Introduction:Urticaria and AngioedemaUrticaria Angioedema
Etiology of Urticarial Reactions:Allergic TriggersAcute UrticariaDrugsFoodsFood additivesViral infections–hepatitis A, B, C–Epstein-Barr virusInsect bites and stingsContactants and inhalants(includes animal dander and latex)Chronic UrticariaPhysical factors–cold–heat–dermatographic–pressure–solarIdiopathic
Chronic Urticaria & AngioedemaDefinition: Hives occurring greater than 6 weeksHives and angioedema (40%)Hives alone (40%)Angioedema alone (20%)Etiology:Difficult to determine, cause rarely foundCommon in 3rdand 4thdecade of lifeUsually not foods, drugs, pollens, infections, “dyes”Bad News: May last years….
HEURISTIC SUBDIVISIONSca1. Acute urticaria - less than 6 weeks; history implicatescause in approx. 50%; difficult to study in clinical trials; goodprognosis.2. Chronic urticaria - greater than 6 weeks; workupindicated; easier to study; often persistent.3. Chronic idiopathic urticaria - subset of chronic urticaria inwhich workup fails to pinpoint cause; diagnosis by exclusion; nothomogeneous.
• Immune-mediated urticaria• The type I allergic immunoglobulin (Ig) E response isinitiated by antigen-mediated IgE immune complexes thatbind and cross-link Fc receptors on the surface of mast cellsand basophils, thus causing degranulation with histaminerelease.• The type II allergic response is mediated by cytotoxic T cells,causing deposits of immunoglobulins, complement, andfibrin around blood vessels. This leads to urticarialvasculitis.• The type III immune-complex disease is associated withsystemic lupus erythematosus and other autoimmunediseases that cause urticaria.[
• Non--immune-mediated urticaria• Complement-mediated urticaria includes viral and bacterialinfections, serum sickness, and transfusion reactions.Urticarial transfusion reactions occur when allergenicsubstances in the plasma of the donated blood product reactwith preexisting IgE antibodies in the recipient. Certaindrugs (opioids, vecuronium, succinylcholine, vancomycin,and others) as well as radiocontrast agents cause urticariadue to mast cell degranulation through a non-IgE-mediatedmechanism
Physical UrticariasReproducible by environmental factorsPhysical stimuliMost frequently in young adultsEpisodic and often limited to areas of inciting stimulusUsually, unresponsive to corticosteroidsOverall, treatment with non-sedating antihistamines
Examples of Physical UrticariasAnswer: Dermatographism1. If you stroke the skin, and a hive occurs?2. If you place an ice cube on the forearm, and afterremoval of ice cube, hive occurs?Answer: Cold-induced urticaria3. If hives occur when the patient sweats orexposure to heat?Answer: Cholinergic urticaria or localized heaturticaria
Urticarial Vasculitis (Rare)Inflammatory injury of capillaries and postcapillaryvenules in the skin.Etiology: Manifestation of systemic diseaseClinically:Hives persisting > 24 hours± pruriticPainful, stinging, burning sensation“Leaves a trace”–Faint residual hyperpigmentation, indicating red bloodcell extravasation
The Pathogenesis of Chronic Urticaria:Cellular Mediators
Role of Mast Cells in Chronic Urticaria:Lower Threshold for Histamine ReleaseRelease threshold decreased by:Cytokines & chemokinesin the cutaneousmicroenvironmentAntigen exposureHistamine-releasing factorAutoantibodyPsychological factorsRelease threshold increased by:CorticosteroidsAntihistaminesCromolyn (in vitro)Cutaneous mast cell
An Autoimmune Basis for ChronicIdiopathic Urticaria: Antibodies to IgE
Angioedema (Swelling)Edema of the deep layers of the dermis and subcutaneoustissue.Non-pitting edemaSkin is not hotNon-dependent areasIt is not: “pre-tibial pitting edema”
• The swelling of the affected area of angioedema is a result ofthe fast onset of increase of local vascular permeability insubmucosal and subcutaneous tissue. IgE-mediated mastcell activation and degranulation, key elements of an allergicreaction, often manifest as urticaria and angioedema. Non–IgE-mediated mast cell activation/mediator release mayexplain certain autoimmune-mediated and idiopathicangioedema
• Patients usually describe swelling of the face (eg, eyelids,lips), tongue, hands, and feet. It can be acute or chronic, andeach episode of angioedema may last a few hours to a fewdays. A local burning sensation and pain can be observedwithout pronounced itchiness or local erythema.
• Abdominal pain can sometimes be the only presentingsymptom of angioedema. Throat tightness, voice changes,and trouble breathing may indicate airway involvement.• For acute and new-onset angioedema, special attentionshould be directed to the potential relationship with food ordrug intake, insect stings, or other unusual exposures. Forchronic and recurrent cases, ask the patient about potentialtriggers, medication use and associated medical history,family history, and past evaluation.
Allergic angioedema• Allergic angioedema is often associated with urticaria. It istypically observed within 30 minutes to 2 hours afterexposure 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 allergicangioedema. Typical examples are angioedema induced bynonsteroidal anti-inflammatory drugs (NSAIDs) andintravenous contrast material; aspirin (ASA) is the mostcommon culprit.
Nonallergic angioedema• Nonallergic angioedema does not involve IgE or histamine;urticaria is generally not associated with this type ofangioedema.• Hereditary angioedema (HAE) is perhaps the prototype ofthis type of angioedema. Decreased functional C1-INHproduction leading to unchecked bradykinin production arebelieved to be the fundamental changes in HAE types I andII.Acquired angioedema (AAE) also has decreased C1-INHfunction due to autoantibody production or acceleratedconsumption of C1-INH.
Idiopathic angioedema• The causes of idiopathic angioedema are, by definition, notidentifiable. Furthermore, the exact mechanisms are unclear.[11, 12]Some may be associated with urticaria. Based onresponses to medication, some cases are thought to bemediated by mast cell activation, albeit IgE-independent.• Physical urticaria/angioedema: Common triggers includeheat, cold, emotional stress, and exercise. Nonspecific mastcell 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 idiopathicangioedema are treated with same measures.• Most cases can be managed well with outpatient treatmentalone. Antihistamines as described in the urticaria article areoften used as the first-line treatment for angioedema
• For moderate to severe cases, close monitoring is oftennecessary. Diphenhydramine (50) mg IM/IV is helpful.Hydrocortisone (200 mg) or Solu-Medrol (40-60 mg) IV mayreduce the possibility of relapse.• For laryngeal swelling and airway obstruction, closemonitoring of the airway is mandatory. Epinephrine (1:1,000)should be administrated IM at 0.01 mg/kg or 0.3 mg repeatedevery 10-15 min, if necessary. Occasionally, intubation oreven tracheostomy may be necessary. These patientsshould 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-mediatedangioedema.• Epinephrine does not work as well as in histamine-mediatedangioedema. Its value for treating acute HAE attacks islimited.• Severe abdominal pain may sometimes be the onlypresenting symptom for these patients when seekingemergency medical care.• Supportive care includes pain control and relief of nausea.
• Fresh frozen plasma (2 units) has been shown to be helpfulin certain patients. However, fresh frozen plasma worseningan acute attack of laryngoedema has also been reported. Ifthis treatment is used, be ready to intubate or perform atracheostomy, if necessary.• Antifibrinolytics (eg, Amicar or Traxeminic acid) may behelpful.
Initial Workup of UrticariaPatient historySinusitisArthritisThyroid diseaseCutaneous fungal infectionsUrinary tract symptomsUpper respiratory tract infection(particularly important in children)Travel history (parasitic infection)Sore throatEpstein-Barr virus, infectiousmononucleosisInsect stingsFoodsRecent transfusions withblood products (hepatitis)Recent initiation of drugsPhysical examSkinEyesEarsThroatLymph nodesFeetLungsJointsAbdomen
Laboratory Assessment forChronic UrticariaPossible tests for selected patientsStool examination for ovaand parasitesBlood chemistry profileAntinuclear antibody titer (ANA)Hepatitis B and CSkin tests for IgE-mediatedreactionsInitial testsCBC with differentialErythrocyte sedimentation rateUrinalysisRAST for specific IgEComplement studies: CH50CryoproteinsThyroid microsomal antibodyAntithyroglobulinThyroid stimulating hormone (TSH)
Urticaria Associated WithOther ConditionsCollagen vascular disease (eg, systemic lupus erythematosus)Complement deficiency, viral infections (including hepatitis Band C), serum sickness, and allergic drug eruptionsChronic tinea pedisPruritic urticarial papules and plaques of pregnancy (PUPPP)Schnitzler’s syndrome
H1-Receptor Antagonists:Pros and Cons for Urticaria and AngioedemaFirst-generation antihistamines (diphenhydramineand hydroxyzine)Advantages: Rapid onset of action, relatively inexpensiveDisadvantages: Sedating, anticholinergicSecond-generation antihistamines (astemizole,cetirizine, fexofenadine, loratadine)Advantages: No sedation (except cetirizine); no adverseanticholinergic effects; bid and qd dosingDisadvantages: Prolongation of QT interval; ventriculartachycardia (astemizole only) in a patient subgroup
An Approach to the Treatment ofChronic Urticaria
Treatment of Urticaria:Pharmacologic OptionsAntihistamines, othersFirst-generation H1Second-generation H1Antihistamine/decongestantcombinationsTricyclic antidepressants(eg, doxepin)Combined H1 and H2 agentsBeta-adrenergic agonistsEpinephrine for acute urticaria(rapid but short-lived response)TerbutalineCorticosteroidsSevere acute urticaria–avoid long-term use–use alternate-day regimenwhen possibleAvoid in chronic urticaria(lowest dose plus antihistaminesmight be necessary)MiscellaneousPUVAHydroxychloroquineThyroxine
Atopic Dermatitis: Acute, Subacute,and Chronic LesionsAcute Cutaneous LesionsErythematous, intensely pruritic papules and vesiclesConfined to areas of predilection–cheeks in infants–antecubital–poplitealSubacute Cutaneous LesionsErythema excoriation, scalingBleeding and oozing lesionsChronic LesionsExcoriations with crustingThickened lichenified lesionsPostinflammatory hyperpigmentationNodular prurigo
Atopic Dermatitis:Physical Distribution by Age Group
Immune Response in Atopic DermatitisMarkedly elevated serum IgE levelsPeripheral blood eosinophiliaHighly complex inflammatory responses > IgE-dependentimmediate hypersensitivityMultifunctional role of IgE (beyond mediation of specificmast cell or basophil degranulation)Cell types that express IgE on surface–monocyte/macrophages–Langerhans’ cells–mast cells–basophils
Atopic Dermatitis:Tests to Identify Specific TriggersSkin prick testing for specific environmentaland/or food allergensRAST, ELISA, etc, to identify serum IgE directed to specificallergens in patients with extensive cutaneous involvementTzanck smear for herpes simplexKOH preparation for dermatophytosisGram’s stain for bacterial infectionsCulture for antibiotic sensitivity for staphylococcal infection;supplement with bacterial culturesCultures to support tests bacterial, viral, or fungal
Topical CorticosteroidsRanked 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, perioraldermatitis, rosaceaSystemic effects:Depend on potency, site of application, occlusiveness,percentage of body covered, length of useMay cause adrenal suppression in infants and small childrenif used long term
Antihistamines and Other TreatmentsStandard TreatmentOral antihistamines to relieve itchingMoisturizer to minimize dry skinTopical corticosteroidsHard-to-manage DiseaseAntibioticsCoal tar preparations (antipruritic and anti-inflammatory)Wet dressings and occlusionSystemic corticosteroidsUV light therapyHospitalization