A Girl With Concentric, Target-Shaped Lesions on Her Hands, Arms, and Legs

A 13-year-old girl presented to the pediatric urgent care clinic with concerns of headache, fever, pharyngitis, cough, and myalgia. She reported having had a fever (38.0°C) and a dry, hacking cough for the past 7 days. A mildly pruritic erythematous skin eruption had developed over the last 3 days, about which she was most concerned. She had no complaints of pain. She had no past history or family history of a similar skin eruption. Her past medical history was unremarkable. She had been taking acetaminophen to treat her symptoms. Her immunizations were up to date.

The patient appeared nontoxic and was well hydrated. She was in no respiratory distress. An intermittent cough was noted. Her oropharynx was slightly erythematous without purulence. Intermittent rales were heard in the lower lung fields on chest auscultation. A chest radiograph revealed peribronchial interstitial infiltrates.

A circular erythematous skin eruption, polymorphous in nature, was noted. Skin findings revealed target-like lesions on her hands, arms, and legs (Figure). Most lesions had well-defined borders and appeared as concentric rings of different skin colors—notably, dark centers surrounded by lighter rims and encircled by outermost erythema. Erythematous macules, papules, and wheals also were present. Some macules appeared papular and others appeared plaque-like within the center. Concentric rings of erythema were noted.

Sputum testing later confirmed the underlying cause of her cutaneous findings.

What explains the girl’s skin lesions and other symptoms?

(Answer and discussion on next page)

Answer: Erythema multiforme triggered by infection

Erythema multiforme (EM), also termed EM minor, is a relatively common skin disorder caused by a delayed hypersensitivity reaction. This dermatologic eruption often is triggered by infection or specific medications.^1,2

EM was first described in the 1860s by Austrian dermatologist Ferdinand von Hebra as an acute, self-limited condition with characteristic erythematous papules and plaques.^3,4 A life-threatening variant, termed of EM major or Stevens-Johnson syndrome (SJS), was reported in 1922 by American pediatricians Albert M. Stevens and Frank C. Johnson.^5,6 SJS is characterized by prolonged high fever, a disseminated cutaneous eruption of erythematous or purpuric macules and plaques, and marked mucous membrane involvement of the conjunctivae, buccal mucosa, and genitalia.

The delineating terms erythema multiforme minor and erythema multiforme major were coined in 1950 by British dermatologist Bernard A. Thomas.^7,8

Clinical Manifestations

EM is a polymorphic (occurring in many forms, hence multiforme) eruption of macules, papules, and target lesions (also called iris lesions). Iris lesions appear as central bullae or vesicles with surrounding concentric erythema. These target-like circular lesions are fixed and characteristically have a sharp margin, a regular round shape, and 3 concentric color zones: a dusky or dark red center; a surrounding pale pink ring that is raised due to local edema; and a bright red outermost ring. Atypical target lesions with 2 zones—a dusky or dark red center and a paler pink ring with indistinct borders—also are possible. Lesions may show the Koebner phenomenon (isomorphic response), as they can develop at sites of prior skin trauma.

Skin lesions erupt and evolve over 72 to 96 hours. Lesions of various stages of development may be present and can number in the hundreds. The eruption tends to be symmetric and can affect any part of the body. The lesions appear suddenly on the dorsal hands and feet and spread centrally along the extremities toward the trunk. The body distribution favors the distal extremities,⁹ with the upper extremities affected more often than the lower extremities. The extensor surfaces of the arms and legs are particularly involved, with groupings commonly appearing on the elbows and knees.¹⁰ The palms and soles frequently are involved.¹¹ The lesions may be associated with a mild itching or burning sensation. There may be mild mucous membrane involvement, or none at all. In approximately 50% of cases, a small number of mucosal lesions (5 to 10 on average) develop a few days after skin lesions appear and most often affect the buccal mucosa and/or the lips.¹¹

This acute and self-limiting eruption usually resolves without complications. Recurrence is possible.¹²

Epidemiology, Etiology, Pathophysiology

EM is diagnosed more often in boys and men than in girls and women, with a male to female ratio of 3 to 2. The condition affects all ages but is diagnosed more frequently in persons from 20 to 40 years old.^13,14 Approximately 20% of EM cases are diagnosed in children and adolescents.¹⁵ There is no known racial or ethnic predilection.

EM initially was thought to be part of a clinical spectrum of disease that included EM minor, EM major (SJS), and toxic epidermal necrolysis (TEN). Within this spectrum, EM minor was considered the mildest form and TEN the most severe.¹⁶ In 1993, a useful clinical classification for EM, SJS, and TEN was proposed based on the skin lesion pattern and the amount of body surface area (BSA) that had detached from the epidermis (eg, blisters, denuded areas, erosions) at the worst stage of the disease process.¹⁷ With little or no mucous membrane involvement and less than 10% BSA epidermal detachment, EM was classified as a distinct condition separate from the clinical spectrum of SJS and TEN.^9,17 In more than 50% of cases of EM, an underlying trigger is not identified, and the cause is unknown.¹ Infection (viral, bacterial, and fungal), medications, and vaccines are known triggers of EM. Infectious diseases and medications are the more common triggers in children.¹⁰

Infectious Triggers

Infection is the trigger in approximately 90% of EM cases. More than 50% of these cases are triggered by herpes simplex virus (HSV) infection, with the culprit being HSV-1 more often than HSV-2.⁹ In one study of the HSV genotypes found in the cutaneous lesions of patients with HSV-associated EM, 66.7% of cases were related to HSV-1, 27.8% to HSV-2, and 5.6% to coinfection with HSV-1 and HSV-2.¹⁸ However, most persons with HSV infection do not develop EM. Those who develop HSV-associated EM may have clinically apparent HSV, may have an HSV reactivation, or may not have an apparent HSV infection at the time.^19,20 The HLA-DQw3 antigen type is more often found in patients with HSV-associated EM.

HSV-associated EM is a delayed-type hypersensitivity reaction (cell-mediated or type IV hypersensitivity), characterized by a delayed response of 48 to 72 hours after antigen exposure. This reaction occurs with the transport of HSV DNA fragments to distant skin sites by blood mononuclear cells. HSV genes in these viral fragments are expressed on keratinocytes, leading to the recruitment of HSV-specific CD4⁺ T_H1 cells (helper T cells involved in cell-mediated immunity). CD4⁺ cells respond to viral antigens by producing interferon-γ, initiating an inflammatory cascade.^15,21 HSV-associated EM appears 3 to 14 days after the viral infection.

Mycoplasma pneumoniae is the second most common trigger for this delayed hypersensitivity reaction and often is the etiology of EM in children.⁹ Our patient’s clinical history and presentation strongly suggested that her EM trigger was M pneumoniae infection. Results of polymerase chain reaction (PCR) testing of a sputum sample were positive for M pneumoniae, confirming it as the infectious trigger. PCR testing is the method of choice for the rapid direct detection of M pneumoniae, especially if the test is performed within 21 days of the onset of symptoms.²² Sputum PCR testing has replaced hybridization and direct antigen detection owing to its higher sensitivity and early diagnostic advantage.²² Immunoglobulin M and immunoglobulin G testing with enzyme-linked immunosorbent assay and complement fixation require acute and convalescent samples and are not as sensitive early on in the disease process. Bacterial culture testing for M pneumoniae is not recommended due to the organism’s fastidious nature, the length of time (approximately 4 weeks) required for growth to occur, and the test’s relatively high cost.²³

Other infectious triggers of EM are Epstein-Barr virus, parapoxvirus, varicella-zoster virus, adenovirus, hepatitis C virus, HIV, and cytomegalovirus. Infections with Yersinia, Treponema pallidum, Histoplasma, and Mycobacterium also have been associated with EM.¹

Medications and Vaccines

Various medications have been reported as EM triggers, with sulfonamides as the most common; other medication triggers are barbiturates, hydantoins, nonsteroidal anti-inflammatory drugs, penicillins, tetracyclines, and phenothiazines.² Specific medications such as metformin, adalimumab, bupropion, and ciprofloxacin also have been implicated.

Drug-associated EM lesions test positive for tumor necrosis factor α, but not interferon-γ as in HSV-associated EM, suggesting a different pathologic mechanism.²⁴ Medication-triggered EM accounts for approximately 10% of cases; thus, it is important to expand the differential diagnosis to other dermatologic diagnoses such as SJS, TEN, generalized fixed drug eruption, exanthematous (morbilliform) drug eruption, or urticaria. Iris lesions with dusky or purpuric centers may appear similar to the lesions of pityriasis rosea, lupus erythematosus, urticaria, or urticarial vasculitis. EM must be differentiated from the autoimmune bullous diseases if bullous lesions are present.^9,25 Vaccine-triggered EM has been reported in association with the tetanus-diphtheria, hepatitis B, and smallpox vaccines.^9,26

Diagnosis and Management

EM is a clinical diagnosis. Dermatologic target lesions support the diagnosis. Care involves attempting to determine the underlying trigger. If a trigger is identified, clinical management is directed at either treating the suspected infection or discontinuing the causal drug. In most cases, no treatment is required, since the rash usually resolves by itself over several weeks without complications.

Supportive and symptomatic treatment may be necessary. Moist compresses, oral antihistamines, and topical corticosteroids can relieve EM symptoms. Acetaminophen is recommended to reduce pain and fever. Oral prednisone dosed at 0.5 to 1 mg/kg/day (maximum 80 mg/d) for 4 to 5 days may be used in patients whose clinical presentation involves the oral mucosa. However, the use of oral corticosteroids for the treatment of EM remains controversial, since no controlled studies have shown a true benefit. Immunosuppression induced by oral corticosteroid use may harm patients with underlying HSV-triggered EM.^9,11

Skin biopsy to help exclude other dermatologic conditions may be indicated if the clinical picture is unclear.⁹ EM has a characteristic histology, but it is not considered diagnostic. The histology varies with the age of the lesion, its appearance, and which part of the target lesion is biopsied. Laboratory testing may be performed to identify pathogens commonly associated with EM. Oral antiviral therapy (eg, acyclovir) for HSV infection or antibiotic therapy (eg, erythromycin/macrolide) for M pneumoniae may be required.

EM can recur with multiple episodes per year for many years. In most recurrent cases, the trigger is infection with HSV-1 or HSV-2. Although antivirals do not effectively treat an existing rash, recurrent EM can be treated with daily oral acyclovir dosed at 5 mg/kg/day twice daily (maximum 400 mg twice daily). Placebo-controlled double-blind studies have illustrated acyclovir’s effectiveness in suppressing recurrent EM.²⁷ For patients who have a poor response to acyclovir, a regimen of valacyclovir or famciclovir may be tried.²⁸ Once a patient has been free of recurrence for 4 months, the daily antiviral dose can be reduced with the goal of eventual discontinuation. Recurrent EM also is associated with certain HLA antigen types: HLA-B15, B35, A33, DR53, and DQB1*0301, and specifically for recurrent HSV-triggered EM, DQw3.¹⁹

Other treatments used to suppress recurrent EM are dapsone,²⁹ hydroxychloroquine,¹³ azathioprine, thalidomide, cyclosporine, mycophenolate mofetil, and photochemotherapy with psoralen and ultraviolet light.⁹ These treatment approaches require the care of a dermatologist. Evidence supporting their use is limited, but they have shown clinical benefit for some patients.

EM typically resolves spontaneously without residual scarring over 1 to 4 weeks, with an average of 3 weeks. EM does not progress to SJS or TEN.¹¹ In some cases, hyperpigmented areas of skin discoloration may remain.  

Germaine L. Defendi, MD, MS, is an associate clinical professor of pediatrics at Olive View–UCLA Medical Center in Sylmar, California.

References

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