Annular lesions with dark centers

This The Clinical Advisor CME activity consists of 3 articles. To obtain credit, read Progressive, diffuse scalp hair loss in a woman and Fleshy papule on the left cheek of a young boy. Then take the post-test here.Case #1Urticaria is...

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This The Clinical Advisor CME activity consists of 3 articles. To obtain credit, read Progressive, diffuse scalp hair loss in a woman and Fleshy papule on the left cheek of a young boy. Then take the post-test here.

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Case #1

Urticaria is a hypersensitivity reaction that is usually characterized by transient, pink or skin-colored edematous papules and plaques. The lifetime occurrence of urticaria in the general population is 1% to 5%; however, depending on the range of ages and method of sampling, urticaria may be reported in as much as 25% of the general population.¹Urticaria has been reported in all ethnicities, but one study suggests that urticaria may be more prevalent in China, when compared with European populations.²Urticaria has been reported in all age groups as well.²For most causes of urticaria, females are affected more frequently than males at a ratio of approximately 2 to 1.²

The more common etiologies of urticaria often depend on whether urticaria is acute or chronic and the age of the patient. Acute urticaria is defined as urticaria with a duration of fewer than 6 weeks.³Chronic urticaria is defined as urticaria that recurs frequently for more than 6 weeks.³In children who develop acute urticaria, approximately 80% of cases are secondary to infections, most commonly viral infections.³Allergies to foods and medications are also a common cause of acute urticaria in adolescents, but a significant proportion of cases is still caused by infections.³

In addition to viral etiologies, other more common infectious causes include infections of streptococcus, mycoplasma, histoplasmosis, and coccidioidomycosis.³Well-known food triggers of urticaria include dairy products in younger children and nuts, seafood, berries, and grains in older children.³Medications that have been well-described as causes of urticaria include penicillins, cephalosporins, sulfonamides, tetracyclines, anticonvulsants, monoclonal antibodies, and nonsteroidal anti-inflammatory drugs (NSAIDs).³

Chronic urticaria seems to affect adults more than children.³As in acute urticaria, the possible etiologies of chronic urticaria are many; the list includes, but is not limited to, food, food additives, medications, physical causes, immunizations, insect bites, inhalant or contact allergens, autoimmune disorders, and infections.³Infections implicated in chronic urticaria include dental abscesses, sinus infections, urinary tract infections, and otitis.³

Clinically, urticaria is characterized by pink edematous papules that are often in an annular configuration.³By definition, any individual lesion should last no longer than 24 hours. There is often a halo of erythema around the individual urticarial lesions.³Size can vary greatly and ranges from pinpoint-sized papules to large lesions that are several centimeters in diameter.³These large lesions are often referred to as giant urticaria. While classically, individual lesions of urticaria demonstrate central clearing, urticaria may also have ecchymosis-like centers. These bruise-like centers are seen with relative frequency in children, but no published data exist on the incidence of this finding. Ecchymotic centers also tend to be more commonly seen in giant urticaria. In rare cases, a vesicle or bullae may form in the center of urticaria.³However, the bullae is on a skin-colored or pink background, and there is no other surface change, such as scale or crust. If bullae do form in urticaria, it is more commonly seen on the legs and buttocks.³Individual lesions of urticaria can often coalesce into serpiginous or bizarre configurations.³In infants and young children, extension in the subcutaneous tissue may result in swelling of the distal extremities, which can be associated with acrocyanosis.³

The differential diagnosis for urticaria includes dermatologic conditions with urticarial lesions including reactions to insect bites. Insect bite reactions are typically characterized by discrete erythematous and edematous papules or nodules. Insect bites can cluster but typically do not coalesce. While individual insect bite reactions are not specific to an arthropod, the distribution or location of the lesions can provide clues. For example, mosquito and flea bites are most often located on the distal extremities. Bed bug bites characteristically demonstrate a linear array of 3 lesions, known as the “breakfast, lunch, and dinner” sign. When urticaria presents with ecchymotic centers, it is commonly confused with erythema multiforme. Typically, the bruise-like centers of urticaria is a gray-blue hue, in contrast to the “dusky” centers of erythema multiforme, which are more violaceous in appearance. The classic “target” lesion of erythema multiforme is a round lesion that is less than 3 cm in size and has 3 zones of color, a dusky center surrounded by 2 concentric rings of color change.²Surface change, such as crust or bulla formation, is common in erythema multiforme due to epidermal necrosis; whereas in urticaria, surface change is absent as this is a dermal process that spares the epidermis. Some lesions of erythema multiforme may be atypical in appearance with only 2 zones of color, but these lesions will also be more violaceous in appearance, whereas urticaria is pink or skin-colored.

The diagnosis of urticaria is most often made on clinical grounds alone. However, if the diagnosis is in question, a skin biopsy can be helpful. Histopathologic findings include mild dermal edema and perivascular and interstitial infiltrate, often of neutrophils, eosinophils, and lymphocytes. The histopathologic skin findings of urticaria can be quite subtle, so the clinician’s diagnostic acumen is of utmost importance. Whereas acute urticaria often resolves on its own, chronic urticaria often requires a careful history for recent infections, underlying medical conditions, or physical triggers that may be the precipitating cause. In cases of chronic urticaria, referrals to an allergist-immunologist are usually beneficial.


First-line treatment for urticaria is antihistamines, which are often needed on a daily basis.¹For mild acute urticaria with frequent flares, a daily dose of an antihistamine (e.g., cetirizine) for several weeks can be added to diphenhydramine, taken as needed. An alternative regimen to prevent flares is cetirizine every morning, ranitidine twice during the day, and diphenhydramine every night until the acute episode resolves, which may take several weeks. After several weeks, the daily antihistamine(s) can be discontinued to assess if suppressive therapy is needed. For urticaria that is refractory to antihistamines, effective systemic therapies include other anti-inflammatory and immunosuppressive agents, including omalizumab or cyclosporine, which is best managed by an allergist-immunologist.⁵

Our patient’s acute urticaria resolved after approximately 1 week, but she was then lost to follow-up.


Key clinical points on urticaria

Urticaria may have ecchymosis-like centers, and these should not be confused with the dusky centers of erythema multiforme.

Of acute urticaria in children, 80% is triggered by infection, usually of viral etiology.

If patients experience numerous episodes of urticaria on a near daily basis, adding a daily standing dose of antihistamine (e.g., cetirizine) for prophylaxis in addition to diphenhydramine, as needed, is usually beneficial.

Case #2

Erythema multiforme is most common in young adults, with rare cases in children.⁶Males may be slightly more likely than females to develop the condition.⁶There is no known racial or ethnic predilection.⁶

Erythema multiforme most likely represents a skin-directed immune reaction, usually in the setting of infection, in genetically predisposed individuals.⁶The most common infectious etiology associated with the condition is herpes simplex virus (HSV) infection.⁶Almost 50% of patients with erythema multiforme will report a history of herpes labialis, commonly known as cold sores, before, with, or after the onset of erythema multiforme.⁶Less common infectious etiologies include bacterium mycoplasma pneumoniae, fungus histoplasma capsulatum, and parapoxvirus (orf virus).⁶Recurrent episodes of erythema multiforme may be seen, and HSV has been identified as a leading cause.⁷

The primary lesion of erythema multiforme is classically described as a typical target lesion, which presents as 2 concentric rings that are usually less than 3 cm in diameter, are round in shape, and have well-defined borders. The rings form 3 zones of color: a central, dusky, circular zone often with epidermal change (e.g., vesicle, bullae, crust), which is surrounded by a ring of pallor, which is in turn surrounded by a larger erythematous ring.⁶Atypical target lesions that do not present with 3 concentric rings have also been described in the literature and present as sharply demarcated, erythematous, edematous plaques with a central dusky color that is usually associated with epidermal change.³In erythema multiforme, there is typically an abrupt onset of lesions with almost all lesions appearing within 24 hours and with each lesion typically lasting days to weeks. Lesions are usually asymptomatic, but pruritus and burning are fairly common.³

Erythema multiforme can be further classified into minor and major forms.⁶Erythema multiforme minor is characterized by either absent or mild mucosal involvement with few or no systemic symptoms.⁶The major form is notable for severe mucosal involvement with systemic symptoms.⁶Oral or mucosal involvement often starts as bullae that break soon after formation; however, swelling, crusting, and erosions of the buccal mucosa, tongue, lips, or genitalia can be seen.³Most episodes of erythema multiforme tend to heal within 2 to 3 weeks.³

The most common entity encountered on the differential diagnosis is Stevens-Johnson syndrome (SJS), especially in cases of erythema multiforme major, which is associated with major mucosal symptoms. SJS is notable for frank skin necrosis that involves less than 10% of the body’s surface area and is typically associated with significant skin pain. Typical target lesions are notably absent in SJS,⁶but dusky, atypical target lesions may be present; these atypical targets are papular in erythema multiforme and macular in SJS. Additionally, whereas erythema multiforme is often associated with infectious etiologies, such as HSV or mycoplasma pneumonia infections, SJS is chiefly caused by medications.⁶The medications most frequently associated with SJS are allopurinol, sulfasalazine, antibiotics (e.g., aminopenicillins, trimethoprim-sulfamethoxazole), antiretroviral drugs, barbiturates, anticonvulsants (e.g., carbamazepine, phenytoin, lamotrigine), and nonsteroidal anti-inflammatory drugs (e.g., phenylbutazone, piroxicam).⁶Although not traditionally considered on the differential diagnosis of erythema multiforme, if clinicians are unfamiliar with the fact that ecchymotic-like centers may be seen with urticaria, these two entities may be confused. The bruise-like centers of urticaria are often more grey-blue or brown-blue in color than the dusky purplish hue of erythema multiforme. Also, since urticaria is a dermal process, there is typically no epidermal change with scale or crust. In contrast, erythema multiforme is usually associated with some degree of scale, crust, or bullae in the center of the lesion. Unlike erythema multiforme, urticaria rarely involves erosions or ulceration of the mucosa. When urticaria affects the mucosal surfaces, it typically manifests as angioedema, with swelling of the subcutaneous tissue. Lastly, the individual lesions of urticaria are transient and last less than 24 hours, whereas individual lesions of erythema multiforme may last days to weeks.

The diagnosis of erythema multiforme is usually made on clinical grounds alone. If the diagnosis is in question, a skin biopsy is often helpful but not diagnostic. For example, the biopsy findings from erythema multiforme, SJS, and toxic epidermal necrolysis can be indistinguishable, and clinical correlation is necessary. In early erythema multiforme, dyskeratotic keratinocytes are the earliest histopathologic finding.⁶Other variable features are mild spongiosis, focal vacuolar degeneration, superficial dermal edema, and a perivascular infiltrate of mononuclear leukocytes and lymphocytes with exocytosis.^4,6In cases in which HSV is suspected as the underlying etiology, HSV-1 and -2 serologies for immunoglobulin (Ig)G and IgM may be beneficial, or if an active lesion is present, the vesicular fluid can be sent for polymerase chain reaction or direct fluorescent antibody to test for HSV 1 and 2. Testing of other underlying etiologies should be based on the patient’s history or symptomatology.

If an underlying infectious etiology is identified, the infection should be treated; otherwise, the treatment of erythema multiforme is mainly symptomatic. Regimens that have been reported as helpful for symptomatic skin lesions are topical antiseptics or antihistamines.⁶Painful oral lesions may be relieved with a compounded formula of antiseptic and antihistamine rinses and a local anesthetic solution.⁶In severe forms of erythema multiforme, a short prednisone taper may provide symptomatic relief, but there are no randomized, controlled studies on this treatment for erythema multiforme.⁶In patients with frequent recurrences of HSV-associated erythema multiforme, daily prophylaxis with an antiviral (acyclovir, 10 mg/kg/day, in divided doses; or valacyclovir, 500-1,000 mg/day) for a 6-month trial should be considered.⁶Other therapies that have been reported as effective for recurrent erythema multiforme are mycophenolate mofetil, dapsone, hydroxychloroquine, and azathioprine.³

The patient in our case had no history of cold sores and his HSV-1 and -2 serologies were negative. However, the patient was placed on an empiric trial of acyclovir at 20 mg per kg per day in divided doses, as there is one report of recurrent erythema multiforme that is not related to HSV benefiting from suppressive acyclovir.⁸Our patient’s condition remained clear at 2 months after initiating the trial of daily acyclovir.

Key clinical points on erythema multiforme

Many cases of erythema multiforme are idiopathic, but the most common underlying infectious etiology is herpes simplex virus infection.

The classic lesion of erythema multiforme is a target lesion with 3 zones of color or more, often presenting with a central dusky center, surrounding ring of pallor, and outer erythematous ring. However, atypical target lesions are also commonly seen with the common theme of having a dusky center.

A biopsy is helpful with but not diagnostic of erythema multiforme, as other conditions can have similar or identical histologic findings.

Audrey Chan, MD, is a pediatric dermatology fellow at Texas Children’s Hospital in Houston.


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This The Clinical Advisor CME activity consists of 3 articles. To obtain credit, read Progressive, diffuse scalp hair loss in a woman and Fleshy papule on the left cheek of a young boy. Then take the post-test here.

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This The Clinical Advisor CME activity consists of 3 articles. To obtain credit, read Progressive, diffuse scalp hair loss in a woman and Fleshy papule on the left cheek of a young boy. Then take the post-test here.

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