Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9e

Chapter 14: Allergy and Anaphylaxis Brian H. Rowe; Brian Grunau

Content Update: TXA for ACE-Inhibitor- induced angioedema April 2020

Tranexamic acid (TXA) is a readily available, safe, and cost-e�ective therapy for acute trauma and bleeding. Ithas been used in ACE-Inhibitor-induced angioedema and idiopathic angioedema, and  is recommended bysome authors (1).  The mechanism of action is unknown, but it may prevent the plasmin-dependentformation of bradykinin (2) No randomized controlled trials are available (3), but weak evidence fromobservational studies suggests that TXA can be an alternative strategy for ACEI oridiopathic angioedema. The e�ectiveness of TXA in hereditary Cl inhibitor-deficiency angioedema is not ascompelling as for ACEI angioedema (4,5) For a potential airway emergency, the dose is 1 gram IV. See Table14-6.

1) van den Elzen M et al 'E�icacy of treatment of non-hereditary angioedema.' Clin Rev Allergy Immunol2018:54 (3):412-431 PMID 276720782)

2)She�er AL et al 'Tranexamic acid therapy in hereditary angioneurotic edema' NEnglJMed 1972; 287:452-454

 3) Beauchene C et al 'TXA as first line emergency treatment for episodes of bradykinin-mediatedangioedema induced by ACE inhibitors' Rev Med Interne 2018; 39(10):772-776 Doi10.1016/j.revmed.2018.04.014

4) Zanichelli A et al 'Standard care impact on angioedema because of hereditary C1 Inhibitor Deficiency: a 21-month prospective study in a sohort of 103 patients' Allergy 2011; 66:192-96 PMID 21039598

5) Horiuchi T et al 'The use of tranexamic acid for on-demand and prophylactic treatment of hereditaryangioedema-A Systematic Review' J CutanImmunolAllergy. 2018; 1:126-138

ANAPHYLAXIS

INTRODUCTION

Anaphylaxis is a serious allergic reaction, with a rapid onset; it may cause death and requires emergent

diagnosis and treatment. Consensus clinical criteria provide consistency for diagnosis (Table 14-1).1–3

TABLE 14-1

Clinical Criteria for Anaphylaxis

Urticaria, generalized itching or flushing, or edema of lips, tongue, uvula, or skin developing over minutes to

hours and associated with at least 1 of the following:

Respiratory distress or hypoxiaor

Hypotension or cardiovascular collapseor

Associated symptoms of organ dysfunction (e.g., hypotonia, syncope, incontinence)

Two or more signs or symptoms that occur minutes to hours a�er allergen exposure:

Skin and/or mucosal involvement

Respiratory compromise

Hypotension or associated symptoms

Persistent GI cramps or vomiting

Consider anaphylaxis when patients are exposed to a known allergen and develop hypotension

The terms anaphylactic and anaphylactoid were previously applied to immunoglobulin E (IgE)-dependentand IgE-independent events, respectively. Because the final pathway in both events is identical, anaphylaxis

is the term now used to refer to both.4 Hypersensitivity is an inappropriate immune response to generallyharmless antigens, representing a continuum from minor to severe manifestations. Anaphylaxis representsthe most dramatic and severe form of immediate hypersensitivity.

Foods, medications, insect stings, and allergen immunotherapy injections are the most common provokingfactors for anaphylaxis, but any agent capable of producing a sudden degranulation of mast cells or

basophils can induce anaphylaxis (Table 14-2).5,6 Latex hypersensitivity is increasing in prevalence in thegeneral population, with a resultant risk for anaphylaxis. In addition, a significant number of anaphylaxis

cases have no identified cause, termed idiopathic anaphylaxis.7 The lifetime individual risk of anaphylaxis is

estimated to be 1% to 3%, but the prevalence of anaphylaxis may be increasing.8 Although allergic reactions

are a common cause for ED visits,9 anaphylaxis is likely underdiagnosed.10,11

TABLE 14-2

Common Causes for Anaphylaxis, Anaphylactoid, and Allergic Reactions

Drugs

β-Lactam antibiotics

Acetylsalicylic acid (ASA)

Trimethoprim-sulfamethoxazole

Vancomycin

NSAIDs

Virtually any drug

Others

Hymenoptera stings

Insect parts

Molds

Radiographic contrast material

Vaccines

Latex

Blood products

Foods and Additives

Shellfish

Soybeans

Nuts (peanuts and tree nuts)

Wheat

Milk

Eggs

Salicylates

Seeds

Sulfites

Mammalian meat (galactose-alpha-1,3-galactose [alpha-gal])

PATHOPHYSIOLOGY

Anaphylaxis, for the most part, arises from the activation of mast cells and basophils through a mechanism

involving crosslinking of IgE and aggregation of the high-a�inity receptors for IgE.6 Upon activation, mastcells and/or basophils quickly release preformed mediators from secretory granules that include histamine,tryptase, carboxypeptidase A, and proteoglycans. Downstream activation of phospholipase A2, followed by

cyclooxygenases and lipoxygenases, produces arachidonic acid metabolites, including prostaglandins,leukotrienes, and platelet-activating factor. The inflammatory cytokine, tumor necrosis factor-α, is releasedas a preformed mediator and also as a late-phase mediator with other cytokines and chemokines.

These mediators are responsible for the pathophysiology of anaphylaxis. Histamine stimulates vasodilationand increases vascular permeability, heart rate, cardiac contraction, and glandular secretion. ProstaglandinD2 is a bronchoconstrictor, pulmonary and coronary vasoconstrictor, and peripheral vasodilator.

Leukotrienes produce bronchoconstriction, increase vascular permeability, and promote airway remodeling.Platelet-activating factor is also a potent bronchoconstrictor and increases vascular permeability. Tumornecrosis factor-α activates neutrophils, recruits other e�ector cells, and enhances chemokine synthesis.These overlapping and synergistic physiologic e�ects contribute to the overall pathophysiology of

anaphylaxis.6

CLINICAL FEATURES

The classic presentation of anaphylaxis begins with pruritus, cutaneous flushing, and urticaria. Thesesymptoms are followed by a sense of fullness in the throat, anxiety, a sensation of chest tightness, shortnessof breath, and lightheadedness. A complaint of a “lump in the throat” and hoarseness heralds life-threatening laryngeal edema in a patient with symptoms of anaphylaxis. These major symptoms may beaccompanied by abdominal pain or cramping, nausea, vomiting, diarrhea, bronchospasm, rhinorrhea,conjunctivitis, and/or hypotension. As the cascade progresses, respiratory distress, decreased level ofconsciousness, and circulatory collapse may ensue. In severe cases, loss of consciousness andcardiorespiratory arrest may result.

In most patients, signs and symptoms begin suddenly, o�en immediately and usually within 60 minutes ofexposure. In general, the faster the onset of symptoms, the more severe the reaction—one half ofanaphylactic fatalities occur within the first hour. A�er the initial signs and symptoms abate, patients are at asmall risk for a recurrence of symptoms caused by a second phase of mediator release, peaking 8 to 11 hoursa�er the initial exposure and manifesting symptoms and signs 3 to 4 hours a�er the initial clinicalmanifestations have cleared. The late-phase allergic reaction is primarily mediated by the release of newlygenerated cysteinyl leukotrienes, the former slow-reacting substance of anaphylaxis. The incidence of thisbiphasic phenomenon has been reported to vary widely up to 20%; however, prospective studies specifically

searching for clinically important biphasic events report a much lower incidence (4% to 5%).12,13

DIAGNOSIS

The diagnosis of anaphylaxis is clinical. Consider anaphylaxis when involvement of any two or more body

systems is observed, with or without hypotension or airway compromise (Table 14-3).1,15 The diagnosis iseasily made if there is a clear history of exposure, such as a bee sting, shortly followed by the multisystemsigns and symptoms described earlier. Unfortunately, the diagnosis is not always easy or clear, becausesymptom onset may be delayed, symptoms may mimic other presentations (e.g., syncope, gastroenteritis,anxiety), or anaphylaxis may be a component of other diseases (e.g., asthma).

Abbreviation: ENT = ear, nose, and throat; GI = gastrointestinal.

TABLE 14-3

Clinical Manifestations of Anaphylaxis

System Signs and Symptoms (approximate incidence)

ENT Oropharyngeal or throat fullness (50%)

Tongue swelling (1%–2%)

Uvular edema/hydrops (1%–5%)

Respiratory Shortness of breath and/or wheezing (45%–50%)

Pharyngeal or laryngeal edema (50%–60%)

Stridor (rare)

Rhinitis (30%–35%)

Cardiovascular Hypotension (30%–35%)

Chest pain (4%–5%)

Skin Urticaria and/or angioedema (60%–90%)

Flushing (45%–55%)

Pruritus only (2%–5%)

GI Nausea, emesis, cramps, or diarrhea (25%–30%)

Neurologic Headache (5%–8%)

Seizure (1%–2%)

The di�erential diagnosis of anaphylactic reactions is extensive, including vasovagal reactions, myocardialischemia, dysrhythmias, severe acute asthma, seizure, epiglottitis, hereditary angioedema, foreign bodyairway obstruction, carcinoid, mastocytosis, vocal cord dysfunction, and non–IgE-mediated drug reactions.The most common anaphylaxis imitator is a vasovagal reaction, which is characterized by hypotension,pallor, bradycardia, diaphoresis, and weakness, and sometimes by loss of consciousness.

Laboratory investigations are of minimal utility and should be limited in the ED setting.16 Serum histaminelevels, elevated for 5 to 30 minutes a�er reaction, are unhelpful because they are typically normal upon EDpresentation. Tryptase is a neutral protease of unknown function in anaphylaxis that is found only in mastcell granules and is released with degranulation. Serum tryptase levels are elevated for several hours andhave been proposed for later confirmation of a suspected anaphylactic episode. This test, however, has poor

sensitivity; about one third of patients with an acute anaphylaxis episode have a normal serum tryptase level

upon ED arrival,17 and some patients experience severe anaphylaxis without elevated tryptase levels.18

TREATMENT

Triage for all acute allergic reactions should be at the highest level of urgency because of the possibility of

sudden deterioration.10 Current treatment recommendations are derived from the clinical experience of

experts as professed in consensus statements and guidelines.16,19–21

FIRST-LINE THERAPY

Emergency management starts with assessment of airway, breathing, and circulation. Assess vital signs andpulse oximetry. Initiate IV access, oxygen administration, and cardiac rhythm monitoring in patients withsevere symptoms. The first-line therapies for anaphylaxis (airway protection, oxygen, decontamination,

epinephrine, IV crystalloids) have immediate e�ect during the acute stage.20–23

Airway and Oxygenation

In severe anaphylaxis, securing the airway is the first priority. Examine the mouth, pharynx, and neck forsigns and symptoms of angioedema: uvula edema or hydrops, audible stridor, respiratory distress, orhypoxia. If angioedema is producing respiratory distress, intubate early, since any delay may result incomplete airway obstruction secondary to progression of angioedema. Provide supplemental oxygen tomaintain arterial oxygen saturation >90%.

Decontamination

If the causative agent can be identified, termination of exposure should be attempted. Gastric lavage is notrecommended for foodborne allergens and may be associated with complications (i.e., aspiration) anddelays in the administration of more e�ective treatments (e.g., epinephrine). In insect stings, remove anyremaining stinging remnants because the stinger continues to inject venom even if it is detached from theinsect (see Chapter 211, “Bites and Stings”).

Epinephrine

Epinephrine (adrenaline) is a mixed α1- and β-receptor agent. The α1-receptor activation reduces mucosal

edema and treats hypotension, β1-receptor stimulation increases heart rate and myocardial contractility, and

β2-receptor stimulation provides bronchodilation and limits further mediator release.16 Epinephrine is the

treatment of choice for anaphylaxis.16,19,24,25 However, observational studies indicate that it is underused,

o�en dosed suboptimally, and underprescribed upon discharge for potential future self-administration.9,11

Most of the reasons proposed to withhold epinephrine are flawed, and the therapeutic benefits of

epinephrine exceed the risk when given in appropriate routes and doses, even in elderly patients.24

In patients without signs of cardiovascular compromise or collapse, administer epinephrine IM (Table 14-

4).26 Repeat every 5 to 10 minutes according to response or if relapse occurs. Injections into the thigh are

more e�ective at achieving peak blood levels than injections into the deltoid area.26 Intramuscular dosing isrecommended because it provides higher, more consistent, and more rapid peak blood epinephrine levels

than SC administration.26,27 For convenience and accurate dosing, many EDs have adopted the use ofepinephrine autoinjectors, such as EpiPen® (0.3 milligrams of epinephrine for adults; Dey, L.P., Napa, CA) andEpiPen Junior® (0.15 milligrams of epinephrine for children <30 kg; Dey, L.P.); however, recent shortages inproduction have demonstrated the need for multiple sources of the drug. Some evidence suggests that

expired epinephrine autoinjectors retain potency many months to years a�er their expiration date.28 Whileretaining an expired EpiPen® may be a reasonable safety strategy for patients, it does not negate the need fora new prescription.

TABLE 14-4

Drug Treatment of Anaphylaxis and Allergic Reactions

Drug Adult Dose Pediatric Dose

First-Line Therapy

Epinephrine IM: 0.3–0.5 milligram (0.3–0.5 mL of

1:1000 dilution); or EpiPen® 0.3 milligram

epinephrine (or equivalent

preformulated product)

IM: 0.01 milligram/kg (0.01 mL/kg of

1:1000 dilution) or EpiPen Junior® 0.15

milligram of epinephrine (or equivalent

preformulated product)

IV bolus: 100 micrograms over 5–10 min;

mix 0.1 milligram (0.1 mL of 1:1000

dilution) in 10 mL NS and infuse over 5–

10 min

IV infusion: start at 1 microgram/min;

mix 1 milligram (1 mL of 1:1000 dilution)

in 500 mL NS and infuse at 0.5 mL/min;

titrate dose as needed

IV infusion: 0.1–0.3 microgram/kg per

min; titrate dose as needed; maximum,

1.5 micrograms/kg per min

Oxygen Titrate to SaO2 ≥90% Titrate to SaO2 ≥90%

IV fluids: NS or LR 1–2 L bolus 10–20 mL/kg bolus

Second-Line Therapy

H1 Blockers

Diphenhydramine 25–50 milligrams IV, IM, or PO every 6 h 1 milligram/kg IV, IM, or PO every 6 h

H2 Blockers

Ranitidine 50 milligrams IV over 5 min 0.5 milligram/kg IV over 5 min

Cimetidine 300 milligrams IV 4–8 milligrams/kg IV

Corticosteroids

Drug Adult Dose Pediatric Dose

Hydrocortisone 250–500 milligrams IV 5–10 milligrams/kg IV (maximum, 500

milligrams)

Methylprednisolone 80–125 milligrams IV 1–2 milligrams/kg IV (maximum, 125

milligrams)

Prednisone 40–60 milligrams PO daily or 20–30

milligrams PO twice daily

1–2 milligrams/d PO divided twice a day

or daily

To be used a�er initial IV dose (for

outpatients: 3–5 d; tapering not

required)

To be used a�er initial IV dose (for

outpatients: 3–5 d; tapering not

required)

Treatment of Bronchospasm, Add:

Albuterol

(salbutamol)

Single treatment: 2.5–5.0 milligrams

nebulized (0.5–1.0 mL of 0.5% solution)

Single treatment: 1.25–2.5 milligrams

nebulized (0.25–0.5 mL of 0.5% solution)

4–6 pu�s from MDI with holding chamber 4–6 pu�s from MDI with holding

chamber

Both repeated every 20 min as needed Both repeated every 20 min as needed

Continuous nebulization: 5–10

milligrams/h

Continuous nebulization: 3–5

milligrams/h

Ipratropium

bromide

Single treatment: 250–500 micrograms

nebulized

Single treatment: 125–250 micrograms

nebulized

4–6 pu�s from MDI with holding chamber 4–6 pu�s from MDI with holding

chamber

Both repeated every 20 min as needed Both repeated every 20 min as needed

Magnesium sulfate 2 grams IV over 20 min 25–50 milligrams/kg IV over 20 min

Treatment for Patients on β-Blockers with Refractory Hypotension, Add:

Abbreviations: H1 = histamine-1; H2 = histamine-2; LR = lactated Ringer’s; MDI = metered-dose inhaler; NS = normal

saline; SaO2 = arterial oxygen saturation.

Drug Adult Dose Pediatric Dose

Glucagon 1 milligram IV every 5 min until

hypotension resolves, followed by 5–15

micrograms/min infusion

50 micrograms/kg IV every 5 min

Most patients with anaphylaxis need only a single dose of epinephrine IM. Blood pressure should be checkedin patients taking β-blockers, because epinephrine use may result in severe hypertension secondary tounopposed α-adrenergic stimulation. Age is not a barrier to epinephrine IM injections in patients withanaphylaxis.

If the patient is refractory to treatment despite repeated doses of epinephrine IM or has signs ofcardiovascular compromise or collapse, then an epinephrine IV bolus and/or infusion should be instituted.The initial epinephrine IV bolus is a dilute solution of 100 micrograms (0.1 milligram) IV, given over 5 to 10minutes.

If the patient is refractory to the initial bolus, institute an epinephrine IV infusion, starting at 1microgram/min and titrating to e�ect. There is a higher risk of cardiovascular complications when

epinephrine IV is used to treat anaphylaxis.29 It should be stressed that the initial IV bolus dose is very dilute,is given over 5 to 10 minutes, and should be stopped immediately if dysrhythmias or chest pain occur.

IV Crystalloids

Hypotension is generally the result of distributive shock and responds well to fluid resuscitation.16 A bolus of1 to 2 L (10 to 20 mL/kg in children) of isotonic crystalloid solution should be administered concurrently with

epinephrine. There is no evidence that albumin or hypertonic saline should replace crystalloids.30

SECOND-LINE THERAPY

The second-line anaphylaxis treatments include corticosteroids, antihistamines, inhaled bronchodilators,

vasopressors, and glucagon.16,19–21 These drugs are used to treat anaphylaxis refractory to the first-line

treatments or associated with complications and also to prevent recurrences.23

Corticosteroids

Patients with anaphylaxis o�en receive corticosteroids to prevent protracted and biphasic reactions,

although evidence for clinical benefit is scant and primarily derived from acute asthma studies.19–21,23,31–33

Methylprednisolone, 80 to 125 milligrams IV (2 milligrams/kg in children; up to 125 milligrams), andhydrocortisone, 250 to 500 milligrams IV (5 to 10 milligrams/kg in children; up to 500 milligrams), are equallye�ective. The mineralocorticoid e�ects of corticosteroids are ranked in declining order. Hydrocortisone andcortisone have the strongest e�ects, followed by prednisone. Methylprednisolone and dexamethasone havethe lowest mineralocorticoid e�ect and produce less fluid retention than hydrocortisone and cortisone andthus are preferred for the elderly and for those in whom fluid retention would be problematic.

Antihistamines

Consensus guidelines recommend that most patients with anaphylaxis should receive an H1 antihistamine,

such as diphenhydramine, 25 to 50 milligrams IV by slow infusion or via IM injection,16,19–21,23 although

clinical benefit is unproven.34 In severe cases, especially with circulatory shock, guidelines recommend H2

antihistamines, such as ranitidine or cimetidine,19–21,23 although evidence for benefit is lacking.35

Cimetidine should not be used for patients who are elderly (side e�ects), have multiple comorbidities(interference with metabolism of many drugs), have renal or hepatic impairment, or whose anaphylaxis iscomplicated by β-blocker use (cimetidine prolongs metabolism of β-blockers and may prolong anaphylacticstate). A�er the initial IV dose of corticosteroids and antihistamines, the patient may be switched to oraladministration (Table 14-4).

Vasopressors

In patients with anaphylaxis and shock resistant to initial treatment, including repeated doses of IMepinephrine, oxygen, and IV crystalloids, initiate IV epinephrine infusion. If dangerous dysrhythmias ortachycardia result from epinephrine, other agents (e.g., dopamine, dobutamine, epinephrine,norepinephrine, phenylephrine, or vasopressin) may be e�ective, and superiority from a specific agent has

not been demonstrated.16,19–21 Clinicians should use the agent they feel most comfortable with and titrateaccording to the clinical response.

AGENTS FOR ALLERGIC BRONCHOSPASM

A β2 bronchodilator, such as intermittent or continuous nebulized albuterol/salbutamol, should be instituted

if wheezing is present. Asthmatics are o�en more refractory to the treatment of allergic bronchospasm. Forsevere bronchospasm refractory to inhaled albuterol/salbutamol, inhaled anticholinergics and IV

magnesium sulfate can be added (Table 14-4).31,36 Bronchodilators should be given at a lower dose and at aslower rate in elderly patients. IV aminophylline is not recommended. Leukotriene receptor antagonists arenot e�ective for the treatment of anaphylaxis.

GLUCAGON

Concurrent use of β-blockers is a risk factor for severe prolonged anaphylaxis. For patients taking β-blockerswith hypotension refractory to fluids and epinephrine, glucagon IV should be used every 5 minutes until

hypotension resolves, followed by an infusion (Table 14-4).16,19–21 The side e�ects of glucagon includenausea, vomiting, hypokalemia, dizziness, and hyperglycemia.

DISPOSITION AND FOLLOW-UP

With appropriate initial treatment, admission to hospital is rare, only required in about 1% to 4% of acute

allergic reactions treated in the ED.9,13 All unstable patients with anaphylaxis refractory to treatment or inwhom airway interventions were required should be admitted to the intensive care unit. While patients who

receive epinephrine IM should be observed in the ED, the precise duration of observation is unclear.12,13

Otherwise healthy patients who remain symptom free for one or 6 hours a�er appropriate treatment can be

discharged home with less than 5% or 3% incidence, respectively of a biphasic reaction.14

Consider prolonged observation in patients with a past history of severe reaction and those using β-blockers.

Although the risk of important biphasic reactions a�er ED discharge is low,13 patients who live alone, residelong distances from medical care, have significant comorbidity (including but not limited to asthma), or areelderly should be observed longer before discharge.

Patients with severe allergic reactions or anaphylaxis are usually discharged with prescriptions forantihistamines and corticosteroids for 3 to 5 days and a prescription for an epinephrine autoinjector.Although prolonged corticosteroid treatment should not be required for most patients, an aggressive longer-term approach (1 to 2 weeks or until symptoms are controlled) appears to reduce the frequency of relapses

in patients with idiopathic anaphylaxis.7

Discharge instructions should provide recommendations to prevent future episodes (Table 14-5).37 For allallergic reactions, instruct the patient on how to avoid future exposure to the causative agent (if the agent isknown). Prescribe an epinephrine autoinjector to patients with serious allergic reactions or anaphylaxis withclear instructions on the use of the autoinjector. Overall, less than one third of patients and parents ofchildren with anaphylaxis can demonstrate the e�ective use of an epinephrine autoinjector device, soeducation is a key component of discharge instructions. If delay in filling a prescription is anticipated,patients can be discharged from the ED with an epinephrine autoinjector (EpiPen®). Reinforce thisprescription with documentation in the ED discharge instructions. Because allergic occurrences areunpredictable, prescriptions should include su�icient samples for multiple locations (e.g., home, vehicle,work), and patients should be advised to carry epinephrine with them at all times. Unfortunately, research inthe United States suggests that fewer than half of children, adolescents, and adults carry their epinephrine

autoinjector devices with them.38

TABLE 14-5

Discharge Planning for Patients With Anaphylaxis

Education

Identification of inciting allergen, if possible

Instructions on use of medications and epinephrine autoinjector

Advice about personal identification/allergy alert tag

Prescriptions for current reaction

Antihistamines: Diphenhydramine, 25–50 milligrams PO every 6–8 h for 3–5 d

Corticosteroids: Prednisone, 40–60 milligrams PO daily or 20–30 milligrams PO twice daily for 3–5 d

Prevention

Instructions on avoiding future exposure

Prescription for future reactions

Epinephrine autoinjector (at least 2)

Referral of selected patients to allergist

Refer patients with severe or frequent allergic reactions to an allergist for in-depth preventive management

and attempts at allergen identification.39 O�er patients information about this syndrome (e.g., fromwebsites), advice on advocacy groups, and education regarding food contamination for food allergies, andencourage wearing of personal identification alerts about this condition (e.g., MedicAlert® bracelets).Because of the potential for severe and prolonged future reactions, patients with anaphylaxis on β-blockersshould be switched to an agent from a di�erent therapeutic class.

ALLERGIES AND ANGIOEDEMA

URTICARIA

Urticaria, or hives, is a cutaneous reaction marked by acute onset of pruritic, erythemic wheals of varying

size that generally are described as “fleeting.”40 Erythema multiforme is a more pronounced variation ofurticaria, characterized by typical “target” skin lesions. Although these manifestations may accompany manyallergic reactions, they also may be nonallergic; many acute urticarial reactions are due to viruses, especiallyin children, and present as hives persisting or recurring for more than 24 hours. Obtain a detailed history; ifan etiologic agent can be identified (e.g., cold, exercise, food), future reactions may be avoided.

Treatment of urticarial reactions is generally supportive and symptomatic, with attempts to identify and

remove the o�ending agent. H1 antihistamines, with or without corticosteroids,41–43 are usually prescribed;

however, some evidence suggests the addition of corticosteroids to nonsedating antihistamines is no better

than antihistamines alone in preventing relapse or reducing itch.41 Epinephrine can be considered in severe

or refractory cases. The addition of an H2 antihistamine, such as ranitidine, may also be useful in more

severe, chronic, or unresponsive cases. Cold compresses may be soothing to a�ected areas. Referral to anallergy specialist is indicated in severe, recurrent, or refractory cases.

ANGIOEDEMA

Angioedema is a similar reaction as urticaria, but with deeper involvement characterized by edemaformation in the dermis, generally involving the face and neck and distal extremities. Angioedema of the

tongue, lips, and face has the potential for airway obstruction.44 Although angioedema is caused by a varietyof agents, an angiotensin-converting enzyme inhibitor is a common trigger, with angioedema occurring in

0.1% to 0.7% of patients taking angiotensin-converting enzyme inhibitors.45,46 The pathophysiology ofangiotensin-converting enzyme inhibitor–induced angioedema is complex, involving both bradykinin and

substance P.45,46

Management of angiotensin-converting enzyme inhibitor–induced angioedema is supportive, with special

attention to the airway,47 which can become occluded rapidly and unpredictably. Drugs used to treat allergicreactions, such as epinephrine, antihistamines, and corticosteroids, are not beneficial because angiotensin-

converting enzyme inhibitor–induced angioedema is not mediated by IgE.45,46  Tranexamic acid is a  goodfirst-line agent.  Icatibant, a bradykinin-2 antagonist, is an e�ective agent to reduce swelling and shorten

time to complete resolution (Table 14-6).48 C1 esterase inhibitor (human) at a dose of 1000 U IV also appears

e�ective based on a case series compared to historical controls.49 Ecallantide, a kallikrein inhibitor, is not

e�ective in angiotensin-converting enzyme inhibitor–induced angioedema.50

Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; FDA = U.S. Food and Drug Administration; HAE =

hereditary angioedema.

*Proprietary names provided to aid in recognition

†Not FDA approved for ACEI-induced angioedema

TABLE 14-6

Pharmacologic Treatment of Angioedema in Adults

Agent* Recommended Adult Dose Comments

Tranexamic Acid 1 gram IV E�ective in ACEI-induced angioedema and possibly

in idiopathic angioedema

C1 esterase inhibitor

[human]

(Berinert®)

20 U/kg IV for HAE

1000 U IV for ACEI-induced

angioedema

E�ective in HAE and ACEI-induced angioedema†

Adverse side e�ects include headache, abdominal

pain, nausea, diarrhea, and vomiting

C1 esterase

inhibitor[recombinant]

(Ruconest®)

50 U/kg IV (maximum

dose, 4200 U)

E�ective in HAE, but e�ectiveness in laryngeal

attacks not established

No data for ACEI-induced angioedema

Adverse side e�ects include headache and vertigo

Icatibant

(Firazyr®)

30 milligrams SC E�ective in HAE and ACEI-induced angioedema†

Bradykin-2 receptor antagonist

Single dose highly e�ective: about 10% require

second dose

90% experience mild local reactions: pain, swelling,

erythema

Ecallantide

(Kalbitor®)

30 milligrams SC (in 3

separate 10-milligram or

1-mL injections)

E�ective in HAE, but not ACEI-induced angioedema

Kallikrein inhibitor

Risk of anaphylaxis in up to 4%

May repeat 30-milligram dose within 24 h if reaction

persists

Adverse side e�ects include headache, nausea,

fatigue, diarrhea, nasopharyngitis, injection site

reactions, and vomiting

Immediate withdrawal from the angiotensin-converting enzyme inhibitor is indicated, and anotherantihypertensive should be prescribed, with the important exception that angiotensin II receptor–blockingagents should not be used. Most cases resolve in a few hours to days, so patients with mild swelling and noevidence of airway obstruction should be observed for 12 to 24 hours and discharged if swelling diminishes.Rebound or recurrent swelling will not occur unless the patient takes an angiotensin-converting enzymeinhibitor again.

Hereditary angioedema is a rare autosomal dominant disorder due to deficiency in C1 esterase inhibitor,

either low levels (type I) or a dysfunctional enzyme (type II).51,52 About 25% of cases are due to new

mutations.53 The disorder is characterized by acute edematous reactions involving the upper respiratorysystem, so� tissue of extremities or trunk, or gastrointestinal tract. Attacks can last from a few hours to 1 to 2days. Minor trauma o�en precipitates an acute episode; however, triggers are o�en elusive. Typicaltreatments for allergic reactions, such as epinephrine, corticosteroids, and antihistamines, are ine�ective.The best screening test is the C4 level. A C4 level <30% of normal suggests hereditary angioedema.

Acute attacks can be shortened by a C1 esterase inhibitor (either human plasma derived or recombinant), the

bradykinin-2 receptor antagonist icatibant, or the kallikrein inhibitor ecallantide (Table 14-6).54,55 Freshfrozen plasma may be used if C1 esterase inhibitor is not available, although the dosing is not standardized,

with 2 to 3 units described in most case reports.56 Prophylaxis of acute attacks is possible with attenuatedandrogens, such as stanozolol 2 milligrams PO TID or danazol 200 milligrams PO TID. Treatment of patients iscomplex and best done in coordination with the appropriate specialist.

FOOD ALLERGY REACTIONS

Hypersensitivity reactions to ingested foods are generally caused by IgE-coated mast cells lining the GI tractreacting to ingested food proteins and, rarely, to additives. Their frequency is rising for unknown reasons andvaries based on age (more common in children), country of origin, and definitions and confirmatory tests

used.52 Dairy products, eggs, nuts, and shellfish are the most commonly implicated foods.57,58

A detailed dietary history within the 24 hours of allergic symptoms may provide the best clues to food allergy,with particular attention to other allergic history and prior reactions. Diagnosis is o�en di�icult, however,

and it may require multiple episodes before an o�ending agent is identified.58 Symptoms of food allergyinclude swelling and itching of the lips, mouth, and pharynx; nausea; abdominal cramps; vomiting; anddiarrhea. Cutaneous manifestations, such as angioedema and urticaria, as well as anaphylaxis, can occur.Treatment for mild reactions is supportive, with the administration of antihistamines to lessen symptoms.More severe reactions and anaphylaxis are managed as described earlier.

Mammalian meat allergy or galactose-alpha-1,3-galactose (alpha-gal) allergy is an IgE-mediated allergic

reaction to ingestion of red meat containing the mammalian oligosaccharide epitope alpha-gal.59 Alpha-galis found in all mammals except Old World monkeys, apes, and humans. Bites (o�en unrecognized) fromcertain ticks, such as the Lone Star tick in the United States, can transfer this carbohydrate to humans,

stimulating the production of the antibody implicated in a delayed allergic response triggered by theconsumption of mammalian meat products. The onset is usually about 4 hours (range, 3 to 8 hours) a�er

eating meat, manifested by urticaria, angioedema, gastroenteritis, or anaphylaxis.60,61 Treatment is thesame as for urticaria or anaphylaxis of any cause, and control is maintained by avoidance of eating anymammalian meat. Duration of allergy is unknown. Alpha-gal allergy is an increasing cause of allergic andanaphylactic reactions, reported most commonly in the middle United States and the north, central, and

southern Atlantic states, where the Lone Star tick is prevalent.62

To identify this syndrome, ask the patient about recent meat ingestion within 8 hours prior to the onset ofsymptoms, as well as prior episodes. Diagnosis is confirmed by blood testing with a positive reaction to

specific IgE alpha-gal antibodies.59 The results of testing are not immediately available to the ED; however, itis definitely worthwhile obtaining the assay and ensure diagnostic follow-up along with epinephrineautoinjector prescription because repeated anaphylactic reactions can be life threatening.

ALLERGIC DRUG REACTIONS

Adverse reactions to drugs are common; however, true hypersensitivity reactions probably account for <10%

of these occurrences, with the majority anaphylaxis from IgE-mediated drug reactions.63 Although mostdrugs are small organic molecules, generally unable to stimulate an immune response alone, when a drug ormetabolite becomes protein bound, either in serum or on cell surfaces, the drug–protein complex canbecome an allergen and stimulate immune system responses. Thus, the ability of a drug or its metabolites tosensitize the immune system depends largely on the ability to bind to tissue proteins. Many di�erent drugsand treatments can cause allergic reactions and anaphylaxis.

Penicillin is the drug most commonly implicated in eliciting true allergic reactions and accounts forapproximately 90% of all reported allergic drug reactions and about 75% of fatal anaphylactic drug

reactions.64 Fatal reactions can occur without a prior allergic history; <25% of patients who die of penicillin-induced anaphylaxis exhibited allergic reactions during previous treatment with the drug. Parenteralpenicillin administration is more than twice as likely to produce fatal allergic reactions as is oraladministration. The cross-reactivity of penicillin allergy with cephalosporins is about 10%, so patients with aprevious life-threatening or anaphylactic reaction to penicillin should not be given cephalosporins.

The clinical manifestations of drug allergy vary widely. A generalized reaction similar to immune-complex orserum sickness reactions is very common, especially with trimethoprim-sulfamethoxazole and certaincephalosporins (cefaclor being the most frequent). While sulfa moieties are contained in many drugs, sulfaallergic reactions upon exposure to the nonantibiotic sulfas are uncommon. See Chapter 206,“Antimicrobials,” for more discussion of drug allergies.

Serum sickness usually begins in the first or second week a�er initiation of the drug and can take manyweeks to subside a�er drug withdrawal. Generalized malaise, arthralgias, arthritis, pruritus, urticarialeruptions, fever, adenopathy, and hepatosplenomegaly are common signs and symptoms. Drug fever may

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occur without other associated clinical findings and may also occur without an immunologic basis.Circulating immune complexes are probably responsible for the lupus-like reactions caused by some drugs.

Other reactions are possible. Cytotoxic reactions include penicillin-induced hemolytic anemia. Skineruptions include erythema, pruritus, urticaria, angioedema, erythema multiforme, and photosensitivity.Severe reactions, such as those seen in Stevens-Johnson syndrome and toxic epidermal necrolysis, may alsooccur. Delayed hypersensitivity reactions may manifest as contact dermatitis from drugs applied topically.

Diagnosis is determined by a careful history. Treatment is supportive, with oral or parenteral antihistaminesand corticosteroids. Drug cessation is important, but reactions can continue. Referral to an allergy specialistis indicated for severe reactions.

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