Acute and Chronic Urticaria

Acute and Chronic Urticaria:Evaluation and TreatmentPAUL SCHAEFER, MD, PhD, University of Toledo College ofMedicine and Life Sciences, Toledo, Ohio

Urticaria commonly presents with intensely pruritic wheals, sometimes with edema ofthe subcutaneous or interstitialtissue. It has a lifetime prevalence of about 20%. Although often self-limited -and benign, it can cause significant dis-comfort, continue for months to years, and uncommonly represent a serious systemic disease or life-threatening aller-gic reaction. Urticaria is caused by immunoglobulin E- and non—immunoglobulin E-mediated release of histamineand other inflammatory mediators from mast cells and basophils. Diagnosis is made clinically; anaphylaxis mustbe ruled out. Chronic urticaria is idiopathic in 80% to 90% of cases. Only a limited nonspecific laboratory workupshould be considered unless elements of the history or physical examination suggest specific underlying conditions.The mainstay of treatment is avoidance of triggers, if identified. The first-line pharmacotherapy is second—generation

H, antihistamines, which can be titrated to greater than standard doses. First—generation H, antihistamines, H, anti-histamines, leukotriene receptor antagonists, high-potency antihistamines, and brief corticosteroid bursts may beused as adjunctive treatment. In refractory chronic urticaria, patients can be referred to subspecialists for additionaltreatments, such as omalizumab or cyclosporine. More than one-half of patients with chronic urticaria will have

resolution or improvement of symptoms within a year. (Am Fam Physician. 2017;95(ll):7l7-724. Copyright © 2017

American Academy of Family Physicians.)

This clinical contentconforms to AAFP criteriafor continuing medical

education (CME). See CME

Quiz on page 697. Authordisclosure: No relevantfinancial affiliations.

V Patient information:A handout on this topic,written by the author ofthis article, is availableat http://www.aafp.org/afp/2017/0601Ip717-S1.html.

Scan the QR code belowfor easy access to thepatient information hand-out on the AFP mobile site.

Iune 1, 2017 ‘ Volume 95, Number 11

rticaria is a common dermato-logic condition that typicallypresents with intensely pru-ritic, well-circumscribed, raised

wheals ranging from several millimeters toseveral centimeters or larger in size. Urticariacan occur with angioedema, which is local-ized nonpitting edema of the subcutaneousor interstitial tissue that may be painful andwarm. The intense pruritus can cause signif-icant impairment in daily functioning anddisrupt sleep.‘ Typically otherwise benignand self-limited, urticaria can be a symptomof life—threatening anaphylaxis or, rarely,indicate significant underlying disease.

Urticaria can appear on any part of theskin. The wheals can be pale to brightly ery-thematous in color, often with surroundingerythema. The lesions are round, polymor-phic, or serpiginous, and can rapidly growand coalesce (Figures 1 through 3). Angio-edema presents primarily in the face, lips,mouth, upper airway, genitalia, and extrem-ities. The onset of symptoms for urticariaor angioedema is rapid, usually occurringover minutes. Individual urticarial lesionstypically resolve in one to 24 hours withouttreatment, although additional wheals can

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erupt in new crops. Angioedema may takedays to resolve?

Urticaria, with or without angioedema,can be classified as acute or chronic. Urti-caria that recurs within a period of less thansix weeks is acute. Recurring chronic urti-caria lasts longer than six weeks. Urticariacan present in persons of any age, with a

lifetime prevalence of approximately 20%.Chronic urticaria has a lifetime prevalenceof approximately 0.5% to 5%.“

EtiologyUrticaria and angioedema have similar under-lying pathophysiologic mechanisms: hista-mine and other mediators released from mastcells and basophils. If the release occurs in thedermis, it results in urticaria, whereas if therelease occurs in the deeper dermis and sub-cutaneous tissues, it results in angioedema.Immunoglobulin E (IgE) often mediates thisrelease, but non—IgE and nonimmunologicmast cell activation also can occur. Prote-ases from aeroallergens and activation of thecomplement system have been proposed as

examples of non-lgE triggers.‘ There may be a

serologic autoimmune component in a subsetof patients with chronic urticaria, including

American Family Physician 717

Urticaria

Figure 1. Sharply demarcated annular urti-carial plaques.

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Figure 2. Coalescing urticarial papules.

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antibodies to IgE and the high—affinity IgEreceptor. However, the clinical significanceof these autoantibodies is unclear.‘-5 Anti—IgE

antibodies can also be found in atopic derma-titis and several autoimmune diseases.

There are a number of identified causes

of urticaria (Table 1).“'7*‘ Common causes

include allergens (Figure 4), food pseudo-allergens (foods that contain histamine or

salicylates, or cause the release of histaminedirectly), insect envenomation, medications,and infections.“-7" Infections are the mostcommon cause of urticaria in children.‘°

Recommendation

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.,REceMMsupAnoNs—moM TH'E>_CHOOSlNG.‘\9IISELY’CA‘,MPAiGN

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Do not routinely do diagnostic testing in

patients with chronic urticaria.

Do not rely on antihistamines as first-linetreatment in severe allergic reactions.

American Academy of Allergy,Asthma, and Immunology

American Academy of Allergy,Asthma, and Immunology

tions/search. htm.

Source: For more information on the Choosing Wisely Campaign, see http://wvi/w.choosingwiseIy.org. For supporting citations and to search Choosing Wisely recom-

mendations relevant to primary care, see http://wwwaafp.org/afp/recommenda

718 American Family Physician www.aafp.org/afp

Figure 3. Serpiginous erythematous urticarialplaques.


The infectious agents commonly associ-ated with urticaria include various viruses(e.g., rhinovirus, rotavirus, Epstein—Barr,hepatitis A, hepatitis B, hepatitis C, herpessimplex, human immunodeficiency virus),bacteria (e.g., urinary tract infections,streptococcus, mycoplasma, Helicobacterpylori), and parasites. Medications, notablybeta—lactam antibiotics, typically cause urti-caria via allergic reactions, although some

medications (e.g., aspirin, nonsteroidalanti—inflammatory drugs [NSAIDS], van-

comycin, opiates) can also trigger urticariathrough direct mast cell degranulation.

In some patients, physical stimuli, includ-ing pressure, cold (Figure 5), heat, and theraising of the core body temperature (cho-linergic urticaria; Figure 6), cause urticariathat tends to be chronic." Systemic disease

is an uncommon cause of urticaria. Illnessesthat have been associated with urticaria or

angioedema include I-Iashimoto thyroiditis,mastocytosis, systemic lupus erythematosus,Sjogren syndrome, rheumatoid arthritis,vasculitis (Figures 7 and 8), celiac disease,

and lymphoma.” Causes of acute urticariaoften can be identified during the patient

Volume 95, Number 11 ° Iune I, 2017

Table 1. Causes of Urticaria

Immunoglobulin E (IgE) mediatedAeroallergens

Contact allergen

Food allergens

Insect venom

Medications

Parasitic infections

Non-lgE immunologically mediatedAeroallergens (proteases)

Autoimmune disease

Bacterial infections ~

Cryoglobulinemia

Fungal infections

Lymphoma

Vasculitis

Viral infections

Nonimmunologically mediated

Contact allergen

Elevation of core body temperature

Food pseudoallergens

Light

Mastocytosis

Medications (direct mast cell degranulation)

Physical stimuli (cold, heat, pressure, vibration)

Water

Information from references 4, 7, and 8.

Figure 4. Allergic contact urticaria showingconfluent urticarial plaques of the hands.


history, although 80% to 90% of chronicurticaria cases are idiopathic.”

EvaluationThe diagnosis of urticaria is usually clini-cal. The first step in evaluating urticaria andangioedema is a history and physical exami-nation to characterize the lesions and helpidentify causes. History elements that shouldbe elicited include onset, timing (e.g., with

lune 1, 2017 ' Volume 95, Number 11

Figure 5. Urticarial plaque caused by expo-sure to cold.


Figure 6. Cholinergic urticaria showing anurticarial papule at the center of a larger ery-thematous flare.Image used with permission from VisuaIDx.

Figure 7. Urticarial vasculitis showing fixed,erythematous, urticarial plaques with blanch-ing halos.

Image used with permission from Visua/Dx.

Figure 8. Urticarial vasculitis showing fixed,urticarial plaques and hemosiderin patches.

Image used with permission from VisualDx.

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Urticaria

American Family Physician 719

Urticaria

the menstrual cycle, if an association is sus-

pected), location, and severity of symptoms;associated symptoms, which may suggest

anaphylaxis; and potential environmentaltriggers. Other important parts of the his-tory include medication and supplement use,

(especially new or recently changed dosages),allergies, recent infections, travel history,family history of urticaria and angioedema,and complete review of systems to identifypossible causes and symptoms of systemic

Table 2. Urticaria—Associated History and PhysicalExamination Findings with Possible Etiologies

Clinical clue Possible etiology

Abdominal pain, dizziness, hypotension, largeerythematous patches, shortness of breath,stridor, tachycardia

Dermatographism, physical stimuli

Food ingestion temporally related to symptoms

High-risk sexual behavior or illicit druguse history

Infectious exposure, symptoms of upperrespiratory tract or urinary tract infections

Joint pain, uveitis, fever, systemic symptoms

Medication use or change

Pregnancy

Premenstrual flare—up

Smaller wheals (1 to 3 mm); burning or itching;brought on by heat, exercise, or stress

Thyromegaly, weight gain, cold intolerance

Travel

Weight loss (unintentional), fevers, night sweats

Wheals lasting longer than 24 hours,nonblanching papules, burning or otherdiscomfort, residual hyperpigmentation,fevers, arthralgias

Anaphylaxis

Physical urticaria

Food allergy

Hepatitis B or C

(cryoglobulinemia) virus,human immunodeficiencyvirus

Infection

Autoimmune disease

Medication allergy or directmast cell degranulation

Pruritic urticarial papulesand plaques of pregnancy

Autoimmune progesteronedermatitis

Cholinergic urticaria

Hypothyroidism

Parasitic or other infection

Lymphoma

Urticarial vasculitis(Figures 7 and 8)

information from references 4, 7, 8, 74, and 15.

720 American Family Physician www.aafp.orglafp

illnesses. Sexual history, illicit drug use his-tory, and transfusion history may provideimportant information about the risk ofinfectious causes, such as viral hepatitis andhuman immunodeficiency virus.

The physical examination should includevital signs, identification and characteriza-tion of current lesions and their completeextent, testing for dermatographism (i.e.,urticaria that appears in the pattern oflocal-ized pressure elicited by stroking with theblunt end ofa pen or tongue blade), and car-

diopulmonary examination to help rule outanaphylaxis and infectious causes. Exami-nation of the eyes, ears, nose, throat, lymphnodes, abdomen, and musculoskeletal sys-

tem may help identify underlying causes.

Table 2 lists clinical clues from the historyand physical examination that suggest cer-

tain etiologies for urticaria.“'7'3"“5It is critical to rule out anaphylaxis, which

has findings or symptoms involving otherorgan systems beyond the skin, such as thepulmonary (wheezing, stridor), cardiovascu-lar (tachycardia, hypotension), gastrointesti-nal (diarrhea, vomiting, abdominal pain), or

nervous system (dizziness).2"'9 Several der-matologic conditions can be confused withurticaria. Elements of the history and physi-cal examination can help distinguish amongthese conditions (Table 3).“'7'“5

Laboratory workup in the absence of indi-cations of an underlying cause is not neces-

sary.“"‘ lfthe history or physical examinationsuggests a specific cause or underlying dis-ease, targeted testing is appropriate.2"‘*°"‘ Forexample, presentation that suggests urticar-ial vasculitis should prompt a skin biopsy,whereas if the history suggests an allergictrigger, allergy testing may be useful afterresolution of symptoms. With chronic urti-caria, or in acute cases if there are patientor parental concerns, a limited nonspecificworkup including a complete blood countwith differential, erythrocyte sedimentationrate and/or C-reactive protein testing, liverenzymes, and thyroid-stimulating hormonemeasurement can be considered to rule outunderlying causes. When the history sug-gests a physical urticaria, challenge test-ing with standardized physical stimuli can

Volume 95, Number 11 ' lune 1, 2017

confirm the diagnosis.""7 Allergy testing is

not recommended unless there is specificindication of an allergic cause.‘

General Principles of TreatmentMethods of treatment for urticaria are thesame for adults and children. The mainstayof treatment is avoidance of identified trig-gers. It is also recommended that patientsavoid using aspirin, alcohol, and NSAIDS, as

well as avoid wearing tight clothing, because

these may worsen symptoms. Iftrigger avoid-ance is impossible, no trigger is identified,or symptom relief is needed despite triggeravoidance, H,—antihistamines are first—line

pharmacotherapy. Second—generation H,antihistamines such as loratadine (Clari-tin), desloratadine (Clarinex), fexofenadine(Allegra), cetirizine (Zyrtec), and levoceti-rizine (Xyzal) are relatively nonsedating at

standard dosages and are dosed once per day.

First-generation H, antihistamines, such

as diphenhydramine (Benadryl), hydroxy-zine, chlorpheniramine, and cyprohepta-dine, are faster acting and, in some cases,

have parenteral forms. However, they requiremore frequent dosing and have more adverse

effects, including sedation, confusion, dizzi-ness, impaired concentration, and decreased

psychomotor performance. Because of anti-cholinergic adverse effects, first—generation

H, antihistamines should be used with cau-

tion in older patients. Individual responsesto a given antihistamine vary, and there is

no strong evidence that a particular antihis-tamine is superior. Potential adverse effectsshould be discussed with patients before ini-tiating therapy.

TREATMENT OF ACUTE URTICARIA ANDANGIOEDEMA

Second—generation H, antihistamines are

first—line medication for the treatment ofacute urticaria. In some cases, they may betitrated to two or even four times the nor-

mal dose to control symptoms.“-9 Withhigher doses, there is greater possibility ofadverse effects.

If symptoms are not sufficiently con-

trolled with second-generation H, antihista-mines, H, antihistamines such as cimetidine

June 1, 2017 ' Volume 95, Number 11

(Tagamet), famotidine (Pepcid), and raniti-dine (Zantac) may be added.” In severe

cases, corticosteroids such as prednisone or

prednisolone (0.5 to 1 mg per kg per day)may be added for three to 10 days to controlsymptoms.“-9""

If systemic symptoms are suggested, espe-

cially when an identified trigger is associatedwith anaphylaxis (e.g., insect envenomation,certain foods), it may be prudent to pre-scribe epinephrine autoinjectors in sufficientnumbers so that the patient will have one

for home, one for work or school, and one

for the car, as appropriate. Patients should

Urticaria

Table 3. Conditions That May Be Confused with Urticaria

Condition Distinguishing characteristics

Arthropod bites

Atopic dermatitis

Bullous pemphigoid

Contact dermatitis

Erythema multiforme

Fixed-drug reactions

Henoch-Schonleinpurpura

Mastocytoma

Mastocytosis, diffusecutaneous

Morbilliform drugreactions

Pityriasis rosea

Urticaria pigmentosa

Viral exanthem

Lesions lasting several days, insect exposure history

Maculopapular, scaling, characteristic distribution

Lesions lasting more than 24 hours, blistering, Nikolskysign (light friction causes erosion or vesicle)

Indistinct margins, papular, persistent lesions,

epidermal component present

Lesions lasting several days, iris-shaped papules, targetappearance, may have fever

Offending drug exposure, not pruritic, often bullous,hyperpigmentation

Lower extremity distribution, purpuric lesions, systemicsymptoms

Yellow to orange pigmentation, Darier sign (a wheeland flare-up reaction produced by stroking the lesion),flushing, bullae, occurs most commonly in children

Normal to ye||ow—brown skin color, diffuse thickening,bullae

Maculopapular, associated with medication use

Lesions lasting weeks, herald patch, Christmas treepattern, often not pruritic

Smaller lesions (1 to 3 mm), orange to brownpigmentation, Darier sign (a wheel and flare-upreaction produced by stroking the lesion)

Not pruritic, prodrome, fever, maculopapular lesions,individual lesions lasting days

Information from references 4, 7, 8, and 15.

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722 American Family Physician

follow up in two to six weeks to evaluatetreatment success and tolerance.

Treatment of acute angioedema is largelythe same as treatment for urticaria, althoughcorticosteroids may be more commonly rec-

ommended.” However, angioedema of thelarynx and massive angioedema ofthe tongueare medical emergencies because of therisk of airway obstruction, and they requireintramuscular epinephrine and airway man-

agement. Patients with angioedema that pre-viously threatened airway compromise shouldbe prescribed epinephrine autoinjectors.

TREATMENT OF CHRONIC URTICARIA

Most of the data on treatment of urticariainvolve chronic cases. Current guidelinessuggest a stepwise approach to treatingchronic idiopathic urticaria” (Figure 9‘). Aswith acute urticaria, the first step is second-generation H, antihistamines."‘*°"°"‘ Forimproved symptom control, the medicationshould be dosed daily, rather than on an

as—needed basis." Although there are some

differences among published guidelines on

the specifics of the subsequent steps,“" theAmerican Academy of Allergy, Asthma, andImmunology and the American College ofAllergy, Asthma, and Immunology recom-

mend that if first-line treatment is insuf-ficient, the second step is implementationof one or more of the following additionalstrategies: the second—generation H, anti-histamine can be titrated up to two to fourtimes the usual dose 2’; a different second-generation H, antihistamine can be added;first-generation H, antihistamines may be

added at nighttime; H, antihistamines maybe added”; and leukotriene receptor antago-nists, such as montelukast (Singulair) andzafirlukast (Accolate), can also be added,especially in patients with NSAID intoler-ance or cold urticaria."

Ifsymptomatic control is still not achieved,the third step is addition and titration ofhigh-potency antihistamines as tolerated, such as

hydroxyzine or the tricyclic antidepressantdoxepin (possesses markedly more antihis-taminic effect than diphenhydramine). Thefourth step is referral to a subspecialist foruse of immunomodulatory agents. There are

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a number of such agents, but the data on theeffectiveness in chronic urticaria for most are

weak at best.”*’‘ The two agents with the mostrobust data are omalizumab (Xolair) andcyclosporine (Sandimmune).’-"9 For control-ling flare-ups in chronic urticaria, a three- to10-day burst of corticosteroids (prednisoneor prednisolone up to 1 mg per kg per day)is sometimes used; long-term use is not

Stepwise Treatmentof Chronic Urticaria

Step 1

Start second—generation H, antihistamine

If insufficient control

Step 2

One or more of the following:

Titrate second-generation H, antihistamineto two to four times normal dose

Add a different second-generation H,

antihistamine

Add H, antihistamine

Add first-generation H, antihistamine at night

Add leukotriene receptor antagonist

If insufficient control

V

Step 3

Add high-potency antihistamine hydroxyzineor doxepin and titrate as tolerated

lf insufficient control

7

Step 4

Consider referrals for immunomodulatorytherapy such as omalizumab (Xolair) or

cyclosporine (Sandimmune)

NOTE: If symptoms are severe, a short course (3 to70 days) of systemic corticosteroids (e.g., oral pred-nisone, 0.5 to 1 mg per kg per day) may be addedat steps I, 2, or 3.

Figure 9. Stepwise treatment of chronicurticaria.Adapted with permission from Bernstein IA, Lang DM,Khan DA, et al. The diagnosis and management of acuteand chronic urticaria: 2014 update. 1 Allergy Clin lmmunol.20I4,‘733(5):e1277.e52.

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Urticaria

H, antihistamines, H, antihistamines, andleukotriene receptor antagonists may be addedto control symptoms of chronic urticaria.

EvidenceClinical recommendation rating References Comments

It is important to rule out underlying anaphylaxis C 2,4,9 Evaluate vital signs and symptoms involving otherin patients presenting with urticaria. organ systems such as pulmonary, cardiovascular,

neurologic, or gastrointestinal.

An extensive laboratory workup for urticaria is C 2, 4, 9, 16 Complete blood count with differential, erythrocytenot generally recommended. Additional testing sedimentation rate or C-reactive protein, thyroid-can be performed if the presentation suggests stimulating hormone, urinalysis, and liver functionunderlying causes requiring confirmation. tests can be considered.

Second-generation H, antihistamines are safe A 2,4, 9, 19,20 Second-generation H, antihistamines are recommendedand effective symptomatic therapy for urticaria. over older antihistamines because of adverse effect

profiles. All H, antihistamines appear to be effective.

If needed to control symptoms of urticaria, C 2, 4, 9 A higher risk of adverse effects is present with highersecond-generation H, antihistamines can be doses. Limited effectiveness data are available.titrated to two to four times the normal dose.

A short course of systemic corticosteroids may C 2, 4, 9 Few clinical data support this recommendation, but ithelp control severe cases of urticaria. is widely practiced.

Other medications such as first-generation B 2, 4, 9 Several studies have produced varying results, butthese are generally safe medications with some

evidence of benefit.

A = consistent, good—quality patient—or/ented evidence,’ B = inconsistent or limited—qua/ity patient-oriented evidence; C = consensus, disease—oriented

evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aat’p.org/afpsort.

recommended because of adverse effects.Potent topical corticosteroids may have a ben-efit in localized delayed-pressure urticaria."

Once symptoms are adequately controlled,physicians should consider stepping downtreatment sequentially. Empiric eliminationdiets are not recommended. Ifan underlyingcause of chronic urticaria is identified, thecondition should be treated or the patientreferred to an appropriate subspecialist.

PrognosisAcute urticaria is typically self—limited andresolves with proper avoidance of triggers.With chronic urticaria, a prospective cohortstudy found that 35% of patients are symp-tom free within one year, with another 29%having some reduction ofsymptoms. Sponta-neous remission occurred within three years

in 48% of the cases of idiopathic chronicurticaria, but only 16% of the cases of physi-cal urticaria.” Another prospective studyin children found remission rates at one,three, and five years to be 18%, 54%, and68%, respectively.” Patients may experiencerepeated episodes throughout their lives.

lune I, 2017 ’ Volume 95, Number 11

This article updates previous articles on this topic by

Schaefer‘ and Muller.”

Data Sources: A search was conducted in PubMedClinical Queries using urticaria with each category and

systematic review. Also searched were the Agency forHealthcare Research and Quality Evidence Reports,

Cochrane Database of Systematic Reviews (completereviews), Dynamed, Essential Evidence Plus, Institute forClinical Systems Improvement, National Guideline Clear-

inghouse, and UpToDate. Search dates: February to May2016, and January 2017.

The AuthorPAUL SCHAEFER, MD, PhD, is vice chair and associate pro-fessor in the Department of Family Medicine and assistantdean for student affairs at the University of Toledo (Ohio)College of Medicine and Life Sciences.

Address correspondence to Paul Schaefer, MD, PhD, Uni-versity of Toledo Health Sciences Campus, MS 1179, 2240Dowling Hall, 3000 Arlington Ave., Toledo, OH 43614(e—mail: [email protected]). Reprints are notavailable from the author.

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Volume 95, Number 11 ° lune 1, 2017

Documents

Acute and Chronic Urticaria