Urticaria and Angioedema – 4 Interesting Facts

Sharing is caring!

Interesting Facts

  1. Urticaria is generally mediated by histamine, which causes edema in upper and mid-dermis, forming pruritic wheals (hives)
    • Chronic urticaria lasts longer than 6 weeks and is treated with second-generation antihistamines (which may be dosed up to 4 times the usual dose, if needed), with consideration for addition of another agent in refractory cases (1 of the following: first-generation antihistamines at bedtime, H₂ antagonists, montelukast, omalizumab [anti-IgE], or cyclosporine)
    • Acute urticaria generally responds to second-generation antihistamines and lasts less than 6 weeks
  2. Angioedema is generally mediated by bradykinin, which causes edema in deeper layers of mucous membranes and skin
    • Recurrent angioedema attacks (frequently from hereditary angioedema) are usually treated preferentially with C1 inhibitor replacement, icatibant, or ecallantide, using fresh frozen plasma if C1 inhibitor or other treatments are not available
    • Short-term prophylaxis (eg, before an invasive procedure) of hereditary angioedema requires C1 inhibitor, fresh frozen plasma, or high-dose 17α-alkylated androgens; if C1 inhibitor deficiency is acquired, antifibrinolytic agents work better (aminocaproic acid or tranexamic acid)
    • Long-term prophylaxis of recurrent angioedema attacks (frequently from hereditary angioedema) is indicated when on-demand therapy is not successful; recommended agents are C1 inhibitor, 17α-alkylated androgens (at lowest effective dose), and antifibrinolytics
  3. ACE inhibitor–associated angioedema is managed largely by discontinuation of the ACE inhibitor; icatibant may be used if needed to treat the angioedema
  4. Idiopathic histaminergic acquired angioedema is treated with antihistamines

Pitfalls

  • Epinephrine, corticosteroids, and antihistamines are not recommended to treat hereditary angioedema; these medications are ineffective 1
  • Recurrent angioedema may occur in patients with ACE inhibitor–associated angioedema who are subsequently prescribed an angiotensin receptor blocker (2%-17% of patients), but most patients may safely use an angiotensin receptor blocker without recurrence 1
  • Avoid chronic opioid administration in patients with hereditary angioedema because patients with frequent attacks are at risk for opioid dependence
  • Avoid estrogen-containing contraceptive pills in women with hereditary angioedema
  • Consider an ACE inhibitor as a cause of angioedema in patients who have been on the medication for long periods

Urgent Action

  • Emergent airway management may be required in patients who develop anaphylaxis or laryngeal angioedema
    • Have equipment near the bedside
    • Intubate at signs of significant upper airway compromise (eg, hoarseness, stridor, hypoxemia)
    • Cricothyroidotomy may be needed if airway is too edematous or distorted for intubation
    • Other options include percutaneous tracheostomy or standard tracheostomy under local anesthesia if the conditions are otherwise controlled
  • Instruct patients with recurrent angioedema to call emergency services (eg, 911) if an attack occurs that involves the oropharynx or airway or causes any degree of breathing difficulty

Terminology

Clinical Clarification

  • Angioedema is a vascular reaction, mainly mediated by bradykinin (a vasodilator), that occurs in the deeper layers of mucous membranes and dermis. It is characterized by blood vessel dilation locally, with a permeability increase that causes tissue swelling 2
  • Urticaria is defined by development of angioedema and/or wheals (hives), mediated mainly by histamine, with wheals caused by upper and mid-dermis edema associated with dilation of lymphatic vessels and postcapillary venules of the upper dermis 3

Classification 2

  • Acute spontaneous urticaria
    • IgE mediated
    • Mast cell (histamine) mediated independent of IgE
  • Chronic spontaneous urticaria
    • Mast cell (histamine) mediated independent of IgE
  • Chronic inducible urticaria (physical urticaria)
    • Mast cell (histamine) mediated independent of IgE
      • Dermographic urticaria (elicited by mechanical shearing forces)
      • Cold contact urticaria (elicited by cold objects/air/wind/fluid)
      • Pressure urticaria, immediate and delayed (elicited by vertical pressure; delayed form has typical latency of 4-6 hours; range, 0.5-24 hours) 4
      • Heat contact urticaria (elicited by localized heat)
      • Solar urticaria (elicited by UV and/or visible light)
      • Vibratory urticaria (elicited by vibratory forces)
      • Contact urticaria (elicited by contact with a substance causing urticaria)
      • Cholinergic urticaria (elicited by body temperature increase caused by physical exercise, hot baths, or spicy foods)
      • Aquagenic urticaria (elicited by water)
      • Exercise-induced urticaria (elicited by physical exercise, with or without food)
  • Angioedema (hereditary, acquired, or idiopathic)
    • Bradykinin mediated; inherited
      • Hereditary angioedema type 1: C1 inhibitor deficiency
      • Hereditary angioedema type 2: C1 inhibitor defect
      • Hereditary angioedema type 3: normal C1 inhibitor; sometimes involves F12 gene (coagulation factor XII) mutation
    • Bradykinin mediated; not inherited
      • Acquired C1 inhibitor deficiency
        • Catabolism or consumption of C1 esterase inhibitor
          • Usually secondary to B-cell disorder (eg, lymphoma)
        • Autoimmune with antibodies directed against C1 esterase inhibitor
      • ACE inhibitor–induced angioedema
    • Histamine mediated; unknown cause
      • Idiopathic histaminergic acquired angioedema

Diagnosis

Clinical Presentation

  • From Kasparis C et al: Urticaria and angioedema. In: Lebwohl MG et al, eds: Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 4th ed. London, UK: Elsevier; 2014:777-80, Unnumbered Figure.Urticaria. – Urticaria is the result of transient leakage of plasma from the dermal vasculature and is characterized by short-lived, itchy, raised wheals due to dermal edema. In angioedema, the swelling is deeper, resulting in more diffuse and prolonged edema, particularly affecting the face. These conditions are defined as chronic if symptoms have lasted longer than 6 weeks.
  • From Limsuwan T et al: Acute symptoms of drug hypersensitivity (urticaria, angioedema, anaphylaxis, anaphylactic shock). Med Clin North Am. 94(4):691-710, 2010, Figure 5.Urticaria and angioedema. – Urticaria and angioedema involving eyelids, forehead, and face, associated with conjunctivitis and bronchospasm, after positive oral aspirin challenge.
  • From James WD et al: Contact dermatitis and drug eruptions. In: James et al, eds: Andrews’ Diseases of the Skin. 12th ed. Philadelphia, PA: Elsevier. 2016:90-135.e2, Figure 6-27.Angioedema and urticaria.

History

  • Acute urticaria
    • Wheals of variable number and size present for fewer than 6 weeks
    • Pruritus (90%) or burning sensation associated with wheals 5
    • Systemic symptoms (up to 25%) 6
      • May represent anaphylaxis if onset is rapid
        • Cough
        • Wheezing
        • Breathlessness
        • Dizziness
        • Tachycardia
      • Rhinorrhea
      • Flushing
      • Gastrointestinal disturbances (eg, abdominal pain, nausea, vomiting, diarrhea)
      • Fever
      • Conjunctivitis
      • Arthralgias
    • Patient may report being able to induce the swelling by self-exposure to a precipitating stimulus
    • Fleeting nature of individual wheals as they return to a normal appearance in 1 to 24 hours (or less) 3
  • Chronic urticaria
    • Wheals of variable number and size present for 6 weeks or longer 4
    • Patient typically cannot identify a precipitating cause of the condition
    • Associated systemic symptoms also may be seen
  • Angioedema (hereditary or acquired C1 inhibitor deficiency or idiopathic with normal C1 inhibitor)
    • Discrete episodes of nonpruritic, nonpitting tissue swelling associated with pain
      • Recurrent skin swelling involving any of the following or a combination of them:
        • Extremities in almost 50% of attacks 2
          • Patients may be unable to walk owing to severity of painful swelling in feet and legs
          • Compartment syndromes may develop
        • Abdomen in almost 50% of attacks 2
          • Recurrent gastrointestinal attacks involve severely painful abdominal cramping (associated with circulatory symptoms due to hypotension), nausea, and vomiting
          • Attacks may be so severe that the patient has undergone unnecessary surgery
        • Genitourinary tract
          • Causes significant pain, and voiding may be difficult
        • Face
        • Oropharynx
        • Larynx
      • During a lifetime, nearly 100% of patients experience both abdominal and extremity attacks and over 50% have at least 1 laryngeal episode 2
      • Severity of the disease varies greatly between patients and within a single patient over time
        • Patients not on prophylactic treatment may have swelling every 10 to 20 days, with episodes lasting 2 to 5 days; a few patients swell twice per week 1
    • Pain may be present instead of pruritus
    • Typically not responsive to treatment with antihistamines, epinephrine, or corticosteroids
      • There is a subset of idiopathic angioedema that is mast cell mediated and does respond to antihistamines and corticosteroids at normal or high doses (labeled as angioedema of unknown cause responding to antihistamine or idiopathic histaminergic acquired angioedema)
    • Up to 50% of patients have a prodrome, which may reliably predict upcoming episode 1
      • Erythema marginatum (nonpruritic)
      • Localized tingling
      • Feeling of skin tightness
      • Fatigue
      • Malaise
      • Mood changes
      • Irritability
      • Nausea
      • Thirst
      • Hyperactivity
    • Attacks may be increased by use of ACE inhibitors
    • Specific presentations of angioedema
      • Hereditary angioedema types 1 and 2
        • Attacks last 72 to 96 hours or longer, are severe, and are disabling 1
        • 50% of attacks involve abdomen or extremities 2
        • 50% of patients have at least 1 episode involving the upper airway 2
        • Typically presents in childhood (75% of cases by age 15 years) and worsens with puberty 2
        • 75% to 80% of patients have positive family history 2
      • Hereditary angioedema type 3 (with normal C1 inhibitor level and function)
        • Presentation is similar to that of types 1 and 2 except:
          • More attack-free intervals and fewer attacks
          • Lower percentage of abdominal attacks
          • Higher percentage of facial and cutaneous attacks
          • Fewer multisite attacks
          • No preceding erythema marginatum
          • Older age at symptom onset
        • Typically more severe in women than men
        • Exacerbated by increased estrogen exposure (eg, pregnancy, estrogen therapy)
      • Acquired C1 inhibitor deficiency
        • Presentation is similar to that of hereditary angioedema types 1 and 2 except:
          • Onset after age 40 years 2
          • No family history
      • ACE inhibitor–induced angioedema
        • Typically facial, lip, or tongue swelling
        • Interval between start of medication and onset of angioedema can be months to years; most commonly occurs after the first month of treatment
        • 50% of patients have recurrences of angioedema; may continue for months after cessation of ACE inhibitor 7
        • ACE inhibitor–induced angioedema is a class effect, occurring with any ACE inhibitor
        • Angiotensin receptor blockers may also induce angioedema, but incidence is lower
  • Idiopathic histaminergic (responsive to antihistamines) acquired angioedema 8
    • Symptoms of facial nonpruritic, nonpitting tissue swelling develop rapidly, reaching maximum severity within 6 hours
    • No precipitating factors can be identified
    • No family history or associated diseases

Physical examination

  • Acute urticaria
    • Wheals characterized as pruritic generalized eruptions with circumscribed, blanching erythematous borders and pale, slightly raised centers
    • Angioedema and urticaria are present in 50% of cases 1
      • Angioedema characterized by sudden occurrence of significantly erythematous or skin-colored swelling involving the lower dermis and subcutis, often involved below mucous membranes
    • Palms and soles are spared of lesions
  • Chronic urticaria
    • Wheals present as in acute urticaria
    • Angioedema also is present in 50% of cases 7
      • Most commonly affects eyes, lips, and tongue; less commonly affects feet, hands, and genitals
    • Vasculitic lesions are palpable, typically nonblanching purpuric, and may last several days or longer, leaving residual hyperpigmentation
    • Palms and soles are spared of lesions
  • Angioedema (hereditary or acquired C1 inhibitor deficiency or idiopathic with normal C1 inhibitor)
    • Urticaria not present; no wheals
    • Skin-colored or erythematous swelling of the lower dermis and subcutis with frequent involvement of mucous membranes
      • Most commonly affects:
        • Extremities
        • Abdomen
          • Hypotension may be present, owing to third spacing of fluids
        • Genitourinary tract
        • Face
        • Oropharynx
        • Larynx
          • Stridor or change in voice indicates laryngeal edema
        • Combination of these anatomic areas
          • Signs of impending airway closure include worsening loss of voice, inability to swallow, and respiratory distress
  • Angioedema (idiopathic histaminergic acquired angioedema)
    • As in other forms of angioedema, generally affects the face with skin-colored or erythematous swelling of the lower dermis and subcutis
    • Generally spares laryngeal and gastrointestinal mucosa
    • Urticaria not present; no wheals

Causes and Risk Factors

Causes

  • Acute urticaria
    • Mast cell degranulation may be IgE mediated or non–IgE mediated 6
      • Food ingestion
        • Cow’s milk
        • Egg
        • Fish and seafood
        • Fruit (eg, strawberries, kiwi)
        • Nuts
        • Tomatoes
        • Wheat
      • Drugs
        • ACE inhibitors
        • Acetaminophen
        • Antibiotics, particularly cephalosporins and penicillins
        • Antihistamines
        • Aspirin and other NSAIDs
        • IV immunoglobulins
        • Iodine-based contrast agents
        • Isotretinoin
        • Opioids
        • Progesterone
        • Proton pump inhibitors
        • Vaccines
      • Viral infections (50%-70% of cases) 6
        • Adenovirus
        • Cytomegalovirus
        • Epstein-Barr virus
        • Hepatitis A, B, or C viruses
        • HSV
        • Influenza A virus
        • Rotavirus
        • Varicella-zoster virus
      • Bacterial infections
        • Group A β-hemolytic streptococcus
        • Haemophilus influenzae
        • Staphylococcus aureus
      • Other exposures and conditions
        • Insect bites or stings
        • Latex
        • Scabies
        • Systemic lupus erythematosus
        • Thyroid disease or thyroid papillary carcinoma
      • Idiopathic in 30% to 50% of cases 6
  • Chronic spontaneous urticaria
    • Most cases are idiopathic, but several associations have been noted:
      • Microbes including Helicobacter pylori,hepatitis B and C viruses, group A streptococci, parasites, and Epstein-Barr virus
      • Systemic disorders including malignancy (eg, Hodgkin lymphoma), mastocytosis, connective tissue disorders, hypereosinophilic syndrome, and autoimmune disorders (eg, Hashimoto thyroiditis)
      • Pregnancy (eg, pruritic urticarial papules and plaques of pregnancy)
  • Chronic inducible urticaria
    • Mast cell mediated, not involving IgE
      • Mechanical shearing forces: dermographic urticaria
      • Cold objects/air/wind/fluid: cold contact urticaria
      • Vertical pressure with typical latency of 4 to 6 hours (range, 0.5-24 hours): delayed pressure urticaria 4
      • Localized heat: heat contact urticaria
      • UV and/or visible light: solar urticaria
      • Vibratory forces: vibratory urticaria
      • Contact with a substance causing urticaria: contact urticaria
      • Body temperature increase caused by physical exercise, hot baths, or spicy foods: cholinergic urticaria
      • Water: aquagenic urticaria
      • Physical exercise (with or without food): exercise-induced urticaria
  • Recurrent angioedema
    • Hereditary or acquired decreased level of, or function of, the protease inhibitor SERPING1 (C1 inhibitor; C1INH; C1NH; serpin peptidase inhibitor, clade G, member 1): occurs in hereditary angioedema types 1 and 2 and in acquired C1 inhibitor deficiency
    • Less commonly, familial with normal level and function of C1 inhibitor (hereditary angioedema type 3)
    • Triggers include:
      • Trauma
      • Psychological stress
      • Ovulation
      • Menstruation
      • Contraceptive pills
      • Infectious diseases
      • Pressure

Risk factors and/or associations

Age
  • Younger children tend to present with urticaria rather than angioedema
  • Age of presentation for acute urticaria ranges from 3 months to 88 years, with the average age being the early 20s 6
  • Chronic urticaria usually presents in the third to fifth decades of life 9
  • Hereditary angioedema (types 1, 2, and 3) usually presents in first or second decade of life (occasionally later) 10
  • Acquired C1 inhibitor deficiency usually occurs in middle-aged or older patients without a strong family history of angioedema 11
Sex
  • Women more frequently experience chronic urticaria than men and are at higher risk of experiencing ACE inhibitor–induced angioedema 2
  • No sex differences exist with hereditary angioedema type 1 or 2, but most cases of hereditary angioedema type 3 (with normal C1 inhibitor) are in females 2
Genetics
  • Hereditary angioedema types 1 and 2 are rare autosomal dominant disorders related to mutations of the SERPING1 gene (C1NHC1INH) that codes for C1 inhibitor (OMIM #106100 12)
  • 85% of mutations result in type 1 and 15% account for type 2 2
  • Incidence is 1:50,000 2
Ethnicity/race
  • African Americans have a greater risk of experiencing ACE inhibitor–induced angioedema 2
Other risk factors/associations
  • Smoking increases the risk of ACE inhibitor–induced angioedema

Diagnostic Procedures

Primary diagnostic tools

  • Detailed history and physical examination 4
    • Recognition of urticarial lesions (wheals) versus angioedema (swelling without wheals)
  • Selective laboratory tests to screen for underlying infection and/or inflammatory disorders 4
  • Complement C4 level when angioedema is present, to screen for hereditary angioedema; if low, obtain C1 inhibitor antigenic and functional levels 1
  • Provocative skin testing may be undertaken if chronic inducible urticaria is suspected 4
  • Skin biopsy only when indicated; not typically indicated for initial evaluation 4
    • When condition is refractory to treatment
    • When vasculitis is suspected
    • When immunologic diseases of the skin without urticaria are suspected

Laboratory

  • Acute spontaneous urticaria
    • No laboratory testing is recommended 3
  • Chronic urticaria 3 5
    • CBC to screen for elevated or depressed WBC count suggestive of infection
    • Erythrocyte sedimentation rate or C-reactive protein level to screen for infection and inflammatory processes
    • Allergy testing (skin testing or specific serum IgE measurements) is indicated only if a candidate allergen is suggested by the history
    • In the absence of features suggesting an autoimmune disorder (eg, systemic lupus erythematosus), no evaluation for autoimmune disease is initially necessary
    • Routine testing for thyroid autoantibodies is not recommended without thyroid-related symptoms or a history of thyroid disease
  • Chronic inducible urticaria 4
    • No laboratory testing is routinely indicated
  • Hereditary angioedema
    • Complement C4 level is initial test to screen for hereditary angioedema: low levels (less than 30% of normal mean level) are seen in nearly 100% of patients with hereditary angioedema during attacks 1
    • If C4 level is low, obtain C1 inhibitor antigenic and functional levels 1
      • C1 inhibitor functional level will always be low when antigenic level is low; functional level differentiates the 3 types of hereditary angioedema
        • Type 1 hereditary angioedema: low antigenic level and low functional level
        • Type 2 hereditary angioedema: normal antigenic level and low functional level
        • Type 3 hereditary angioedema: normal antigenic level and normal functional level
          • When C1 inhibitor status cannot be determined or confirmed by laboratory testing, the presence of a strong family history of angioedema without hives that does not respond to high-dose antihistamines is consistent with a diagnosis of hereditary angioedema type 3 (with normal C1 inhibitor)
          • In these patients, a positive finding of F12 (coagulation factor XII) gene mutation (OMIM #610618 13 and OMIM #610619 14) confirms diagnosis of hereditary angioedema type 3 (with normal C1 inhibitor); negative finding does not rule out hereditary angioedema type 3
    • To help differentiate acquired C1 inhibitor deficiency from type 1 hereditary angioedema, measure complement C1q antigen level (not C1q binding) 1
      • C1q antigen level is usually low in patients with acquired C1 inhibitor deficiency and normal in patients with hereditary angioedema type 1

Functional testing

  • Provocative testing to confirm the diagnosis may be useful in evaluation of chronic inducible urticaria 15
    • Dermographic urticaria
      • Stroking skin with a firm object (eg, tongue depressor) will produce a prompt wheal-and-flare response (within minutes)
    • Cold contact urticaria
      • Applying a cold stimulus to the skin (eg, ice cube to the arm) will produce a wheal-and-flare response as the skin warms
    • Delayed-pressure urticaria
      • Suspending 15 lb over the shoulder for 10 to 15 minutes and observing for delayed development of angioedema at the site of pressure is recommended (delay is typically 3-12 hours)
      • Erythematous, deep, painful lesions
    • Heat contact urticaria 4
      • Placing a metal or glass cylinder filled with water at 45 °C against the forearm for 5 minutes and looking for the wheal-and-flare reaction may be diagnostic
    • Solar urticaria
      • Usually, urticaria develops within 1 to 3 minutes of sun exposure; photosensitivity testing with different wavelengths of light evokes reaction
    • Vibratory urticaria
      • Exposing skin to vibrations from a vortex mixer should demonstrate a wheal-and-flare response 16
    • Contact urticaria
      • Can perform normal prick or patch testing to identify the exogenous agent, although testing usually is not performed at initial evaluation
    • Cholinergic urticaria
      • Performing an exercise challenge while passively warming the patient may induce urticaria
      • Wheals are typically 1 to 3 mm 4
    • Aquagenic urticaria
      • Applying a 35 °C water compress to skin of upper body for 30 minutes and observing a wheal-and-flare reaction is diagnostic
      • Wheals are typically 1 to 3 mm 4
    • Exercise-induced urticaria
      • Performing an exercise challenge in a controlled environment may be necessary to diagnose

Differential Diagnosis

Most common

  • IgE-mediated angioedema in the setting of anaphylaxis
    • Life-threatening, IgE-mediated allergic reaction
    • Most patients present with urticaria and/or angioedema
    • Rapid development of symptoms (minutes to hours) involving multiple organ systems
    • Serum tryptase level greater than 11.5 ng/mL (obtained within 3 hours of symptom onset) 17
    • Hypotension rapidly develops
    • Respiratory compromise is likely
    • Responds to epinephrine
  • Erythema multiforme
    • Typical lesion is target lesion (bull’s-eye lesion) with concentric erythematous rings and intervening rings that are nearly normal in color, ranging in size from 2 to 20 mm
    • Lesions lack the central zone of normal skin or erythema seen in urticaria
    • Usually lesions are symmetrically located and involve extremities (dorsum of hands, elbows, feet, and knees)
    • Oral mucosal lesions in 70% or more of cases of erythema multiforme 18
    • Complete recovery in 1 to 4 weeks 18
  • Contact dermatitis (allergic or irritant)
    • Acute irritant contact dermatitis presents with erythematous, swollen, and painful or pruritic ulcerations of skin
    • Chronic contact dermatitis presents as eczematous changes of skin, including cracking, fissures, erythema, and dryness
    • Allergic contact dermatitis presents with erythema, scaling, and itching at contact site; eyelid involvement is frequently noted
  • Systemic lupus erythematosus
    • Can flare, producing (in some cases) scaly papules that expand with central clearing to form annular lesions
    • Tends to affect young to middle-aged women
    • Symptoms of myalgias and arthritis may be present
    • Associated with a positive anti-Ro antibody measurement
  • Mastocytosis
    • Skin is most common site of involvement of mastocytosis
    • Urticaria pigmentosa is most common skin condition in adults and children with mastocytosis with slightly raised papules or yellow-tan to red-brown macules, mainly over trunk and legs
    • Palms, face, scalp, and soles are usually spared
    • Associated with flushing, pruritus, and blistering (mainly in children)
    • Elevated serum tryptase level (higher than 20 ng/mL) indicates need for bone marrow biopsy 17
    • Detection of KIT (c-kit, CD117) mutation at codon 816 in bone marrow or blood
    • Diagnosis requires bone marrow biopsy and is made according to WHO criteria; presence of 15 or more mast cells per aggregate is a major criterion 19
  • Urticarial vasculitis
    • Cutaneous lesions may not be differentiated from allergic urticaria clinically
    • Usually, lesions are nonblanching, purpuric, and palpable
    • Angioedemalike lesions may be present
    • Lesions are associated with painful or burning dysesthesia
    • Lesions may last several days or longer and leave residual hyperpigmentation
    • Nausea, vomiting, diarrhea, and abdominal pain are present in up to 30% of patients 20
    • Arthralgias and arthritis are present in up to 75% of patients (mainly ankles, feet, hands, elbows, and knees) 20
    • Proteinuria and/or hematuria are present in up to 60% of patients 20
    • Pulmonary disease, including chronic obstructive pulmonary disease, occurs in up to 55% of patients 20
    • Reduced levels of C1, C2, C4, and C3
    • Lesional skin biopsy showing leukocytoclastic vasculitis is gold standard for diagnosis

Treatment

Goals

  • Achieve complete control of symptoms
  • Identify and eliminate or avoid stimulating factors

Disposition

Admission criteria

Emergent airway management may be required in patients who develop anaphylaxis or laryngeal angioedema

Closely observe patients with oropharyngeal or laryngeal angioedema

  • Admit to a facility that can perform intubation or tracheostomy should it become necessary. Closely monitor for signs and symptoms of impending airway closure, including change in voice, loss of ability to swallow, and difficulty in breathing
  • After emergency management of upper airway edema, admit patients to a facility with intensive care available until all symptoms resolve
Criteria for ICU admission
  • Need for intubation or tracheostomy

Recommendations for specialist referral

  • Refer to allergist/immunologist:
    • All patients with known or suspected hereditary angioedema
    • For assistance with diagnosis (provocation testing and assessment of differential diagnoses) and management of chronic urticaria

Treatment Options

Acute spontaneous urticaria 4

  • Monotherapy with second-generation antihistamine
    • First-generation antihistamines are also effective but can be associated with sedation
  • Brief course of oral corticosteroid may be required (up to 10 days) 3
  • Epinephrine if cannot exclude diagnosis of anaphylaxis
  • If patient is in distress and not responding to urgent use of antihistamines, corticosteroids, or epinephrine, then consider hereditary angioedema type 1 or 2 (C1 inhibitor deficiency or defect) and treat accordingly

Chronic spontaneous urticaria 4

  • Monotherapy with second-generation antihistamine
    • Start with normal dose and increase up to 4 times the usual dose
  • Add H₂ antagonist or montelukast (leukotriene receptor antagonist) to second-generation antihistamine if patient is not responsive to second-generation antihistamine alone
  • Consider a first-generation antihistamine (eg, hydroxyzine) given at bedtime if condition is poorly responsive, or doxepin (antidepressant with H₁ and H₂ antagonist activity but no dosing guidelines available)
  • Chronic urticaria that is not responsive to maximum antihistamine therapy is considered refractory
    • Short-term use of corticosteroids may be indicated as third line therapy
    • Omalizumab (anti-IgE) or cyclosporine if condition is still refractory (under supervision of an allergy/immunology specialist) 3 4 21

Chronic inducible urticaria 4

  • Eliminate or reduce exposure to causative factor
  • Monotherapy with second-generation antihistamine
    • Start with normal dose and increase up to 4 times the usual dose
  • Add H₂ antagonist (no dosing recommendations are available) or montelukast (leukotriene receptor antagonist) to second-generation antihistamine if not responsive to second-generation antihistamine alone
  • Consider a first-generation antihistamine (eg, hydroxyzine) dosed at bedtime if condition is poorly responsive, or doxepin (antidepressant with H₁ and H₂ antagonist activity, but no dosing guidelines available)
  • Short-term use of corticosteroids may be indicated as third line therapy
  • Omalizumab (anti-IgE) or cyclosporine if condition is still refractory (under supervision of an allergy/immunology specialist) 3 4 21

Angioedema (recurrent) 1

  • If laryngeal edema is suspected based on history and physical examination findings, ensure that emergency equipment for airway management is readily available
  • Hereditary angioedema type 1 or 2
    • Acute attacks (on-demand therapy; effective agent is available directly to patient or prearranged for and administered at a medical facility)
      • C1 inhibitor
        • Recommended as first line therapy for acute attacks 22
        • Median time to onset of relief: 15 minutes for laryngeal attacks, 20 minutes for abdominal attacks, and 28 minutes for facial attacks 22
        • Home therapy is known to be effective and safe and may be applied in some cases of recurrent angioedema 1
      • Icatibant (bradykinin B₂ receptor antagonist)
        • Approved for self-administration with good safety profile 1
      • Ecallantide (plasma kallikrein inhibitor)
        • Approved only for use in a medically supervised setting owing to anaphylactoid reactions in 2% to 3% of patients
      • Fresh frozen plasma if other treatments are not available
    • Short-term prophylaxis (eg, before surgery, invasive procedure, or dental work other than cleaning)
      • C1 inhibitor infusion up to 12 hours before procedure (preferred) 1
      • Fresh frozen plasma
      • High-dose 17α-alkylated androgens taken 5 to 7 days before and 2 days after procedure
    • Regular, long-term prophylaxis (indicated when, despite on-demand therapy, patient has 12 moderate to severe attacks per year or more than 24 days per year affected by hereditary angioedema) 23
      • C1 inhibitor
      • 17α-alkylated androgens (at lowest effective dose)
      • Aminocaproic acid
      • Tranexamic acid
  • Acquired C1 inhibitor deficiency 1
    • Acute attacks
      • C1 inhibitor (although it is less effective in this setting owing to formation of anti–C1 inhibitor antibodies)
      • Ecallantide
      • Icatibant
      • Fresh frozen plasma
    • Prophylaxis
      • Treatment of underlying condition
      • Aminocaproic acid (better response)
      • Tranexamic acid (better response)
      • 17α-alkylated androgens (less effective)
  • ACE inhibitor–associated angioedema
    • Discontinuation of ACE inhibitor 1
    • Icatibant and fresh frozen plasma have been used to control the angioedema; no controlled trials to support use 1
    • Recurrent angioedema may occur in patients with ACE inhibitor–associated angioedema who are subsequently prescribed an angiotensin receptor blocker (2%-17% of patients), but most patients may safely use an angiotensin receptor blocker without recurrence 1

Idiopathic angioedema, not due to C1 inhibitor deficiency 7

  • Treatment determined by whether condition responds to antihistamines or not
  • Typically, if wheals are present, then condition is likely to respond to antihistamines
  • If no urticarial lesions, then bradykinin is probable mediator and response to icatibant is expected
    • If presentation is consistent with idiopathic histaminergic–acquired angioedema (ie, rapid onset of symptoms, facial involvement without laryngeal involvement, no wheals), then treat with antihistamines 8

Pain of angioedema often requires opioid analgesics 1

Nausea and vomiting due to abdominal angioedema often require antiemetics

Drug therapy

  • Acute and chronic urticaria
    • Second-generation antihistamine
      • Cetirizine oral syrup or tablet
        • Cetirizine Hydrochloride Oral syrup; Children less than 2 years of age: 2.5 mg PO once daily; may increase to 2.5 mg PO twice daily if needed. 
        • Cetirizine Hydrochloride Oral syrup; Children 2 to 5 years: 2.5 mg PO once daily; may increase to 5 mg once daily or 2.5 mg twice daily if needed.
        • Cetirizine Hydrochloride Oral tablet; Children and Adolescents 6 years and older: 5 to 10 mg PO once daily.
        • Cetirizine Hydrochloride Oral tablet; Adults: 5 to 10 mg PO once daily.
        • Cetirizine Hydrochloride Oral tablet; Geriatric Adults: 5 to 10 mg PO once daily for ages 65 to 76 years; 5 mg PO once daily for ages 77 years and older. Geriatric patients are more sensitive to anticholinergic effects. OTC labeling recommends asking a doctor before use.
      • Cetirizine IV dosage (acute urticaria only)
        • FDA approved October 2019
        • Cetirizine Hydrochloride Solution for injection; Infants 6 months and older: 2.5 mg IV once every 24 hours as needed. 24
        • Cetirizine Hydrochloride Solution for injection; Children 1 to 5 years: 2.5 mg IV once every 24 hours as needed. 24
        • Cetirizine Hydrochloride Solution for injection; Children 6 to 11 years: 5 mg or 10 mg IV (depending on symptom severity) once every 24 hours as needed. 24
        • Cetirizine Hydrochloride Solution for injection; Children and Adolescents 12 years and older: 10 mg IV once every 24 hours as needed. 24
        • Cetirizine Hydrochloride Solution for injection; Adults: 10 mg IV once every 24 hours as needed. 24
      • Fexofenadine oral suspension or tablet
        • Fexofenadine Hydrochloride Oral suspension; Infants and Children 6 months and up to 2 years: 15 mg PO twice daily.
        • Fexofenadine Hydrochloride Oral suspension; Children 2 to 11 years: 30 mg PO twice daily.
        • Fexofenadine Hydrochloride Oral tablet; Adults, Adolescents, and Children 12 years and older: 60 mg PO twice daily. Alternatively, 180 mg PO once daily.
      • Loratadine oral syrup or tablet
        • Loratadine Oral syrup; Children 2 to 5 years: 5 mg PO once daily. Do not to exceed 5 mg in 24 hours.
        • Loratadine Chewable tablet; Adults, Adolescents, and Children 6 years and older: 10 mg PO daily. Do not exceed 10 mg in 24 hours.
    • First-generation antihistamine
      • Diphenhydramine oral syrup or tablet
        • Diphenhydramine Hydrochloride Oral syrup; Children 6 to 12 years: 12.5 mg PO every 4 to 6 hours as needed. Max: 75 mg/24 hours.
        • Diphenhydramine Hydrochloride Oral capsule; Adults and Adolescents: 25 mg PO every 4 to 6 hours as needed. Max: 150 mg/24 hours.
      • Hydroxyzine oral solution or tablet
        • Hydroxyzine Hydrochloride Oral solution; Children less than 6 years: 50 mg/day PO, in divided doses. Alternatively, some pediatric texts recommend 2 mg/kg/day PO given in divided doses every 6 to 8 hours as needed. Other alternatives include 15 mg/m2/day given in divided doses.
        • Hydroxyzine Hydrochloride Oral solution; Children and Adolescents 6 years and older: 50 to 100 mg/day PO, in divided doses. Alternatively, some pediatric texts recommend 2 mg/kg/day PO given in divided doses every 6 to 8 hours as needed. Other alternatives include 15 mg/m2/day given in divided doses.
        • Hydroxyzine Hydrochloride Oral tablet; Adults: 25 mg PO 3 to 4 times per day as needed.
    • Leukotriene receptor antagonist
      • Montelukast
        • Montelukast Sodium Chewable tablet; Children and Adolescents: Adding montelukast to non-sedating antihistamine therapy is recommended if symptoms persist 1 to 4 weeks after optimal antihistamine dosing. Specific dosing guidelines not provided, use typical age-adjusted doses (i.e., 4 mg/day for children aged 5 years or younger, 5 mg/day for children 6 to 14 years, and 10 mg/day for adolescents aged 15 years or older).
        • Montelukast Sodium Oral tablet; Adults: 10 mg PO once daily in combination with a non-sedating antihistamine is recommended for refractory urticaria; montelukast should only be added to a treatment regimen after optimal dosing of a non-sedating antihistamine fails to control the urticaria.
    • Antidepressant
      • Doxepin
        • Doxepin Hydrochloride Oral capsule; Adults: 50 to 150 mg PO given as a single dose at bedtime or in 2 to 3 divided doses. Initiate at the low end of the dosing range in the geriatric patient; slowly titrate and closely observe for anticholinergic effects or oversedation. 4
    • Corticosteroids
      • Prednisone
        • Prednisone Oral tablet; Adults: Short courses of 30 mg/day to 50 mg/day PO can be given during the late phase of an acute reaction. FDA-approved dosage: 5 to 60 mg/day PO, depending on disease severity for angioedema; taper as clinically indicated.
    • Omalizumab 3 4 21
      • For refractory chronic inducible urticaria and chronic spontaneous urticaria (under supervision of an allergy/immunology specialist)
      • Omalizumab (Hamster) Solution for injection; Children and Adolescents 12 years and older: 150 mg or 300 mg subcutaneously every 4 weeks. Dosing is independent of serum IgE and body weight. Periodically reassess the need for continued treatment.
      • Omalizumab (Hamster) Solution for injection; Adults: 150 mg or 300 mg subcutaneously every 4 weeks. Dosing is independent of serum IgE and body weight. Periodically reassess the need for continued treatment.
    • Cyclosporine 3 4 21
      • For refractory chronic inducible urticaria and chronic spontaneous urticaria (under supervision of an allergy/immunology specialist)
      • Cyclosporine Oral capsule; Adults, Adolescents, and Children 2 years and older: 3 mg/kg/day PO in 2 divided doses. 25
  • Angioedema: acute attacks
    • C1 esterase inhibitor
      • Plasma-derived nanofiltered C1 inhibitor, human
        • C1 esterase inhibitor (Human) Solution for injection [Angioedema treatment]; Children and Adolescents: 20 International Units/kg IV.
        • C1 esterase inhibitor (Human) Solution for injection [Angioedema treatment]; Adults: 20 International Units/kg IV.
      • Recombinant human C1 inhibitor (conestat alfa)
        • C1 esterase inhibitor (Recombinant) Solution for injection; Adolescents: 50 International Units/kg/dose (Max: 4200 International Units/dose) slow IV over approximately 5 minutes; may repeat once if symptoms persist; max: 2 doses per 24 hours. Efficacy not established for HAE patients with laryngeal attacks.
        • C1 esterase inhibitor (Recombinant) Solution for injection; Adults: 50 International Units/kg/dose (Max: 4200 International Units/dose) slow IV over approximately 5 minutes; may repeat once if symptoms persist; max: 2 doses per 24 hours. Efficacy not established for HAE patients with laryngeal attacks.
    • Bradykinin B₂ receptor antagonist
      • Icatibant
        • Icatibant acetate Solution for injection; Adults: 30 mg subcutaneously once. May repeat every 6 hours PRN. Max: 90 mg/24 hours.
    • Plasma kallikrein inhibitor
      • Ecallantide
        • Ecallantide Solution for injection; Adults, Adolescents, and Children >= 12 years: 30 mg subcutaneously given as three 10-mg (1 mL) injections. May repeat entire dose within 24-hour period if attack persists.
    • Fresh frozen plasma
      • Fresh frozen plasma
        • Fresh frozen plasma; Adults: 1 to 4 units IV titrated to control of symptoms. 26
  • Angioedema: short-term prophylaxis
    • C1 esterase inhibitor
      • Plasma-derived nanofiltered C1 inhibitor, human
        • C1 Esterase Inhibitor (Human) Solution for injection; Adults and Adolescents: 1,000 to 2,000 units IV up to 6 hours before procedure. 2
    • 17α-alkylated androgens
      • Danazol
        • Danazol Oral capsule; Adults: 6 to 10 mg/kg/day PO in divided doses to a maximum of 200 mg 3 times daily, taken for 5 to 7 days before and 2 days after procedure. 2
    • Fresh frozen plasma
      • Fresh frozen plasma
        • Fresh frozen plasma; Children: 10 mL/kg IV up to 6 hours before procedure. 2
        • Fresh frozen plasma; Adults: 2 units IV up to 6 hours before procedure. 2
  • Angioedema: long-term prophylaxis
    • C1 esterase inhibitor
      • Plasma-derived nanofiltered C1 inhibitor, human
        • IV dosing
          • C1 esterase inhibitor (Human) Solution for injection; Children 6 to 11 years: 500 units IV over at least 5 minutes every 3 to 4 days. Adjust the dose according to individual response, up to 1,000 units every 3 to 4 days.
          • C1 esterase inhibitor (Human) Solution for injection; Children and Adolescents 12 to 17 years: 1,000 units IV over at least 10 minutes every 3 to 4 days. For patients who do not respond adequately, doses up to 2,500 units (Max: 100 units/kg) every 3 to 4 days may be considered based on individual patient response.
          • C1 esterase inhibitor (Human) Solution for injection; Adults: 1,000 units IV over at least 10 minutes every 3 to 4 days. For patients who do not respond adequately, doses up to 2,500 units (Max: 100 units/kg) every 3 to 4 days may be considered based on individual patient response.
        • Subcutaneous dosing
          • C1 esterase inhibitor (Human) Solution for injection; Adults: 60 International Units/kg subcutaneously twice weekly (every 3 or 4 days).
    • 17α-alkylated androgens
      • Danazol
        • Danazol Oral capsule; Adults: Initially, 200 mg PO 2 to 3 times per day. If a favorable response, may reduce dosage by half at intervals of 1 to 3 months. If there is an unfavorable response (in the form of an attack of angioedema during treatment), the dose may be increased by up to 200 mg/day.
      • Oxandrolone
        • Oxandrolone Oral tablet; Children: 0.1 mg/kg/day PO (2.5 mg/week to 7.5 mg/day). 2
        • Oxandrolone Oral tablet; Adults: minimal effective dose, not to exceed 10 mg/day PO. 2
    • Aminocaproic acid
      • Aminocaproic Acid Oral solution; Children: 50 mg/kg PO twice daily is usual dose, with range from 20 mg/kg PO twice daily to 100 mg/kg PO twice daily. 2
      • Aminocaproic Acid Oral tablet; Adults: 16 g/day PO in divided doses every 4 or 6 hours for up to a month then 2 to 12 g/day PO in 2 to 4 divided doses. Usual dose: 2 g PO 3 times daily (range, 1 g PO twice daily to 4 g PO 3 times daily).
    • Tranexamic acid
      • Tranexamic Acid Oral solution; Children: 20 mg/kg PO twice daily is usual dose, with range from 10 mg/kg PO twice daily to 25 mg/kg PO 3 times daily. 2
      • Tranexamic Acid Oral tablet; Adults: 0.5 to 3 g/day PO in divided doses for longer-term prophylaxis. Usual dose: 1 g PO twice daily (range: 0.25 to 1.5 g PO twice daily). For perioperative prophylaxis, 1 g PO every 6 hours beginning 48 hours before procedure and continuing for additional 48 hours.

Nondrug and supportive care

Instruct patients with recurrent angioedema to call emergency services (eg, 911) if an attack occurs that involves the oropharynx or airway or causes any degree of breathing difficulty

When angioedema involves the abdomen, aggressive IV hydration is recommended to correct decreased intravascular volume due to third spacing

When the underlying cause of urticaria or angioedema is known, encourage patient to avoid that cause 4

Encourage patients with chronic urticaria to avoid aspirin and NSAIDs, tight clothing, and heat because these factors may exacerbate the condition 4

Have female patients with hereditary angioedema avoid estrogen-containing contraceptive pills

Provide annual influenza vaccination to all patients who have hereditary angioedema

Provide hepatitis A and B vaccination to all patients with hereditary angioedema who are receiving blood products 27

Procedures
Airway management 28

General explanation

  • If patient is conscious and intubation is not required, place patient in a semiprone position with head down to help maintain airway (recovery position)
  • Fiberoptic nasopharyngoscopy may help determine degree of airway compromise and need for intubation, but use caution so as not to accelerate airway closure via trauma
  • Immediately intubate when hoarseness, stridor, or hypoxemia are present
  • Edema extent and location may interfere with intubation, requiring surgical management of airway
    • Cricothyroidotomy may be needed if emergent tracheostomy is not feasible
      • Commercial cricothyroidotomy kits are available, but inserting a large-bore IV catheter by puncturing the cricothyroid membrane is effective, fast, and relatively safe; 3 mm is minimal diameter of tube inserted
    • In a controlled situation, a surgical tracheostomy may be performed, but significant swelling may still require performance of a cricothyroidotomy
    • Percutaneous tracheostomy may be considered

Indication

  • Angioedema with suspicion of laryngeal edema

Comorbidities

  • A significant proportion of patients with acquired angioedema with C1 inhibitor deficiency have an underlying B-cell disorder (eg, malignant lymphoma or monoclonal gammopathy of undetermined significance) 7

Special populations

  • For children: use the same therapeutic approach as for adults; second-generation antihistamines are preferred
  • For pregnant and lactating women: manage urticaria in the same way as for other adults, with a preference for second-generation antihistamines
    • In pregnant women, treat hereditary angioedema using C1 inhibitor for prophylaxis before delivery interventions, including vacuum extraction, forceps delivery, and cesarean section
      • Normal vaginal delivery does not require prophylaxis, but keep C1 inhibitor available
      • Avoid androgens, tranexamic acid, and aminocaproic acid during pregnancy

Monitoring

  • Reevaluate patients who have chronic urticaria every 3 to 6 months to determine efficacy and necessity of continued drug therapy 4
  • In patients treated with cyclosporine, monitor serum concentrations, blood pressure, and renal function
  • In patients treated with 17α-alkylated androgens, perform liver function tests every 6 months and hepatic ultrasonography annually 1
  • Once the diagnosis of hereditary angioedema is established, there is no need to recheck C1 inhibitor or C4 levels

Complications and Prognosis

Complications

  • Anaphylactic shock
    • IgE-mediated acute urticaria may present with systemic symptoms that can develop into anaphylaxis and lead to shock
  • Respiratory arrest
    • Laryngeal angioedema (experienced by at least 50% of patients with hereditary angioedema at least once in a lifetime) may require emergent intubation or tracheostomy to maintain the airway 2
  • Avoid chronic opioid administration in patients with hereditary angioedema because patients with frequent attacks are at risk for opioid dependence

Prognosis

  • Most cases of acute urticaria resolve within 2 to 3 weeks 6
  • Duration of chronic urticaria varies; however, physical urticarias can persist for many years 4
  • Hereditary angioedema attacks increase over 2 days, then generally resolve over another 2 to 5 days; hereditary angioedema varies in frequency of attacks—ranging from weekly to annually—and attacks are often unpredictable 1
    • Patients not receiving prophylactic therapy may experience swelling every 10 to 20 days 1
    • Symptoms may improve during pregnancy
    • In 1 study of families with hereditary angioedema in which there had been a death from laryngeal edema, a 40% risk of fatal airway obstruction was noted among the remaining family members with hereditary angioedema 1

Screening and Prevention

Screening

At-risk populations

  • First-degree family members of any patient known to have hereditary angioedema 29

Screening tests

  • In the United States, C4 level is recommended 29
    • Concern about sensitivity and specificity with C1 inhibitor levels has led to the recommendation in the United States to obtain C4 levels instead
  • In Canada, screening for hereditary angioedema is done with C1 inhibitor levels 30
    • Canadian 2010 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema recommended repeating the test for hereditary angioedema at least once to confirm

Sources

Zuraw BL et al: A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 131(6):1491-3, 2013

Cross Reference

Sharing is caring!

Diphenhydramine

Diphenhydramine Brand Names Aid to Sleep | Alka-Seltzer Plus Allergy | Aller-G-Time...

Dinutuximab

Dinutuximab Brand Name– Unituxin What is Dinutuximab Dinutuximab is a...

You cannot copy content of this page

shares
15585

Sign up to receive the trending updates and tons of Health Tips

Join SeekhealthZ and never miss the latest health information

15856
Scroll to Top