin (Ig) E on the surface, which can be activated by cross- 6.7 years. (10) Spontaneous chronic urticaria, which is the
linking with IgE. Mast cells can also be activated through the most common type in children, has no known underlying
interaction of IgG with the IgE receptor. This activation cause or triggers. Inducible chronic urticaria is associated
results in intracellular signaling and eventual downstream with a physical stimulus. These can include pressure, cold,
effects. Degranulation of the mast cell results in the release sun, and vibration. The most common cause is dermato-
of histamine, serotonin, proteases, and tumor necrosis graphic urticaria, which is estimated to account for 38% of
factor a. (1) Activated mast cells also release cytokines, such cases. (10) Cholinergic urticaria is another subset of phys-
as interleukin-1, which results in continued inflammation. ical urticaria that results from an increase in body tem-
(1) Together, these substances result in the development of perature, such as when sweating, exercising, or taking a
inflammation and, eventually, hives. hot shower. (8) Cholinergic urticaria wheals are usually
small and pinpoint. (8) Chronic urticaria has also been
associated with infections, such as Helicobacter pylori,
Acute Urticaria Epstein-Barr virus, hepatitis B, and hepatitis C. (10) If
Approximately 10% to 20% of the population will experience the history is suggestive of chronic urticaria, no specific
acute urticaria at some time in their life. (2) Acute urticaria diagnostic evaluation is indicated. If symptoms are sug-
has many causes, with the most common being viral infec- gestive of urticarial vasculitis (lesions that last longer than
tions, which has been attributed to approximately 40% of 24 hours, skin changes such as discoloration or bruising,
acute urticaria cases in both adults and children, with close or lesions that are palpable/nonblanching), the patient
to 60% in pediatric cases alone. (3)(4) Note that urticaria can should have a skin biopsy.
occur both during and after an illness. Other potential Chronic urticaria is more common in patients, including
causes of acute urticaria include medications (6.3%), insects children, with autoimmune disease. Both hypothyroidism
(2.5%), and foods (1.3%) (Table 1). (5) As these percentages and hyperthyroidism are more common in patients with
show, a specific cause of urticaria cannot always be identi- chronic urticaria. In addition, patients with chronic urticaria
fied. An allergy evaluation, including percutaneous skin are more likely to have thyroid autoantibodies even with
prick testing and serum specific IgE levels, is warranted normal thyroid function. Other autoimmune diseases found
in the appropriate clinical setting, such as urticaria associ- in patients with chronic urticaria include celiac disease,
ated with food ingestion or medications. Of note, most IgE- Sjögren disease, systemic lupus erythematosus, rheumatoid
mediated reactions, such as acute urticaria, occur within 2 arthritis, type 1 diabetes mellitus, and cryoglobulinemia.
hours of exposure. Two studies looking at food reactions (11)
showed that 100% of milk-allergic patients developed symp- Although chronic urticaria is not life-threatening, it greatly
toms within 60 minutes of exposure, 79% of egg-allergic affects quality of life. The Chronic Urticaria Quality of Life
patients developed symptoms within 90 minutes of exposure, Questionnaire is a validated set of questions to help assess

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TABLE 1. Causes of Acute and Chronic Urticaria
ACUTE URTICARIA CHRONIC URTICARIA

Illness Spontaneous
Viral Physical
Bacterial Cold
Parasitic Solar
Medications Aquagenic
Antibiotics Pressure
Nonsteroidal anti-inflammatory drugs Vibratory
Narcotics Cholinergic
Radiocontrast media Autoimmune
Insects
Wasps
Hornets
Bees
Yellow jackets
Fire ants
Foods
Aeroallergens

the effect of chronic urticaria (https://www.itchingforanswers. loratadine, and fexofenadine are safe and effective in the pedi-
ca/docs/CU-Q2OL-Questionnaire.pdf ). Compared with atric population. For chronic urticaria in pediatric patients
healthy individuals, patients with chronic urticaria had (age 1–17 years), doses may need to be increased to 4 times
reduced physical and psychological scores. (12) In addi- the standard dose to be effective. (10) This dosing is not
tion, scores were similar to patients with acne and worse approved by the Food and Drug Administration (FDA), and
than patients with psoriasis. (12) Other studies have also risks (mild increase in the incidence of somnolence and
found higher levels of anxiety and depression in these greater risk of adverse effects such as dry mouth and
patients. (12) constipation) and benefits (improved control of urticaria)
First-line therapy for chronic urticaria is second-generation, should be reviewed with patients/caregivers. For patients
nonsedating antihistamines (Table 2). Cetirizine, levocetirizine, unresponsive to this therapy, sedating antihistamines, such

TABLE 2. Treatment of Urticaria and Angioedema

CONDITION TREATMENT

Acute urticaria Long-acting, nonsedating antihistamines

Avoidance of trigger if identified
Chronic urticaria/angioedema Long-acting, nonsedating antihistamines at
standard dosing
Increase dose of long-acting, nonsedating
antihistamine up to 4 times standard dosing
Sedating antihistamines
Omalizumab
Cyclosporine
Hereditary angioedema Prophylaxis: Berinert, Cinryze, and Haegarda
Treatment: Berinert, ecallantide, conestat alfa,
and icatibant

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 as hydroxyzine, at standard dosing can be tried. When vascular permeability. This type of angioedema is com-
patients are unresponsive to high-dose antihistamines, monly accompanied by urticaria, suggesting that an-
omalizumab has been shown to be effective. Omalizumab gioedema without urticaria is bradykinin mediated
is a monoclonal antibody that targets IgE and limits and not histamine mediated. Bradykinin results in
binding for IgE to high-affinity IgE receptors on mast cells vasodilation and increased vascular permeability. (19)
and results in downregulation of the IgE receptor. Oma- Angioedema can result when too much bradykinin is
lizumab is approved for patients 12 years and older for being synthesized or when it is not being broken down.
chronic urticaria. Dosing is 150 or 300 mg subcutaneously (19)
every 4 weeks and is not dependent on body weight or There are many causes of angioedema. Most cases are
serum IgE level. (10) Cyclosporine has also been shown to idiopathic, with no underlying cause identified. Angioe-
improve hives and pruritus in patients with chronic urti- dema can be associated with allergic triggers, such as
caria; however, this is an off-label use and is reserved for foods, medications, insect stings, and aeroallergens.
refractory cases given potential adverse effects (kidney (20) These allergens cause angioedema through IgE-
damage, hypertension, infection, headache). (1) The typical mediated mechanisms. Delayed angioedema has been
starting dose is 3 mg/kg divided into 2 daily doses. Blood described in the pediatric population after ingestion of
pressure, kidney function, and fasting lipid levels should mammalian meats, which is thought to be due to allergy
be monitored closely while patients are receiving cyclo- to galactose-a-1,3-galactose. (21) Angioedema due to an
sporine. (13) Fortunately, chronic urticaria is self-limiting allergy usually presents with urticaria, but it has been
in many patients, especially children and those with no estimated that 10% to 15% of patients determined to have
identifiable trigger; almost 50% are in remission after 1 angioedema with an allergic trigger presented with angioe-
year. (14) Approximately 30% of patients may continue to dema alone. (17)
have symptoms beyond 5 years, and this group has not Infections, particularly viral infections, are a common
been well studied. (15) cause of angioedema, especially in the pediatric population.
Although the appearance of chronic urticaria is alarm- Implicated infectious agents include herpes simplex, cox-
ing, it is not life-threatening, and epinephrine autoinjector sackie A and B, hepatitis B, and Epstein-Barr virus; angioe-
is not routinely indicated. The exception is cold-induced dema has been associated with otitis media, pharyngitis,
urticaria. Extensive cold contact, for example with water sinusitis, and urinary tract infections. (17) Parasitic infec-
submersion, has the potential to result in anaphylaxis. (16) tion, such as with trichinosis, can cause angioedema. (13)
Therefore, patients with cold-induced urticaria should Medications such as nonsteroidal anti-inflammatory drugs
be prescribed an epinephrine autoinjector and educated and angiotensin-converting enzyme inhibitors can also
on how to use it. (16) Cold avoidance as able is also cause angioedema. Angiotensin-converting enzyme inhib-
recommended. itor angioedema can present at any time while taking the
medication. Swelling occurs over hours and can last 1 to 3
days. (18)
ANGIOEDEMA
Hereditary angioedema is an uncommon (1 in 10,000 to
Angioedema is nonpitting swelling of the submucosal or 1 in 150,000 affected worldwide), autosomal dominant
subcutaneous tissue. Typically this is asymmetrical, non- condition that causes decreased levels or decreased func-
dependent, and nonpruritic. It can occur in the extremities, tion of C1-inhibitor protein, which leads to increased levels
abdomen, head/neck, and throat, which can be a medical of bradykinin. C1-inhibitor dysfunction can be acquired,
emergency due to airway compromise. (17) Angioedema commonly due to underlying autoimmune disease or
may be associated with urticaria (w40% of cases), usually malignancy, which is rare in the pediatric population.
due to histamine release, or without urticaria, typically kinin (22) These forms of angioedema usually do not present
mediated. (18) Studies have suggested that 15% to 25% of the with urticaria, which can be a helpful distinguishing factor.
population experiences an episode of angioedema at some In patients with hereditary angioedema, symptoms ini-
point in life. (15) Similar to urticaria, angioedema is classi- tially present during late childhood and early adolescence.
fied as acute if it occurs for less than 6 weeks and as chronic Approximately 50% of patients have their first attack before
if it occurs for more than 6 weeks. 10 years of age. (22) Symptoms typically worsen during
Angioedema can be caused by mast cell degranulation, puberty and continue throughout adulthood. The time
through similar mechanisms as described previously herein between attacks is variable and can range from weeks to
for urticaria, resulting in increased inflammation and years. Most attacks occur without an identifiable trigger,

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but some proposed triggers include cold, trauma, medi- mediated it does not typically respond to corticosteroids,
cations, infections, and stress. (22) antihistamines, or epinephrine.
There are many conditions that mimic angioedema.
Contact and irritant dermatitis can cause swelling and
ANAPHYLAXIS
erythema. (13) Schnitzler syndrome typically presents with
angioedema, nonpruritic rash, fever, and bone pain. (23) Anaphylaxis is defined as an acute, potentially life-
Swelling can also be a concern in a variety of connective threatening systemic reaction that may include respira-
tissue disorders, such as systemic lupus erythematosus, tory distress, hypotension, urticaria, angioedema, and
dermatomyositis, and Sjogren syndrome. Structural abnor- gastrointestinal symptoms (vomiting, diarrhea). (24) Al-
malities, such as superior vena cava syndrome and other though urticaria can be very concerning for parents, ana-
causes of obstruction to the venous outflow tract, can create phylaxis occurs more rapidly and involves more than 1
swelling that mimics angioedema. (22) body system. Anaphylaxis is caused by a similar mechanism
Diagnosis of angioedema relies heavily on clinical his- as urticaria and angioedema, resulting in systemic vasodi-
tory, including symptoms, associated physical findings, lation, increased vascular permeability, and bronchospasm.
and possible triggers. If history is suggestive of an IgE- Anaphylaxis can present differently at different ages. Chil-
mediated mechanism, percutaneous skin testing and/or dren younger than 6 years are more likely to experience
antigen specific IgE serum testing should be performed. If vomiting and cough. Older children (approximately 12 years
there is concern for hereditary or acquired angioedema of age) are more likely to experience throat/chest tightness,
(patients without accompanied urticaria), a C4 level is an dizziness, hypotension, and cardiovascular collapse. (25) It
appropriate initial screen, which would be low in these is estimated that the lifetime prevalence of anaphylaxis is
conditions. A C1-inhibitor level and function can be ob- 0.05% to 2.0%. (26) The incidence of anaphylaxis is 3 times
tained if there is high clinical suspicion. If the results of higher in patients 0 to 4 years of age than in any other age
this testing are normal, the diagnosis of idiopathic urti- group, and most episodes occur within the first 2 years of
caria is made, and no further evaluation is typically life. (26) Death from anaphylaxis is rare (0.12–1.06 deaths
warranted. per million person-years). (27) Drugs are the most common
First-line management of angioedema is avoidance if a cause of fatal anaphylaxis. (28) In pediatric patients, deaths
trigger has been identified. Similar to chronic urticaria, are most common in adolescents, which has been attributed
antihistamines titrated up to 4 times standard dosing have to an increase in risk-taking behaviors. (26) Risk factors for
been used (Table 2). For refractory patients, sedating an- severe anaphylaxis include asthma and underlying respira-
tihistamines (such as hydroxyzine) or immunomodula- tory/cardiac disease. (29)
tors (omalizumab or cyclosporine) have been added in There are many causes of anaphylaxis (Table 3). In infants
the pediatric population. (17) For patients with hereditary and young children, the most common cause of anaphylaxis
angioedema, there are also numerous FDA-approved C1- is food, with dairy, egg, and peanut being the most com-
inhibitor replacements for both acute attacks and prophy- monly identified culprits. (25) Tree nuts are also a cause of
laxis. There are currently 3 plasma-derived C1-inhibitor anaphylaxis in school-age children, with one studying find-
concentrates—Berinert
, Cinryze
, and Haegarda
— ing the highest prevalence of cashew and hazelnut. (25)
available for prophylaxis in the United States. Cinryze (Takeda Galactose-a-1,3-galactose in mammalian meat can caused
Pharmaceutical Co, Lexington, MA) is FDA approved for pa- delayed angioedema, as mentioned earlier, and anaphylaxis
tients 6 years and older for prophylaxis; it is used off-label for several hours after exposure. (21) Food dye is not a common
acute treatment. Berinert (CSL Behring, King of Prussia, PA) cause of food allergy. Drugs are also a cause of anaphylaxis
is FDA approved for pediatric patients (age ‡6 years) as a (drug-induced anaphylaxis), and reactions typically appear
treatment for hereditary angioedema and is also used off- in adolescence. Common culprits include antibiotics, anal-
label for prevention. Haegarda (CSL Behring) is approved gesics, and radiocontrast media, which can cause anaphy-
for patients 12 years and older for prophylaxis. Other acute laxis through IgE-mediated mechanisms and direct mast
treatments include a kallikrein inhibitor, ecallantide (age ‡12 cell degranulation. (30) Shellfish allergy does not predispose
years); a recombinant C1-inhibitor preparation, conestat alfa to radiocontrast media allergy. (31) Latex is also a well-known
(age ‡13 years); and a bradykinin B2 receptor antagonist, cause of anaphylaxis. Current research suggests that in the
icatibant (age ‡18 years). Berinert is the only FDA-approved general population the prevalence of latex allergy is approx-
treatment for acute flares in patients younger than 12 years. imately 4.3%. (32) However, the rates are higher in health-
(18) Because hereditary angioedema is not histamine care workers (9.7%) and susceptible patients (7.2%), such as

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 those with spina bifida and bladder exstrophy. (32) Anaphy- can be given safely; however, providers should be aware of
laxis can occur after blood transfusion as well. This can the potential risk of systemic reaction. Review of the
occur in patients with IgA deficiency due to antibodies literature suggests that systemic reaction to subcutaneous
against donor IgA. (33) allergen immunotherapy is less than 1% but can increase
Life-threatening systemic reactions to insect venom are up to 34% on rush protocols (where patients are given
rare. There are approximately 40 deaths per year due to doses more frequently to reach maintenance dosing
insect venom. (34) The risk of a severe systemic reaction is quicker). (39) The risk of systemic reaction increases
approximately 0.4% to 0.8% in children and 3% in adults. during the height of pollen season and with dosing errors.
(35)(36) Most reactions to insect venom are transient local (39) Patients should receive immunotherapy only when
swelling, erythema, or pain, which can be managed sup- they are feeling well, and an assessment of lung function
portively. Large local reactions are characterized by swell- should be obtained before receiving immunotherapy for
ing that is more than 10 cm in a continuous area. Patients patients with asthma. Patients should be monitored for 30
with large local reactions have a less than 10% chance of minutes after injections because most reactions would
anaphylaxis and, therefore, do not require insect venom occur during this time. Sublingual immunotherapy is
immunotherapy. (37) Patients with systemic cutaneous available for grass (age 5–65 years), ragweed (age 18–65
reactions are also considered to be at low risk for anaphy- years), and dust mites (age 18–65 years). Patients receive
laxis and do not require immunotherapy. However, life- the first dose in a provider’s office and take subsequent
style considerations (such as frequent time outdoors or doses at home. The FDA requires that a script for self-
hobbies with exposure to stinging insects), risk factors for injectable epinephrine be provided. The risk of systemic
future stings, and distance from health-care facilities need reaction is lower with sublingual therapy than with sub-
to be considered. Patients with a history of anaphylaxis to cutaneous therapy and is estimated to be approximately 1
venom should be referred to an allergist for testing and per 100 million. (40)
likely initiation of venom immunotherapy because they Exercise-induced anaphylaxis (EIA) and food-dependent
have at least a 50% risk of anaphylaxis with subsequent EIA (FDEIA) are 2 rare but significant entities that clinicians
stings. Venom immunotherapy is effective at decreasing should be aware of. In EIA, symptoms of anaphylaxis can be
the risk to less than 5%. (38) In addition to venom immu- caused by a variety of activities, including yard work, walk-
notherapy there is also fire ant immunotherapy. Unlike ing, and running. (41) Symptoms can occur during or after
insect venom immunotherapy, the natural history is not as physical activity, but it is usually difficult to predict attacks.
well established, and patients with limited systemic cuta- In FDEIA, symptoms occur when there is an ingestion of
neous reactions can be considered for immunotherapy. the causative food minutes to several hours before exercise.
(38) Common causative foods include seafood, dairy, and wheat.
Immunotherapy is used for the treatment of allergic Avoidance is the gold standard of treatment. Patients with
rhinoconjunctivitis and insect venom allergy. Subcutane- FDEIA should avoid food ingestion 4 to 6 hours before
ous immunotherapy is commonly given in pediatric exercise. (41)
offices for patient ease and preference. Immunotherapy The mainstay treatment of acute anaphylaxis is the
administration of 1:1,000 epinephrine (0.01 mg/kg, maxi-
mum of 0.5 mg) intramuscularly in the anterolateral thigh,
TABLE 3. Causes of Anaphylaxis which can be repeated every 5 to 15 minutes as needed. (42)
There are no absolute contraindications to the administra-
Foods: peanuts, tree nuts, cow milk, eggs, shellfish, soy, wheat, fish tion of epinephrine, and the delay in administration is
Medications: antibiotics (penicillins, cephalosporins), radiocontrast associated with progression to severe anaphylaxis and
media, neuromuscular blocking agents, chemotherapy, potential death. (42) Airway protection and cardiovascular
nonsteroidal anti-inflammatory drugs, aspirin
support with intravenous fluids should also be used in acute
Insects: wasps, hornets, bees, yellow jackets, fire ants management. In addition to the previously mentioned
Allergy immunotherapy: subcutaneous, sublingual, oral therapies, b-adrenergic agonists, such as albuterol, can be
immunotherapy
used. (42) Antihistamines can be used for symptom control
Latex of urticaria and pruritus that may accompany anaphylaxis
Exercise-induced, food-dependent exercise-induced but should not be used as first-line therapy. In addition,
Idiopathic there is limited evidence that corticosteroids should be used
in anaphylaxis because they have not been shown to

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decrease the risk of biphasic reactions. (43) In a biphasic Parents and children, when age appropriate, should be
reaction, patients will recover from their initial anaphylaxis educated on how to use the autoinjector, with correct use
but will have a recurrence of symptoms without being demonstrated during the visit. They should also be edu-
exposed to the triggering antigen. The second reaction cated on the proper storage and the necessity to carry 2
typically occurs 8 to 10 hours after the initial reaction. autoinjectors at all times given that 30% of patients with
(44) The reaction should be managed as any anaphylaxis. anaphylaxis require a second dose of epinephrine. (42)
Patients should be monitored for 4 to 8 hours after expe- Parents should also be educated that when using an
riencing anaphylaxis. Longer monitoring could be consid- epinephrine autoinjector it is important to immobilize
ered in patients with asthma, in those with a history of the leg during administration to prevent lacerations and
severe/biphasic anaphylaxis, and/or if they required multi- incomplete administration of the medication. If the needle
ple doses of epinephrine. (44) comes out, it should not be inserted again. (47) There are
Patients with a history of anaphylaxis should be pre- websites that show patients how to use an epinephrine
scribed an epinephrine autoinjector. An epinephrine auto- autoinjector, and these should be provided to patients when
injector should also be prescribed to children with a history an autoinjector is prescribed (eg, www.epinephrineautoinject.
of food allergy, even if their initial reaction did not result in com, www.epipen.ca, www.foodallergy.org, www.auvi-q.com).
anaphylaxis. Previous allergic reactions do not predict future Patients and their families should also be given an action
reactions, and anaphylaxis can occur with any allergen plan, with instructions on what symptoms warrant the use
exposure. Children weighing 10 kg or less can receive a of epinephrine. The American Academy of Pediatrics (AAP)
0.1-mg dose (through Auvi-Q
; Kaléo, Richmond, VA), 10 Section on Allergy and Immunology has an allergy and
to 30 kg can receive 0.15 mg, and greater than 30 kg can anaphylaxis plan that can be found on the AAP website
receive 0.3 mg. Auvi-Q is the only epinephrine autoinjector (https://healthychildren.org/SiteCollectionDocuments/
device approved for pediatric patients weighing less than 10 AAP_Allergy_and_Anaphylaxis_Emergency_Plan.pdf). (48)
kg, and it has a shorter needle length. There are many Patients are commonly advised to use epinephrine for
devices for the other weight groups. Table 4 compares some any respiratory symptoms and/or if more than 2 body
of the available devices and their average costs, which will systems are involved, such as hives (skin) with vomiting
vary based on insurance plans. Epinephrine kits with vials or (gastrointestinal). Antihistamines can be used for mild
ampules of epinephrine are a low-cost alternative. However, allergic reactions, such as itching or a few hives, but are
these are not routinely recommended for home use given not first-line treatment for anaphylaxis. Food avoidance
the high rate of error with dosing and timely administration. practices should be discussed, with potential referral to a
(46) dietitian who is familiar with pediatric food allergies. Any

TABLE 4. Comparison of Epinephrine Autoinjectors (45)

AVERAGE COST FOR A 2-
DEVICE DETAILS DEVICE PACKAGE ASSISTANCE PROGRAMS

EpiPen
, EpiPen Jr
(Mylan Inc, Available in 0.15-mg and 0.3-mg $610 Savings card, patient assistance
Canonsburg, PA) prefilled syringes program, school programs
Adrenaclick
(Amedra Same as above $395 Savings coupons
Pharmaceuticals LLC, Horsham,
PA)
Generic autoinjector Same as above $300
Auvi-Q
Credit card sized with audio cues $4,900 Free for commercial insurance,
Available in 0.1-, 0.15-, and 0.3-mg patient assistance program
dosing
Smaller needle size
SymjepiTM (Sandoz Inc, Princeton, Only available in 0.3-mg prefilled $250
NJ) syringes currently
Epinephrine kits Ampules or vials of epinephrine with $20
needle and syringes

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 patient with anaphylaxis should be referred to an allergist for now recommended that infants in these high-risk popu-
evaluation, who can perform testing when appropriate and lations be referred to an allergist at approximately 4 to 6
reinforce teaching. months of age for skin testing, serum IgE testing, and
Food allergy is a significant concern among parents and likely oral challenge to peanut antigen when indicated. (50)
pediatricians. A large population study in Australia used This testing allows for further risk stratification of high-
food challenges to verify food allergies in infants and risk patients, with the hopes of capturing patients who
estimated the prevalence of food allergies to be approxi- have not yet developed peanut sensitization. These patients
mately 10% at 1 year of age. (49) A follow-up study at 4 can then undergo oral challenge to peanut to confirm
years of age showed the prevalence of food allergies to be tolerance. For children with mild eczema, pediatricians
approximately 4%. (49) In recent years, significant studies should encourage the introduction of peanut antigen in-
have shown that early introduction of foods has the poten- to the diet at 6 months of age. This can be accomplished
tial to decrease the risk of developing food allergies, through thinned peanut butter and/or peanut butter–
leading to a change in recommendations of introducing flavored puffed maize (Bamba; Osem USA Inc, Englewood
highly allergic foods. The LEAP (Learning Early About Cliffs, NJ). Infants and young children should not be given
Peanut Allergy) trial showed that early (5–11 months of whole peanuts because they pose a choking hazard. Those
age) introduction of peanuts into high-risk (severe eczema without eczema can be introduced to peanut antigen per
and/or known egg allergy) infants’ diets greatly decreased family preference.
the frequency of the development of peanut allergy in these There are currently no other recommendations on the early
high-risk patients. Based on the results of this study, it is introduction of foods for the prevention of allergies. For example,
the STEP (Starting Time of Egg Protein) trial showed that early
introduction of egg protein into infants’ diets did not signifi-
cantly affect (although there was a trend toward significance) the
Summary development of egg allergy. (51) However, the early introduction
• Based on epidemiologic studies, acute urticaria is common in
of foods has been shown to be safe. In the EAT (Enquiring About
pediatric patients. (2) Although less common than acute urticaria,
chronic urticaria also affects the pediatric population. Chronic
Tolerance) trial, breastfed infants were given highly allergenic
urticaria is not life-threatening but can severely affect quality of foods at 6 months of age, and there were no cases of anaphylaxis.
life and warrants aggressive management. (8)(9)(12) Based on (52) Currently it is not recommended to delay the introduction of
some research evidence as well as consensus data, chronic foods, including highly allergenic foods. Infants should be
urticaria should initially be managed with high-dose introduced to these foods, as well as other non–highly allergic
antihistamines. Patients may require up to 4 times standard
foods, when developmentally appropriate (usually 4–6 months
dosing for symptom control. (10)
of age). This has the potential to limit the development of food
• Based on some research evidence as well as consensus data,
patients with chronic urticaria who do not respond to
allergies with little risk of a systemic reaction. (53)
antihistamines may benefit from omalizumab. (10)
• Based on epidemiologic studies, angioedema is less frequent PRACTICAL TIPS
than urticaria but can occur in the pediatric population (with or
without hives). Angioedema can be treated similarly to chronic • Chronic urticaria rarely has an external trigger. Labo-
urticaria. (15) ratory evaluation and/or skin prick testing is not
• Based on epidemiologic data, anaphylaxis in pediatric patients is indicated in the absence of other systemic symptoms.
most commonly due to foods, medications, and insects. (25)(29) • Epinephrine is first-line therapy for anaphylaxis.
First-line treatment for anaphylaxis is intramuscular epinephrine.
Patients with a known allergy should be prescribed an
(41) Corticosteroids, albuterol, and antihistamines can be used for
symptomatic treatment of anaphylaxis. (43) Patients with a epinephrine autoinjector and educated on how to use it.
history of anaphylaxis should be prescribed an epinephrine • Early introduction of peanuts has been shown to
autoinjector and an anaphylaxis action plan. (42)(48) decrease the risk of peanut allergy. Patients with severe
• Based on some research evidence, early introduction of peanut eczema and/or egg allergy should be referred to an
(approximately 4–6 months of age) may decrease the likelihood allergist for possible peanut introduction at 4 to 6
of the development of peanut allergies in high-risk infants. (50) months of age.
Parents should not delay the introduction of other highly
allergenic foods. (53)
References for this article are at http://pedsinreview.aappu-
blications.org/content/41/6/283.

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2020 Pediatrics in Review
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studying after eating dinner when she suddenly developed swelling of her face and lips.
She is anxious and has some vague abdominal pain, but no vomiting, diarrhea, or
respiratory distress. She is not itchy. Her physical examination is remarkable for nonpitting
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 5. A 2-year-old child is brought to the urgent care center after developing a widespread rash
consisting of red, raised wheals approximately 3 to 5 cm in diameter, oval in shape, and
scattered over his entire body. He vomited twice in the car and is breathing rapidly, with a
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A. Albuterol, 2.5 mg, nebulized inhalation.
B. Diphenhydramine, 12.5 mg orally.
C. Epinephrine, 0.15 mg intramuscularly.
D. Epinephrine, 0.15 mg intravenously.
E. Epinephrine, 0.15 mg subcutaneously.

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 Urticaria, Angioedema, and Anaphylaxis
Jennifer Pier and Theresa A. Bingemann
Pediatrics in Review 2020;41;283
DOI: 10.1542/pir.2019-0056

Updated Information & including high resolution figures, can be found at:
Services http://pedsinreview.aappublications.org/content/41/6/283
References This article cites 50 articles, 4 of which you can access for free at:
http://pedsinreview.aappublications.org/content/41/6/283.full#ref-list
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:immunology_sub
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 Urticaria, Angioedema, and Anaphylaxis
Jennifer Pier and Theresa A. Bingemann
Pediatrics in Review 2020;41;283
DOI: 10.1542/pir.2019-0056

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/41/6/283

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
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