Part 1: Acute Urticaria/Angioedema

The following Annotations are de-tailed explanations of the Algorithm.

* ANNOTATION 1: Patientpresents with possible acuteurticaria and/or angioedemaUrticaria and/or angioedema are gen-erally referred to as acute if they are ofless than 6 weeks duration (see Algo-rithm for acute urticaria).1 Acute urti-caria occurs more commonly in chil-dren and young adults, whereaschronic urticaria is more common in“middle-aged” women.2–5 It is usefulto characterize urticaria as acute in apatient who is experiencing urticaria

for the first time or who has had recur-ring acute urticarial events, versus thepatient who has a history of urticariafor several weeks on a continuous ba-sis. In the former group of patients, theetiology may be readily apparent toboth the patient and the physician. Forexample, the etiology may be obviousin a patient who presents with acuteurticaria after drug administration, aninsect sting, or repetitively followingexposures to cold. If the cause of anacute episode of hives is obvious toboth patient and physician, a detailedhistory and physical are not required.(Proceed to Annotation 3) In con-

trast, the longer the urticaria has beencontinuously present, the more diffi-cult the etiology is to determine.6As many as 15% to 24% of the US

population will experience acute urti-caria and/or angioedema at some timein their lives.7,8 Urticaria should beconsidered when the patient presentswith pruritic (and sometimes painful orburning), erythematous, circumscribed(or coalescent) wheals. Urticarial le-sions commonly involve the extremi-ties and trunk but may appear on anypart of the body. Angioedema mani-fests itself as deeper subcutaneousswelling. Less circumscribed than thelesions of urticaria, angioedema has apredilection for areas of loose connec-tive tissue such as the face, eyelids ormucous membrane involving the lips,and tongue. If tissue distention in-volves sensory nerves, angioedema le-sions may be painful or paresthetic.2,9Location and/or duration of the lesionsmay provide clues to the etiology ofthe process. Thus, lesions due to coldexposure, exercise or dermatogra-phism typically last less than 2 hoursand lesions of urticarial vasculitis ap-pear predominantly on lower extremi-ties and persist without change in mor-phology for longer than 24 to 48hours.10Clinical presentations of urticaria/

angioedema may encompass der-matographism [ie, exaggerated tripleresponse of Lewis (local reddening,edema and surrounding flare)], papularurticaria, localized urticaria, cutaneousand mucosal manifestations of anaphy-laxis/anaphylactoid reactions or an un-derlying disease. Angioedema may oc-cur with or without urticaria. In thelatter circumstance, hereditary or ac-quired C1 esterase inhibitor deficiencyshould be suspected.Acute urticaria and/or angioedema

may begin suddenly, with physicalmanifestations appearing over a periodof minutes to hours, or may evolveinsidiously over a longer period of

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time. The evanescent, transient timecourse of acute urticaria and/or angio-edema lesions is characteristic of theprocess.2,11If angioedema involves the upper

respiratory tract, life-threatening ob-struction of the laryngeal airway mayoccur. Hereditary or acquired angio-edema associated with C1 esterase de-ficiency are particularly prone to thispresentation, although other forms ofangioedema can present with glosso-pharyngeal edema causing hoarsenessand difficulty in swallowing.2,12 Pre-sentations such as this, however, ac-centuate the importance of evaluatingthe patient who presents with acuteurticaria and/or angioedema for theneed of emergency treatment, as urti-caria and/or angioedema may be earlysigns in the evolution of anaphylaxis.A detailed history and physical exam-ination may need to be deferred untilemergency treatment has been admin-istered.

* ANNOTATION 2: DetailedHistory and Physical ExaminationTo maximize the possibility of discov-ering the specific etiology of acute ur-ticaria and/or angioedema, a detailedhistory of the circumstances precedingand surrounding the onset of the con-dition is necessary. This should in-clude, but not necessarily be limited to,the following information: (1) currentor previous medications, herbals, orsupplements (including excipients)which the patient has used and the timethey were started in relationship to theappearance of the lesions; (2) relation-ship to food exposures (ingestion, in-halation, contact) and the onset of ur-ticaria and/or angioedema;13 (3)relationship of potential physical trig-gers, eg, cold, exercise, heat, sweating,pressure, sun (or light) exposure; (4)exposure to infectious processes, suchas a respiratory virus, viral hepatitis, orinfectious mononucleosis; (5) occupa-tional exposure to allergens or irritants;(6) any recent insect sting or bite; (7)contact exposure due to high or lowmolecular weight allergens; (8) aller-gen exposure by inhalation; and (9) acomplete review of systems to include

systemic diseases, such as autoim-mune, connective tissue and lympho-proliferative disorders.2,14,15–25A thorough physical examination

should, at a minimum, include exami-nation of the skin, lymph nodes, eyes,joints, throat, neck, ears, lungs, heart,and abdomen in an effort to detect anassociated underlying condition (eg,connective tissue disorders, thyroid dis-ease, lymphoreticular neoplasms).9,26 (SeeCommentary 1).

* ANNOTATION 3: Is evaluationsuggestive of an underlying cause?Specific findings on physical examina-tion or clues developed from the clin-ical history may direct the evaluationtowards an identifiable trigger for theurticaria and/or angioedema. Pertinentinfectious exposures, food ingestedwithin several hours prior to the ap-pearance of symptoms several hoursafter ingestion, medication use preced-ing the appearance of lesions, or occu-pational exposures may allow the di-agnostic focus to be narrowed to a fewsuspect triggers. These clues are im-portant given the plethora of potentialurticarial triggers and the inherent dif-ficulty in identifying triggers responsi-ble for sporadic urticarial reactions.13(see Commentary 1)On examination, the presence of:

thyroid enlargement (suggesting an au-toimmune process and/or hormonaldysregulation); lymphadenopathy orvisceromegaly (suggesting an underly-ing lymphoreticular neoplasm); orjoint, renal, central nervous system,skin or serous surface abnormalities(suggesting a connective tissue disor-der) will similarly focus the evalua-tion.27 The presence of dermatogra-phism (urtication on stroking of theskin) suggests the presence of a phys-ical urticarial process.28,29 Similarly,examination procedures directed toother suspected physical urticarias,(eg, cold, heat or solar urticaria/angio-edema) can be employed for diagno-sis.30–34 Cold, heat, and light tests areavailable for these respective physicalurticarias.30–34 Localized hives oredema at pressure sites also point to aphysical trigger for the urticarial pro-

cess.13 Pinpoint hives after exercise orheat exposure suggest a possible cho-linergic process.35 Concomitant mani-festations of a more general process (eg,respiratory distress, hypotension, airwayobstruction, gastrointestinal distress) ac-companying urticaria should immedi-ately redirect attention away from hivesas the primary factor to an underlyinganaphylactic process which necessitatesrapid intervention.Patients with acute urticaria and/or

angioedema may represent a complex,multifactorial, evolving process. Eval-uation, diagnosis, and management(both short-term and, if lesions persistbeyond 6 weeks, long-term) may bechallenging. For these reasons, patientspresenting with acute urticaria and/orangioedema, for which the incitingtriggers are not clear and easilyavoided or initial therapy is not opti-mally effective, might be consideredfor referral to an appropriate specialist.

* ANNOTATION 4: SpecificevaluationThe specific evaluation of a patientpresenting with acute urticaria and/orangioedema should focus on the find-ings suggested by the clinical historyand physical examination. Patientswith a specific food, drug or insecthypersensitivity should be evaluatedwith appropriate diagnostic tests. Forinstance, a patient presenting withacute urticaria in temporal relationshipto a specific food, insect sting/bite ordrug may warrant in vivo or in vitroassessment of specific IgE (if avail-able) to that particular allergen in acontrolled setting where the expertiseand equipment needed to treat an ana-phylactic reaction are available. Ifacute mononucleosis is suspected, ap-propriate tests for Epstein-Barr virus(eg, Monospot™) could be confirma-tory. The association of other infec-tions with acute urticaria has not beensufficiently documented to recommendspecific diagnostic tests.36,37 A patientpresenting with recurrent episodes ofacute angioedema of the face, tongueor lips, in association with bouts ofsevere abdominal discomfort withoutassociated urticaria should be evalu-

526 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

ated with specific complement studiesto exclude hereditary or acquired C1esterase inhibitor deficiency. Acute ur-ticaria in association with the adminis-tration of penicillin or a related beta-lactam antibiotic may warrant diagnosticevaluation with penicillin skin testing.Allergen skin testing and/or in vitro testsfor detection of specific IgE antibody toinhalants (eg, animal danders, pollens,molds, etc) may be useful when the his-tory reveals that urticaria/angioedemaoccurs after direct contact with a sus-pected allergen such as direct contactwith animals, weeds, and grass. Physicalfindings of weight loss, lymphadenopa-thy, and visceromegaly would warrant afurther medical evaluation to exclude anunderlying lymphoreticular malignancy.

* ANNOTATION 5: LimitedEvaluation/TreatmentIn the absence of historic or physicalexamination findings leading to a sug-gested underlying cause, a limited lab-oratory diagnostic evaluation (includ-ing a complete blood count withdifferential, urinalysis, erythrocytesedimentation rate, and liver functiontests) may be considered, primarily toidentify occult underlying conditionsat a stage prior to a more overt clinicalpresentation.26 Concomitantly, or fol-lowing such evaluation, interventionalmeasures may be implemented. Aspreviously stated, the immediate ther-apy of acute urticaria and/or angio-edema as part of evolving anaphylaxismay necessarily take temporary prece-dence over diagnostic evaluation. Al-though there may be increased risks inelderly patients and patients with pre-existing cardiovascular diseases, thereare no contraindications to the use ofepinephrine in acute life threateningsituations. Removal of factors that mayaugment or induce urticaria/angio-edema, (eg, NSAIDs or alcohol inges-tion) may result in improvement andwould thus seem appropriate in bothacute and chronic presentations of ur-ticaria/angioedema.38Since histamine is one of the pri-

mary mediators of urticaria, antihista-mine therapy comprises the corner-stone of therapy for acute presentations

of this condition.5 Continuous treat-ment with antihistamines over a periodof weeks may suppress the urticarialprocess until a sustained remission oc-curs. With the advent of second-gener-ation, low-sedating or non-sedatingH1-antihistamines, the impact of treat-ment on mental alertness and quality oflife can be minimized, primarilythrough the avoidance of the daytimesedation associated with the use offirst-generation H1-antihistamines.39–43Use of second-generation H1-antihista-mines, (eg, loratadine, fexofenadine, orcetirizine) may be quite effective incontrolling the urticarial process with-out side effects although cetirizine maybe mildly sedating in some patients.(see Commentary 2).When necessaryto achieve optimal hive and prurituscontrol, as-needed doses of first-gener-ation H1-antihistamines, (eg, hy-droxyzine or diphenhydramine) maybe added to or given in place of theseagents.44 Caution is warranted in care-fully building up the dose of older,sedating antihistamines, especially inthe treatment of patients involved inoccupations that require the operationof machinery or vehicles, or whereconstant mental alertness cannot becompromised.45–49 To facilitate neces-sary medication regimen adjustments,an open line of communication be-tween patient and physician is essentialduring this initial phase of therapy. Ifoptimal doses of H1-antihistamines donot provide adequate hive control, H2-antihistamines, (eg, ranitidine or cime-tidine) may be added to the regime.50Tricyclic antidepressants such as dox-epin, possessing more potent H1 andH2-antihistamine properties than somefirst-generation classical antihistamines,may have a role in therapy, although sideeffects such as dry mouth may limit theirtolerability.51The routine use of glucocorticoste-

roids in the treatment of patients withacute urticaria and/or angioedema israrely necessary.9 When considered es-sential for acute management, shortcourses of oral glucocorticosteroidsrather than depot parenteral prepara-tions are preferred, to lessen the dura-tion of systemic effects.52

There are preliminary reports aboutthe potential usefulness of leukotrienemodifiers in the treatment of chronicurticaria.53,54 Until such potential leu-kotriene-modifying approaches areevaluated in groups of acute urticariapatients, their clinical use remains em-pirical (although potentially justifiablefor patients refractory to conventionaltherapies or in patients for whomavoidance of glucocorticosteroid ther-apy is desired).

* ANNOTATION 6: Is additionalevaluation suggestive of underlyingetiology?In the proper clinical context, the find-ing(s) of specific, confirmatory labora-tory data, [eg, a positive in vitro assayfor a food allergen; a low C4 level;abnormal functional/quantitative as-says of C1-esterase inhibitor protein; apositive skin test for penicillin; or anabnormal hemogram confirmed byspecific hematologic investigations(bone marrow examination, abdominalCT, etc,) supporting the presence of anunderlying lymphoreticular malignan-cy] may verify the initial diagnosticsuspicions of particular specific etiol-ogies for the urticarial process. If acause has not been determined at thispoint, the associated chronicity andcomplexity of the underlying processand its clinical management may war-rant referral to an appropriate specialist.

* ANNOTATION 7: Managespecific conditionWhen a specific etiology of the urti-caria and/or angioedema has beenidentified, avoidance/elimination ofthe inciting trigger(s) assumes the cen-tral role (eg, avoidance of specific foodallergens, drugs, or trauma that inducesangioedema in a patient with heredi-tary or acquired C1 esterase inhibitordeficiency). Although the etiology ofacute urticaria and/or angioedema maybe easier to discover than that ofchronic urticaria and/or angioedema,the cause or causes may still eludeidentification. The patient should becounseled regarding this issue, empha-sizing the benign prognosis of the con-dition, provided that history, physical ex-

VOLUME 85, DECEMBER, 2000 527

amination, or laboratory features do notsuggest a more serious underlying pro-cess.

* ANNOTATION 8: Follow up, ifsymptoms persistThe persistence of urticaria and/or an-gioedema beyond 6 weeks, despite ap-propriate acute evaluation and inter-vention necessitates a reorientationtowards a chronic process, and maythus warrant further evaluation dis-cussed in the accompanying algorithmon evaluation of chronic urticariaand/or angioedema (Part II). At thispoint, referral to an allergist/immunol-ogist is appropriate, especially if theetiology has not been conclusively de-termined.

The following Commentaries (1and 2) provide further details andreferences.

COMMENTARY 1: History andPhysical ExaminationThe differential diagnosis of acute ur-ticaria and/or angioedema must be keptat the forefront during the initial eval-uation of the patient, as urticaria and/orangioedema, or lesions resemblingthese processes, may be the initialsigns of systemic disease. Evaluationof the urticarial process should becharacterized and correlated with asso-ciated historical elements.The following underlying processes,

many of which have prominent derma-tologic findings, should be differenti-ated from urticaria.26Erythema multiforme minor often

involves lesions morphologically re-sembling urticaria, and is triggered bysimilar underlying disorders, eg, infec-tions, drugs, or neoplasms. A more ex-aggerated prodromal phase, accompa-nied by fever, malaise, pharyngalgia,burning or stinging of the lesions andmucosal lesions may develop in thosepatients who progress to erythema mul-tiforme or the Stevens-Johnson syn-drome, potentially fatal processes.Bullous pemphigoid and dermatitis

herpetiformis are both autoimmunebullous/vesiculobullous processes. Earlylesions in both diseases are often very

pruritic and clearly have identifiable ur-ticarial components, often resembling le-sions of papular or cholinergic urticaria.The symmetry of the lesions of derma-titis herpetiformis, and the progressionof the lesions of bullous pemphigoid totypical bullae, usually allow differentia-tion of these disorders.Urticaria is often a component of

serum sickness which is an IgM/IgGimmune complex-mediated hypersen-sitivity response to drug exposure, in-sect stings, or heterologous serum ad-ministration. Immune complexes inslight antigen excess stimulate anaphy-latoxin-mediated histamine release.Arthralgias, fever, and lymphadenopa-thy are prominent. The time course isslower in onset (days to weeks) than anacute, IgE-mediated anaphylactic re-sponse to these same potent triggers.Additionally, the other target organmanifestations of an acute anaphylac-tic reaction (eg, bronchospasm and hy-potension) are not typically present.Urticarial vasculitis may be re-

stricted to the skin or be part of asystemic immune complex and/or au-toimmune disorder. The specific clini-cal characteristics are individual le-sions lasting longer than 24 hours,purpura, bruising, petechiae, livedo re-ticularis, predilection for the lower ex-tremities (versus trunk or arms), pig-mentation of lesions in various stagesof healing, ulceration of lesions, pre-dominance of burning and pain (versuspruritus), and systemic or constitu-tional symptoms such as fever, arthral-gia/arthritis, gastrointestinal symp-toms, myalgias, malaise, or weightloss. These features allow separationof this entity from a more benign urti-carial process.Mast cell releasability syndromes

include (1) cutaneous mastocytosis [ie,urticaria pigmentosa, solitary mastocy-toma, diffuse cutaneous mastocytosis(without urticaria pigmentosa), and tel-angiectasia macularis eruptiva per-stans]; (2) systemic mastocytosis withor without skin involvement; (3) mas-tocytosis in association with hemato-logic disorders (eg, leukemia); (4)lymphadenopathic mastocytosis witheosinophilia; and (5) mast cell leuke-

mia.55 Flushing, hives, itching, bruis-ing, and tingling are common cutane-ous symptoms. Systemic symptomsare diverse depending on the amountand degree of visceral mast cell in-volvement. Darier’s sign may be help-ful in patients with cutaneous masto-cytosis.The morphology of the urticarial le-

sions may give clues to the underlyingtrigger(s). For example, cholinergic ur-ticaria occurs after a rise of body coretemperature (eg, after exercise, heatexposure, or fever). The lesions typi-cally begin as small, generally 1 to3-mm wheals, with large surroundingerythema (“flare”). In contrast, urti-caria presenting in association with ex-ercise-induced anaphylaxis character-istically has larger initial wheals. Thedelayed, point-of-exposure swellingand/or urticaria associated with pres-sure urticaria presents yet another vari-ation in the appearance of the urticarialprocess.Assessment of the prevalence of

findings in a series of adult patientswith urticaria and/or angioedemashowed that urticaria and angioedemawere present in tandem in approxi-mately 50% of cases. In 40% of cases,urticaria was present without accompa-nying angioedema. In the remaining10%, angioedema was exclusivelypresent.6 It is in this latter group thatconcern should be given to the possi-bility of either an underlying comple-ment disorder such as a C1 inhibitordeficiency, or a non-immunologicallymediated adverse drug reaction such asthat seen with angiotensin-convertingenzyme inhibitor (ACE) therapy. Theconcomitant presence of both urticariaand angioedema virtually eliminatesthe possibility of hereditary or ac-quired C1 esterase inhibitor defi-ciency. Isolated angioedema in the up-per extremities should give rise to theconsideration of an obstructive phe-nomenon such as the superior venacava syndrome. The systemic capillaryleak syndrome, which presents withbrawny edema and shock, is an addi-tional differential diagnostic consider-ation.56,57

528 ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

A detailed history of infectious ex-posures, medication use (both pre-scription, over-the-counter, herbal, andother unconventional types), use of vi-tamins and dietary supplements, andfood ingestion temporally related tothe appearance of lesions is impor-tant.58 Acute infections in children maybe associated with acute urticaria.36,37,59Epstein-Barr virus (EBV), hepatitis (A,B, and C),60–63 and gastrointestinal par-asites have been implicated anecdot-ally in the causality of urticarial reac-tions. Food proteins incriminated inthe precipitation of acute allergic urti-caria include peanuts, nuts, fish, shell-fish, wheat, eggs, milk, soybeans, andfruits. Food additives such as benzo-ates, sulfites, monosodium glutamate,butylated hydroxyanisol, butylated hy-droxytoluene, FD&C approved dyesand others have been implicated insome cases of urticaria.64–66 Non-im-munologic high content of or release ofhistamine causing hives and flushingmay occur after ingestion of strawber-ries, cheese, spinach, eggplant, lobster,and tomatoes.67 Bacterial conversionof histidine to high levels of histaminemay occur in contaminated scombroidfish (eg, tuna, mackerel). Among themost common medication triggers ofurticaria are penicillin, other beta-lac-tam antibiotics, opiates, radiocontrastmedia, aspirin, insulin, and many othernon-beta lactam drugs and biologics.[See Disease Management of DrugHypersensitivity: A Practice Param-eter (Ann Allergy Asthma Immunol1999;83:S665–S700)].A social and travel history should be

obtained to highlight possible infec-tious exposures encountered duringtravel, or acute allergen exposures inthe patient’s home or workplace. Oc-cupational history may discover con-tact allergen exposure (eg, chromatesin the cement industry, latex, otherrubber products, and cosmetics) ame-nable to identification by patch testingwith the appropriate allergen(s).68–70Exposure to plants and commonaeroallergens may suggest a source ofsymptoms secondary to contact expo-sure.71–75

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COMMENTARY 2: RepresentativeAgents and Doses for theTreatment of Acute UrticariaCetirizine (Zyrtec):5 to 20 mg, once daily oroccasionally in divideddoses especially ifsomnolence is not aproblem†

Loratadine (Claritin):5 to 10 mg once daily in AMFexofenadine (Allegra):180 mg given once daily or60 mg twice daily

Hydroxyzine HCI: (Atarax orVistaril):10 to 100 mg daily often atbedtime or in divideddoses, titrated to effect orsomnolence.

Diphenhydramine (Benadryl):12.5 to 100 mg per dose q4to 6 hour PRN

Doxepin: (Sinequan)Adults: 25 to 100 mg/dayAdolescents: 25 to 50 mg/day initially up to amaximum of 100 mg/dayChildren: 1 to 3 mg/kg/day

†Julian L. et al. Cetirizine in the treatment ofchronic urticaria Clin Ther 1991;13:81–85.

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