Introduction:

Urticaria and Angioedema

Urticaria Angioedema

Etiology of Urticarial Reactions:

Allergic Triggers

Acute UrticariaDrugs

Foods

Food additives

Viral infections–hepatitis A, B, C–Epstein-Barr virus

Insect bites and stings

Contactants and inhalants (includes animal dander and latex)

Chronic UrticariaPhysical factors

–cold–heat–dermatographic–pressure–solar

Idiopathic

Chronic Urticaria & Angioedema

Definition: Hives occurring greater than 6 weeksHives and angioedema (40%)Hives alone (40%)Angioedema alone (20%)

Etiology:Difficult to determine, cause rarely foundCommon in 3rd and 4th decade of lifeUsually not foods, drugs, pollens, infections, “dyes”Bad News: May last years….

HEURISTIC SUBDIVISIONSca

1. Acute urticaria - less than 6 weeks; history implicates cause in approx. 50%; difficult to study in clinical trials; good prognosis.

2. Chronic urticaria - greater than 6 weeks; workup indicated; easier to study; often persistent.

3. Chronic idiopathic urticaria - subset of chronic urticaria in which workup fails to pinpoint cause; diagnosis by exclusion; not homogeneous.

• Immune-mediated urticaria• The type I allergic immunoglobulin (Ig) E response is initiated

by antigen-mediated IgE immune complexes that bind and cross-link Fc receptors on the surface of mast cells and basophils, thus causing degranulation with histamine release.

• The type II allergic response is mediated by cytotoxic T cells, causing deposits of immunoglobulins, complement, and fibrin around blood vessels. This leads to urticarial vasculitis.

• The type III immune-complex disease is associated with systemic lupus erythematosus and other autoimmune diseases that cause urticaria.[

• Non -immune-mediated urticaria• Complement-mediated urticaria includes viral and bacterial

infections, serum sickness, and transfusion reactions. Urticarial transfusion reactions occur when allergenic substances in the plasma of the donated blood product react with preexisting IgE antibodies in the recipient. Certain drugs (opioids, vecuronium, succinylcholine, vancomycin, and others) as well as radiocontrast agents cause urticaria due to mast cell degranulation through a non-IgE-mediated mechanism

Physical Urticarias

Reproducible by environmental factorsPhysical stimuli

Most frequently in young adultsEpisodic and often limited to areas of inciting stimulusUsually, unresponsive to corticosteroidsOverall, treatment with non-sedating antihistamines

Examples of Physical Urticarias

Answer: Dermatographism

1. If you stroke the skin, and a hive occurs?

2. If you place an ice cube on the forearm, and after removal of ice cube, hive occurs?

Answer: Cold-induced urticaria

3. If hives occur when the patient sweats or exposure to heat?

Answer: Cholinergic urticaria or localized heat urticaria

Urticarial Vasculitis (Rare)

Inflammatory injury of capillaries and postcapillary venules in the skin.Etiology: Manifestation of systemic diseaseClinically:

Hives persisting > 24 hours pruriticPainful, stinging, burning sensation“Leaves a trace”

–Faint residual hyperpigmentation, indicating red blood cell extravasation

The Pathogenesis of Chronic Urticaria:

Cellular Mediators

Histamine as a Mast Cell Mediator

Role of Mast Cells in Chronic Urticaria:

Lower Threshold for Histamine Release

Release threshold decreased by:Cytokines & chemokines

in the cutaneous microenvironment

Antigen exposureHistamine-releasing factorAutoantibodyPsychological factors

Release threshold increased by:CorticosteroidsAntihistaminesCromolyn (in vitro)

Cutaneous mast cell

An Autoimmune Basis for Chronic

Idiopathic Urticaria: Antibodies to IgE

Angioedema (Swelling)

Edema of the deep layers of the dermis and subcutaneous tissue.

Non-pitting edema Skin is not hotNon-dependent areas

It is not: “pre-tibial pitting edema”

• The swelling of the affected area of angioedema is a result of the fast onset of increase of local vascular permeability in submucosal and subcutaneous tissue. IgE-mediated mast cell activation and degranulation, key elements of an allergic reaction, often manifest as urticaria and angioedema. Non–IgE-mediated mast cell activation/mediator release may explain certain autoimmune-mediated and idiopathic angioedema

• Patients usually describe swelling of the face (eg, eyelids,

lips), tongue, hands, and feet. It can be acute or chronic, and

each episode of angioedema may last a few hours to a few

days. A local burning sensation and pain can be observed

without pronounced itchiness or local erythema.

• Abdominal pain can sometimes be the only presenting

symptom of angioedema. Throat tightness, voice changes,

and trouble breathing may indicate airway involvement.

• For acute and new-onset angioedema, special attention

should be directed to the potential relationship with food or

drug intake, insect stings, or other unusual exposures. For

chronic and recurrent cases, ask the patient about potential

triggers, medication use and associated medical history,

family history, and past evaluation.

Allergic angioedema

• Allergic angioedema is often associated with urticaria. It is

typically observed within 30 minutes to 2 hours after

exposure to the allergen (eg, food, drug, venom, latex).

Pseudoallergic angioedema

• Pseudoallergic angioedema is not IgE-mediated. However,

its clinical course and presentation is very similar to allergic

angioedema. Typical examples are angioedema induced by

nonsteroidal anti-inflammatory drugs (NSAIDs) and

intravenous contrast material; aspirin (ASA) is the most

common culprit.

Nonallergic angioedema

• Nonallergic angioedema does not involve IgE or histamine; urticaria is generally not associated with this type of angioedema.

• Hereditary angioedema (HAE) is perhaps the prototype of this type of angioedema. Decreased functional C1-INH production leading to unchecked bradykinin production are believed to be the fundamental changes in HAE types I and II.[20] Acquired angioedema (AAE) also has decreased C1-INH function due to autoantibody production or accelerated consumption of C1-INH.

Idiopathic angioedema

• The causes of idiopathic angioedema are, by definition, not identifiable. Furthermore, the exact mechanisms are unclear.[11, 12] Some may be associated with urticaria. Based on responses to medication, some cases are thought to be mediated by mast cell activation, albeit IgE-independent.

• Physical urticaria/angioedema: Common triggers include heat, cold, emotional stress, and exercise. Nonspecific mast cell activation and degranulation are suspected causes.

Treatment

• Histamine-mediated angioedema

• Histamine-mediated angioedema is either IgE-dependent (eg, allergic reaction due to food or drug) or IgE-independent (eg, radiocontrast media). NSAIDs related and most idiopathic angioedema are treated with same measures.

• Most cases can be managed well with outpatient treatment alone. Antihistamines as described in the urticaria article are often used as the first-line treatment for angioedema

• For moderate to severe cases, close monitoring is often necessary. Diphenhydramine (50) mg IM/IV is helpful. Hydrocortisone (200 mg) or Solu-Medrol (40-60 mg) IV may reduce the possibility of relapse.

• For laryngeal swelling and airway obstruction, close monitoring of the airway is mandatory. Epinephrine (1:1,000) should be administrated IM at 0.01 mg/kg or 0.3 mg repeated every 10-15 min, if necessary. Occasionally, intubation or even tracheostomy may be necessary. These patients should be admitted for at least 24 hours of observation.

• Bradykinin-mediated angioedema• Antihistamines do not work for these patients.• Cortical steroids have limited or no value.

• Monitor and support airway as in histamine-mediated angioedema.• Epinephrine does not work as well as in histamine-mediated

angioedema. Its value for treating acute HAE attacks is limited.• Severe abdominal pain may sometimes be the only presenting

symptom for these patients when seeking emergency medical care.

• Supportive care includes pain control and relief of nausea.

• Fresh frozen plasma (2 units) has been shown to be helpful in certain patients. However, fresh frozen plasma worsening an acute attack of laryngoedema has also been reported. If this treatment is used, be ready to intubate or perform a tracheostomy, if necessary.

• Antifibrinolytics (eg, Amicar or Traxeminic acid) may be helpful.

Initial Workup of Urticaria

Patient historySinusitisArthritisThyroid diseaseCutaneous fungal infectionsUrinary tract symptomsUpper respiratory tract infection

(particularly important in children)Travel history (parasitic infection)Sore throatEpstein-Barr virus, infectious

mononucleosisInsect stingsFoodsRecent transfusions with

blood products (hepatitis)Recent initiation of drugs

Physical examSkinEyesEarsThroatLymph nodesFeetLungsJointsAbdomen

Laboratory Assessment for

Chronic Urticaria

Possible tests for selected patientsStool examination for ova

and parasitesBlood chemistry profileAntinuclear antibody titer (ANA)Hepatitis B and CSkin tests for IgE-mediated

reactions

Initial testsCBC with differentialErythrocyte sedimentation rateUrinalysis

RAST for specific IgEComplement studies: CH50

CryoproteinsThyroid microsomal antibodyAntithyroglobulinThyroid stimulating hormone (TSH)

Histopathology

Group 2:Polymorphous perivascular infiltrateNeutrophilsEosinophilsMononuclear cells

Group 3:Sparse perivascular

lymphocytes

Urticaria Associated With

Other Conditions

Collagen vascular disease (eg, systemic lupus erythematosus)

Complement deficiency, viral infections (including hepatitis B and C), serum sickness, and allergic drug eruptions

Chronic tinea pedis

Pruritic urticarial papules and plaques of pregnancy (PUPPP)

Schnitzler’s syndrome

H1-Receptor Antagonists:

Pros and Cons for Urticaria and Angioedema

First-generation antihistamines (diphenhydramine and hydroxyzine)

Advantages: Rapid onset of action, relatively inexpensive

Disadvantages: Sedating, anticholinergic

Second-generation antihistamines (astemizole, cetirizine, fexofenadine, loratadine)

Advantages: No sedation (except cetirizine); no adverse anticholinergic effects; bid and qd dosing

Disadvantages: Prolongation of QT interval; ventricular tachycardia (astemizole only) in a patient subgroup

An Approach to the Treatment of

Chronic Urticaria

Treatment of Urticaria:

Pharmacologic Options

Antihistamines, othersFirst-generation H1

Second-generation H1

Antihistamine/decongestant combinations

Tricyclic antidepressants (eg, doxepin)

Combined H1 and H2 agents

Beta-adrenergic agonistsEpinephrine for acute urticaria

(rapid but short-lived response)Terbutaline

CorticosteroidsSevere acute urticaria

–avoid long-term use–use alternate-day regimen

when possibleAvoid in chronic urticaria

(lowest dose plus antihistamines might be necessary)

MiscellaneousPUVAHydroxychloroquineThyroxine

Atopic Dermatitis: Acute, Subacute,

and Chronic Lesions

Acute Cutaneous LesionsErythematous, intensely pruritic papules and vesiclesConfined to areas of predilection

–cheeks in infants–antecubital–popliteal

Subacute Cutaneous LesionsErythema excoriation, scalingBleeding and oozing lesions

Chronic LesionsExcoriations with crustingThickened lichenified lesionsPostinflammatory hyperpigmentationNodular prurigo

Atopic Dermatitis:

Physical Distribution by Age Group

Immune Response in Atopic Dermatitis

Markedly elevated serum IgE levels

Peripheral blood eosinophilia

Highly complex inflammatory responses > IgE-dependent immediate hypersensitivity

Multifunctional role of IgE (beyond mediation of specific mast cell or basophil degranulation)

Cell types that express IgE on surface–monocyte/macrophages–Langerhans’ cells–mast cells–basophils

Atopic Dermatitis:

Tests to Identify Specific Triggers

Skin prick testing for specific environmental and/or food allergens

RAST, ELISA, etc, to identify serum IgE directed to specific allergens in patients with extensive cutaneous involvement

Tzanck smear for herpes simplex

KOH preparation for dermatophytosis

Gram’s stain for bacterial infections

Culture for antibiotic sensitivity for staphylococcal infection; supplement with bacterial cultures

Cultures to support tests bacterial, viral, or fungal

Topical Corticosteroids

Ranked from high to low potency in 7 classes–Group 1 (most potent): betamethasone dipropionate 0.05%–Group 4 (intermediate potency): hydrocortisone valerate 0.2%–Group 7 (least potent): hydrocortisone hydrochloride 1%

Local side effects: Development of striae and atrophy of the skin, perioral dermatitis, rosacea

Systemic effects: Depend on potency, site of application, occlusiveness, percentage of body covered, length of use

May cause adrenal suppression in infants and small children if used long term

Antihistamines and Other Treatments

Standard TreatmentOral antihistamines to relieve itchingMoisturizer to minimize dry skin Topical corticosteroids

Hard-to-manage DiseaseAntibioticsCoal tar preparations (antipruritic and anti-inflammatory)Wet dressings and occlusionSystemic corticosteroidsUV light therapyHospitalization