Erythema Multiforme 

Updated: Oct 30, 2018
Author: Jose A Plaza, MD; Chief Editor: William D James, MD 

Overview

Background

Erythema multiforme (EM) is an acute, self-limited, and sometimes recurring skin condition that is considered to be a type IV hypersensitivity reaction associated with certain infections, medications, and other various triggers.[1]

Erythema multiforme may be present within a wide spectrum of severity. Erythema multiforme minor represents a localized eruption of the skin with minimal or no mucosal involvement. The papules evolve into pathognomonic target or iris lesions that appear within a 72-hour period and begin on the extremities (see the following image). Lesions remain in a fixed location for at least 7 days and then begin to heal. An arcuate appearance may be present (see the second image below). Precipitating factors include herpes simplex virus (HSV), Epstein-Barr virus (EBV), and histoplasmosis. Because this condition may be related to recurrent HSV, recurrences of erythema multiforme may follow, with many affected individuals experiencing several recurrences per year.

Target lesion of erythema multiforme. Target lesion of erythema multiforme.
Raised atypical targets and arcuate lesions. Raised atypical targets and arcuate lesions.

Erythema multiforme major is a more severe, potentially life-threatening disorder. One or more mucous membranes are involved and up to 10% of body area may have epidermal detachment. More than 50% of all cases are attributed to medications.

Erythema multiforme versus Steven-Johnson syndrome and toxic epidermal necrolysis

Consensus classification

Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered severity variants of a single entity. There are basically two entities divided into the following: (1) erythema multiforme consisting of erythema minor and major and (2) SJS/TEN.

The clinical descriptions are as follows:

  • Erythema multiforme minor - Typical targets or raised, edematous papules distributed acrally

  • Erythema multiforme major - Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area (TBSA).

  • SJS/TEN - Widespread blisters predominant on the trunk and face, presenting with erythematous or pruritic macules and one or more mucous membrane erosions; epidermal detachment is less than 10% TBSA for Steven-Johnson syndrome / toxic epidermal necrolysis and 30% or more for toxic epidermal necrolysis.

See also Dermatologic Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis and Oral Manifestations of Drug Reactions.

Pathophysiology

The pathophysiology of erythema multiforme (EM) is still not completely understood, but it is probably immunologically mediated and appears to involve a hypersensitivity reaction that can be triggered by a variety of stimuli, particularly bacterial, viral, or chemical products.

Cell-mediated immunity appears to be responsible for the destruction of epithelial cells. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, whereas the dermis displays a slight influx of CD4 lymphocytes. These immunologically active cells are not present in sufficient numbers to be directly responsible for epithelial cell death. Instead, they release diffusable cytokines, which mediate the inflammatory reaction and resultant apoptosis of epithelial cells. In some patients, circulating T cells transiently demonstrate (for < 30 d) a T-helper cell type 1 (TH1) cytokine response (interferon [IFN] gamma, tumor necrosis factor [TNF] alpha, interleukin [IL] 2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine.

Other evidence supports the hypothesis that the disease is the result of cell-mediated immune reactions. Individuals possessing human leukocyte antigen (HLA)–B12 are 3 times more likely to develop this disorder. The classic timing for a primary cell-mediated immune reaction is 9-14 days after the initiation of the offending drug. In recurrent exposure, the reaction occurs within several hours to 1-2 days, which is consistent with the timing of a secondary cell-mediated immune response.

Herpes simplex virus

A major cause of erythema multiforme is the herpes virus (HSV). In fact, recent or recurrent herpes has been reported as the principle risk factor for erythema multiforme.

Herpes-associated erythema multiforme (HAEM) appears to represent the result of a cell-mediated immune reaction associated with HSV antigen.[2, 3] The immunologic reaction affects HSV-expressing keratinocytes. Cytotoxic effector cells, CD8+ T lymphocytes in the epidermis, induce apoptosis of scattered keratinocytes and lead to satellite cell necrosis. Neighboring epidermal cells are HLA-DR positive.

A relationship exists between HLA types A33, B35, B62 (B15), DR4, DQB1*0301, DQ3, and DR53 and recurrent erythema multiforme.[4] In particular, HLA-DQ3 is especially related to recurrent erythema multiforme and may be a helpful marker for distinguishing HAEM from other cutaneous diseases.[5]

Drug hypersensitivity

The disease process also often involves an abnormal metabolism of a responsible drug. As noted above, the keratinocyte is the ultimate target of this disease process, with keratinocyte necrosis being the earliest pathologic finding.

Patients frequently display an altered metabolism of the responsible drug, and are considered to be slow acetylators, both genotypically and phenotypically. This means that an increased proportion of drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 system, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may then behave as haptens by binding covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction.

Etiology

Many suspected etiologic factors have been reported to cause erythema multiforme (EM). Both erythema multiforme and Steven-Johnson syndrome may be induced by medications, but infectious agents are also considered to be a major cause of erythema multiforme. However, approximately 50% of cases are idiopathic, with no precipitating factor identified.

A previous history of erythema multiforme and male sex has also been reported as risk factors, but pregnancy may contribute to development of erythema multiforme as well.

Postvaccination causes include Bacille Calmette-Guérin (BCG) vaccination, oral polio vaccine, vaccinia, and tetanus/diphtheria.

HSV and other infections

Infectious causes are more common in children and are implicated commonly in erythema multiforme.

Erythema multiforme minor is regarded as being commonly triggered by herpes simplex virus (HSV) (types 1 and 2), and HSV is the most common cause in young adults; in fact, many instances of idiopathic erythema multiforme minor may be precipitated by subclinical HSV infection. Among other infections, Mycoplasma species is another common cause.

Bacterial

Bacterial infections that may trigger erythema multiforme include borreliosis, catscratch disease, diphtheria, hemolytic streptococci, legionellosis, leprosy, Neisseria meningitidis, Mycobacterium avium complex, M pneumoniae,[6, 7] pneumococci, tuberculosis, Proteus/Pseudomonas/Salmonella/Staphylococcus/Yersinia species, Treponema pallidum,[8] tularemia, Vibrio parahaemolyticus, Vincent disease, and rickettsial infections. Chlamydial infections include lymphogranuloma venereum and psittacosis.

Viral

Viral infections, including Adenovirus, coxsackievirus B5, cytomegalovirus (CMV), echoviruses, enterovirus, Epstein-Barr virus (EBV), hepatitis A/B/C viruses (HAV/HBV/HCV), HSV, influenza,[9] measles, mumps, paravaccinia, parvovirus B19, poliomyelitis, varicella-zoster virus (VZV), and variola, are other causes, as well as the virus-drug interactions CMV infection–terbinafine[10] and EBV infection–amoxicillin.[11]

Other

Fungal infections such as coccidioidomycosis, dermatophytosis, and histoplasmosis and some parasitic infections, including Trichomonas species and Toxoplasma gondii, may trigger erythema multiforme.

Drugs

More than 50% of cases of erythema multiforme major are related to medication use, but no test reliably proves the link between a single case and a specific drug.

Regarding medications, sulfa drugs are the most common triggers (30%). The second most commonly involved agents are the anticonvulsants, including barbiturates,[12] carbamazepine,[12] hydantoin, phenytoin,[12] and valproic acid.

Causative antibiotics include penicillin, ampicillin, tetracyclines, amoxicillin, cefotaxime, cefaclor, cephalexin, ciprofloxacin,[13] erythromycin, minocycline, sulfonamides, trimethoprim-sulfamethoxazole, and vancomycin.

Antituberculoid agents such as rifampicin, isoniazid, thiacetazone, and pyrazinamide are also known offenders. Antipyretic agents as triggers include analgesics, especially aspirin as well as phenylbutazone, oxyphenbutazone, and phenazone.

Others drugs that may cause erythema multiforme include acarbose, albendazole, alendronate,[14] allopurinol,[12] arsenic, bromofluorene, quinine (Chinine), cimetidine, clofibrate, corticosteroids, diclofenac, didanosine, dideoxycytidine, diphosphonate, estrogen, etretinate, fluconazole, griseofulvin,[15] gabapentin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hydralazine, indapamide, imiquimod,[16] indinavir, lamotrigine,[12] methazolamide, mefloquine, methotrexate, meprobamate, mercurials, minoxidil, nifedipine, nevirapine,[12] nitrogen mustard, nivolumab,[17, 18] nystatin, nonsteroidal anti-inflammatory drugs (NSAIDs), phenolphthalein, piroxicam,[12] pyritinol, progesterone, potassium iodide, sulindac, suramin, saquinavir, thiabendazole, thiouracil, terbinafine, theophylline, vandetanib,[19] verapamil, and dihydrocodeine phosphate.[20]

Contact exposure

Contactants that may induce an erythema multiforme–like eruption include ammoniated mercury, budesonide, bufexamac, capsicum, chloromethylnaphthalene, desoximetasone, dinitrochlorobenzene (DNCB), disperse blue 124, diphenylcyclopropenone, fire sponge (Tedania ignis), herbal medicines (eg, Alpinia galanga),[21] isopropyl-p -phenylenediamine of rubber, nickel, nitrogen mustard, oxybenzone, phenylbutazone, poison ivy,[22] proflavin, resin, rosewood, and triamcinolone acetonide.

Other etiologic factors

The following have also been reported as causes of erythema multiforme:

  • Flavorings and preservatives, such as benzoic acid and cinnamon[23]

  • Immunologic disorders, such as transient selective C4 deficiency of infancy,[24] collagen diseases, vasculitides, sarcoidosis, non-Hodgkin lymphoma, leukemia, multiple myeloma, myeloid metaplasia, and polycythemia

  • Physical or mechanical factors, such as tattooing, radiotherapy, cold, and sunlight

  • Foods, including salmon berries and margarine

  • Malignancy

  • Hormonal

Epidemiology

The exact incidence of erythema multiforme (EM) in the United States is unknown; however, as many as 1% of dermatologic outpatient visits are for erythema multiforme. Globally, the frequency of erythema multiforme is estimated at approximately 1.2-6 cases per million individuals per year.

Before the human immunodeficiency virus (HIV) epidemic among young males, there was a slight female predominance of this disease. However, erythema multiforme is currently more common in younger males (male-to-female ratio, range of 3:2 to 2:1) (mainly second to fourth decades, but can include children and adolescents [20%][25] ). The condition is rare in children younger than 3 years and in adults older than 50 years.

The following medical conditions seem to predispose individuals to a higher risk of developing the disorder: HIV infection, corticosteroid exposure, bone marrow transplant, systemic lupus erythematosus (SLE), graft versus host disease (GVHD), and inflammatory bowel disease (IBD). Individuals undergoing radiation, chemotherapy, or neurosurgery for brain tumors are also at higher risk.

Prognosis

Most cases of erythema multiforme (EM) are self-limited. In erythema multiforme minor, the lesions evolve over 1-2 weeks and ultimately subside within 2-3 weeks without scarring. However, the recurrence of erythema multiforme minor is common (up to one third of cases) and mostly preceded by apparent or subclinical herpes simplex virus (HSV) infection.

Erythema multiforme major has a mortality rate of less than 5% and is directly proportional to the total body surface area of sloughed epithelium. It usually has a more protracted course than erythema multiforme minor; clearing may require 3-6 weeks. Skin lesions usually heal with hyperpigmentation and/or hypopigmentation. Scarring is usually absent, except after secondary infection. Sepsis secondary to loss of the cutaneous barrier is the principle cause of death.

Advanced age, visceral involvement, increased serum urea nitrogen level, and previous bone marrow transplantation are poor prognostic factors. Surprisingly, although the incidence of erythema multiforme is increased among individuals with human immunodeficiency virus (HIV) infection (approaching 1 case per 1000 individuals per year), they do not appear to have a higher mortality rate.

Continuous and persistent erythema multiforme

Two additional rare clinical forms of erythema multiforme have been reported. Continuous erythema multiforme manifests as a prolonged course with overlapping attacks and may be associated with systemic administration of glucocorticoids.

Persistent erythema multiforme has a protracted clinical course over months, is commonly associated with atypical skin lesions, and is commonly resistant to conventional treatment. It has been reported in association with inflammatory bowel disease (IBD), occult renal carcinoma, persistent or reactivated Epstein-Barr virus (EBV) infection, and HSV infection.

Patient Education

Educate patients with erythema multiforme (EM) about appropriate symptomatic treatment, and provide reassurance that disease is usually self-limited. In addition, advise patients of the significant risk of recurrence and emphasize the possible need for suppressing recurrent HSV with appropriate antiviral therapy. (See Monitoring and Prevention.)

For patient information, see Skin Conditions & Beauty Center, as well as Life-Threatening Skin Rashes and Image Collection: Picture of Erythema Multiforme Minor.

 

Presentation

History

In addition to characterizing skin and mucous membrane lesions of erythema multiforme (EM), a complete history should document recent constitutional symptoms, previous history of or current herpes simplex (HSV) or Mycoplasma pneumoniae infection, and all use of prescription and over-the-counter (OTC) medications, with particular attention to those started in the previous 2 months. Patients may have a history of anxiety.

Symptoms

Prodromal symptoms are usually absent or mild in persons with erythema multiforme minor, consisting of a mild, nonspecific upper respiratory tract infection. The abrupt onset of a rash usually occurs within 3 days, starting on the extremities symmetrically, with centripetal spreading. Pruritus is generally absent

In erythema multiforme major, 50% of patients have prodromes similar to an influenzalike prodrome, including moderate fever, general discomfort, cough, sore throat, vomiting, chest pain, and diarrhea (secondary to gastrointestinal [GI] tract ulceration). These symptoms have a classic time course of development and are usually present for 1-14 days before the cutaneous eruption occurs. The lesions begin on the acral areas and spread similarly to the distribution of erythema multiforme minor (ie, usually symmetrical and extend from the face and torso to the trunk and proximal extremities).

Prominent mucosal involvement may also occur in erythema multiforme major. Erosions of the oral mucosa may result in difficulty in eating, drinking, or opening the mouth. Conjunctival involvement may cause lacrimation, photophobia, burning eyes, or visual impairment. Genital lesions are painful and may result in urinary retention; painful micturition due to genitourinary tract ulceration may also occur. Shortness of breath or difficulty in breathing may occur due to tracheobronchial epithelial involvement.

A localized form of erythema multiforme has been reported at the site of marrow aspiration. Half the children with erythema multiforme have a history of herpes labialis or genitalis. Although the onset usually precedes erythema multiforme by 3-14 days, it may still be present at the onset of erythema multiforme.

Physical Examination

The hallmark of erythema multiforme (EM) is a target lesion with variable mucous membrane involvement.

Skin lesions

The initial lesion is a dull-red, purpuric macule or urticarial plaque that expands slightly to a maximum of 2 cm over 24-48 hours. In the center, a small papule, vesicle, or bulla develops, flattens, and then may clear. An intermediate ring develops and becomes raised, pale, and edematous. The periphery gradually changes to become cyanotic or violaceous and forms a typical concentric, “target” lesion. Some lesions consist of only 2 concentric rings (see the first image below). Polycyclic or arcuate lesions may occur (see second image below). Some lesions appear at areas of previous trauma (Koebner phenomenon). Postinflammatory hyperpigmentation or hypopigmentation may occur. The Nikolsky sign is negative (ie, top layers of the skin do not slip away from the lower layers when slightly rubbed).

Target lesion of erythema multiforme. Target lesion of erythema multiforme.
Raised atypical targets and arcuate lesions. Raised atypical targets and arcuate lesions.

Skin distribution

The lesions are symmetrical, predominantly on the acral extensor surfaces of the extremities, and they spread centripetally to involve the abdomen and back. Lesions may also coalesce and become generalized. The palms, neck, and face are frequently involved. Lesions of the soles and flexural aspects of the extremities are less common. A zosteriform distribution may be present.

Mucosal lesions

Mucosal lesions usually heal without sequelae. The mucosal involvement in Stevens-Johnson syndrome is more severe and more extensive than that of erythema multiforme major. Generalized lymphadenopathy often accompanies erythema multiforme major.

Other findings

Mild temperature elevation is usually noted. Hyperventilation and mild hypoxia may result from anxiety or tracheobronchial involvement.

Dehydration may range from mild to massive as a result of the following factors:

  • Evaporation through open skin lesions

  • Poor oral intake secondary to oropharyngeal mucous membrane involvement

  • Profuse diarrhea from involvement of bowel mucosa

  • Increased insensible losses secondary to elevated core body temperature

Complications

Most patients with erythema multiforme (EM) have an uncomplicated course, with the exception of hosts who are immunocompromised and those with secondary bacterial infections of the skin or the mucosa. Healing of the mucosal areas is usually complete.

Scars and strictures of the esophageal, urethral, vaginal, and anal mucosa rarely occur. However, severe oral involvement may be accompanied by difficulty in consuming food and fluid and can result in dehydration, and vaginal and urethral erosions may cause urinary retention and phimosis. Hematocolpos is the result of genital lesions in teenage females. Severe scarring of the genitourinary tract may cause vaginal and urethral stenosis.

Severe eye complications (20%), such as purulent conjunctivitis, anterior uveitis, panophthalmitis, scarring of the conjunctivae, symblepharon, may result in permanent blindness. Other ocular sequelae may include the following:

  • Epiphora secondary to obstruction of the lacrimal ducts

  • Sjögren-like sicca syndrome of dry eyes, punctate keratitis, corneal pannus, and mucin deficiency in tears

  • In-turned eyelashes, corneal scarring, corneal and conjunctival neovascularization, epithelial proliferation with squamous metaplasia, photophobia, burning eyes, visual impairment

Other complications include the following:

  • Patchwork appearance of the skin, with hypopigmented regions and potential hypertrophic scarring

  • Pneumonia / acute respiratory distress syndrome (ARDS)

  • Dehydration and electrolyte disturbances

  • Possible gastrointestinal (GI) hemorrhage, nephritis, and renal failure

 

DDx

Diagnostic Considerations

Although erythema multiforme (EM) is uncommon, the potentially life-threatening nature of the major form of the illness requires that clinicians maintain a high index of clinical awareness. Early diagnosis and aggressive supportive care are the essential elements of care in such severe cases.

Report any suspected erythema multiforme adverse drug reactions to the manufacturer and the appropriate regulatory authorities. Only in this manner can problematic drugs be identified, relabeled, or possibly even withdrawn from the market.

Conditions that should also be considered when evaluating a patient with suspected erythema multiforme include the following:

  • Herpes simplex virus (HSV) infection

  • Mycoplasma pneumoniae infection

  • Acute generalized exanthematous pustulosis

  • Chemical burns, thermal burns

  • Collagen vascular diseases

  • Disseminated lesions of contact dermatitis, exfoliative dermatitis

  • Erythroderma

  • Figurate erythema

  • Granuloma annulare

  • Immunoglobulin A (IgA) linear dermatosis

  • Lichen planus

  • Lupus erythematosus[26]

  • Lyme disease

  • Major oral aphthae, recurrent aphthous ulcers

  • Meningococcemia

  • Mucocutaneous lymph node syndrome

  • Necrotizing vasculitis

  • Pityriasis rosea

  • Secondary syphilis

  • Septicemia

  • Serum sickness

  • Urticaria

  • Viral exanthems

Differential Diagnoses

 

Workup

Approach Considerations

No specific laboratory tests are indicated to make the diagnosis of erythema multiforme (EM), which should be arrived at clinically. The clinical picture can guide laboratory testing in severe cases.

Cultures are indicated in severe cases and should be obtained from blood, sputum, and mucosal lesions.

No specific imaging studies are necessary in most cases, although chest radiography may be useful in cases with respiratory symptoms or signs, particularly if an underlying pulmonary infection is suspected.

CBC Count

The complete blood cell (CBC) count with differential usually reveals moderate leukocytosis with atypical lymphocytes and lymphopenia, possibly secondary to the depletion of CD4 lymphocytes (90% of patients). An eosinophil count greater than 1000/mm3 may also be seen. Neutropenia (30% of patients) may occur and indicates a poor prognosis. A severely elevated total white blood cell (WBC) counts indicate infection. Mild anemia may be present, and thrombocytopenia is found in 15% of patients.

Chemistries and Other Laboratory Tests

Electrolytes values may be abnormal with severe skin and mucous membrane involvement due to fluid losses. These values are useful to guide volume and electrolyte replacement therapy.

Blood urea nitrogen (BUN) and creatinine tests are indicated to screen for renal involvement and dehydration in severe cases requiring hospitalization. Prerenal azotemia and elevated serum urea nitrogen levels may be found and indicate a poor prognosis.

Also in severe cases, the erythrocyte sedimentation (ESR) rate may be elevated, but this is a nonspecific finding. Mildly elevated liver transaminase levels may be found with hepatic involvement.

Immunofluorescence and PCR

Specific herpes simplex virus (HSV) antigens have been detected within keratinocytes by immunofluorescence study. The HSV DNA has been identified primarily within the keratinocytes by polymerase chain reaction (PCR) amplification.

Direct immunofluorescence staining and examination may also identify an alternative diagnosis (eg, pemphigoid, immunoglobulin A [IgA] linear dermatosis.

Biopsy and Histologic Features

Histopathologic examination of a cutaneous punch biopsy may be used to confirm the diagnosis of erythema multiforme (EM) and to rule out the differential diagnosis (see Differentials).A skin biopsy of the cutaneous lesions may also exclude the presence of other blistering disorders, such as in equivocal cases, particularly in absence of target lesions.

Erythema multiforme

Histologically, erythema multiforme is the prototypical vacuolar interface dermatitis showing a lymphocytic infiltrate along the dermoepidermal junction associated with hydropic changes and dyskeratosis of basal keratinocytes (see the following image). This vacuolar change represents individual or small groups of necrotic (apoptotic) keratinocytes. In addition, a characteristic sparse-to-moderate lymphocytic infiltrate is present around the superficial vascular plexuses.

Interface dermatitis with prominent dyskeratotic c Interface dermatitis with prominent dyskeratotic cells in epidermis.

As the lesions progress, partial-to-full-thickness epidermal necrosis, intraepidermal vesiculation, or subepidermal blisters may appear, owing to spongiosis and to the cellular damage of the basal layer of the epidermis. Occasionally, severe papillary edema is present. The dermal inflammatory infiltrate is characterized by high-density lichenoid infiltrate rich in T cells, composed of lymphocytes (CD4+ more abundant than CD8+ in the papillary dermis; in the epidermis, there is a predominance of CD8 T cells and macrophages) and macrophages, with a few neutrophils and occasional eosinophils (particularly in those cases associated with medications).

Erythema multiforme vs SJS/TEN and SSS

Histology and immunochemistry studies have shown that inflammatory infiltrates of erythema multiforme and Steven-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) are strikingly different in density and nature. Erythema multiforme has a high density of cell infiltrate rich in T-lymphocytes. By contrast, SJS/TEN is characterized by a cell-poor infiltrate of macrophages and dendrocytes with strong tumor necrosis factor (TNF)–alpha immunoreactivity. Immune complex deposition is variable and nonspecific. In severe cases, fibrinoid necrosis can occur in the stomach, spleen, trachea, and bronchi.

Histologic examination of skin biopsies in staphylococcal scalded skin syndrome (SSSS) reveals cleavage of cell layers within the epidermis.

 

Treatment

Approach Considerations

For all forms of erythema multiforme (EM), the most important treatment is usually symptomatic, including oral antihistamines, analgesics, local skin care, and soothing mouthwashes (eg, oral rinsing with warm saline or a solution of diphenhydramine, xylocaine, and kaopectate). Topical steroids may be considered. For more severe cases, meticulous wound care and use of Burrow or Domeboro solution dressings may be necessary.

The cause of the erythema multiforme should be identified, if possible. If a drug is suspected, it must be withdrawn as soon as possible. This includes all medications begun during the preceding 2 months. Discontinue all unnecessary medications.

Infections should be appropriately treated after cultures and/or serologic tests have been performed. The use of liquid antiseptics, such as 0.05% chlorhexidine, during bathing helps prevent superinfection. Topical treatment, including that for genital involvement, may be performed with a gauze dressing or a hydrocolloid.

Local supportive care for eye involvement is important and includes topical lubricants for dry eyes, sweeping of conjunctival fornices, and removal of fresh adhesions.

Suppression of herpes simplex virus (HSV) can prevent HSV-associated erythema multiforme, but antiviral treatment started after the eruption of erythema multiforme has no effect on the course of the erythema multiforme.

Prehospital and Emergency Department Care

Mild cases of erythema multiforme require only symptomatic treatment in the emergency department (ED), which may include analgesics or nonsteroidal inflammatory drugs (NSAIDs); cold compresses with saline or Burrow solution; topical steroids; and soothing oral treatments such as saline gargles, viscous lidocaine, and diphenhydramine elixir.

In the most severe cases of erythema multiforme (EM) major, prehospital personnel may need to treat respiratory complications and fluid imbalances aggressively, in the same manner as thermal burns. The following sections pertain to these rare severe cases.

Aggressive monitoring and replacement of fluids and electrolytes are of paramount importance.

Provide supportive respiratory care, including suctioning and postural drainage, as needed. Use analgesics as needed to control pain, which may be severe.

Administer empiric antibiotics if clinical evidence of secondary infection exists. Most authorities advise against routine use of prophylactic antibiotics.

Avoid systemic corticosteroids in minor cases. In severe cases, their use is controversial, because these agents do not improve prognosis and may increase risk of complications.

Hospitalization

Erythema multiforme (EM) major may require hospitalization for the treatment of complications and sequelae (eg, severe mucous membrane involvement is present or with impaired oral intake, dehydration, or secondary infection) and to manage the patient's fluid and electrolytes. The most severe cases should be managed in intensive care or burn units.

If the initial treating facility does not have facilities or experienced individuals to care for critically ill burn patients, the patient should be transferred to a regional tertiary care medical center by the most rapid means available.

Care in a surgical specialty burn unit may provide the greatest likelihood of survival. Areas of denuded skin should be managed like thermal burns, although debridement is best avoided while lesions are still progressing. Eroded areas may be bathed q1-2d with saline or Burrow's solution and dressed with nonadherent dressings.

Treat patients for herpes simplex virus (HSV) or M pneumoniae -related erythema multiforme. Intravenous (IV) antibiotics may be necessary to treat secondary infections. Implement barrier isolation to decrease risk of infection.

Immediately withdraw all potentially causative drugs. The healing process usually takes about 2 weeks, during which time proper skin care is essential. Practice aseptic handling and avoid adhesive materials. Use topical agents such as 0.5% silver nitrate solution or 0.05% chlorhexidine solution to cleanse the skin. Warm these solutions before application. Avoid silver sulfadiazine because of its causative association.

Once the patient has stabilized in the intensive care burn unit, the peak of disease progression has passed, and reepithelialization has begun, it may be appropriate to transfer the patient to a regular surgical ward. Reepithelialization usually takes 10-14 days.

After the acute period of illness has passed and the patient has survived, mucous membrane sequelae may require surgical intervention.

Fluid resuscitation and nutritional support

Several issues make nutritional support critical. A liquid diet and IV fluid therapy may be necessary.

Fluid and electrolytes may be lost through the disrupted skin barrier, and widespread, painful oral erosions may make feeding difficult. In such cases, pass a soft, flexible feeding tube into the stomach or small bowel, and institute appropriate feedings. Oral antacids may be helpful for discrete oral ulcers.

Profuse diarrhea may result from gastrointestinal involvement, making oral or enteral feeding difficult. Parenteral nutrition may be appropriate.

Increased energy expenditure, such as from increased core body temperature, must be recognized and treated appropriately. Nitrogen balance and other nutritional parameters are useful to estimate nutritional needs and to evaluate the efficacy of nutritional therapy.

Fluid and electrolyte resuscitation are approximately 66-75% of that required for a similarly sized burn wound. Administer warmed fluids through a peripheral intravenous angiocatheter at a site removed from the skin eruptions.

Avoid central venous access if at all possible in order to decrease the risk of line infection. Change all catheters, peripheral or central, at regular intervals.

Monitor the adequacy of fluid resuscitation with the use of a urinary bladder catheter. Minimum urine output for adults is 0.5 mL/kg/h; for children, it is 1 mL/kg/h.

Pulmonary support

Patients with tracheobronchial involvement may present with hyperventilation and mild hypoxemia. Careful monitoring and aggressive pulmonary support may lead to early detection and treatment of diffuse interstitial pneumonitis and thus prevent the development of acute respiratory distress syndrome (ARDS).

Other supportive care

Maintain thermoregulation by keeping the environmental temperature at 30-32°C, administering only warmed fluids, and using heating lamps or warming blankets.

The use of a pressure support surface, an air or gel mattress, or a specialty bed is recommended to prevent pressure sores. Use antacids, proton pump inhibitors, or histamine 2 blockers to prevent stress ulceration.

Administer subcutaneous heparin to prevent the development of deep venous thrombosis (DVT).

Consultations

Consultation with the following specialists may be necessary:

  • Dermatologist: For diagnosis and management and for performance of skin biopsies, if indicated

  • Internal medicine specialist or a pediatric specialist: For evaluation of the underlying causes of disorders and systemic sequelae

  • Ophthalmologist: For early consultation in the evaluation and management of ocular involvement; daily examinations for signs of ocular involvement; if necessary, disruption of synechiae can be accomplished by administration of wetting or antibiotic eyedrops

  • Burn or trauma surgeon: For familiarity with caring for critically ill patients with burn wounds who have open wounds

  • Infectious disease specialists: For evaluation of intercurrent infections and treatment recommendations

  • Respiratory therapist: For tracheobronchial involvement

  • Physical or occupational therapists

  • Psychologists, psychiatrists, or social workers may be helpful.

Monitoring and Prevention

The medical professional(s) who treated the patient if he or she was hospitalized should see the patient regularly and provide symptomatic relief, as needed. Such practitioners may include burn or trauma surgeons, ophthalmologists, nephrologists, infectious disease specialists, and gastroenterologists.

The affected skin should be protected from any pressure or shear forces. Otherwise, early institution of physical and occupational therapies is appropriate. To reduce the likelihood of developing hyperpigmentation, recommend the use of sunscreens for 1 year after the incident has resolved.

Once erythema multiforme (EM) due to a drug has been diagnosed, the patient should never be rechallenged with the same drug or any other drug of the same class or similar chemical structure. Chemically related compounds often share a common metabolic pathway that may be abnormal in the affected individual. Sulfonamide-containing ointments should also be avoided.

First-degree relatives of an affected patient have an increased risk of reactions to similar drugs.

Medical Care

Topical corticosteroids are useful for outpatient treatment of patients with limited disease. Controversy exists regarding the use of oral steroids in calming this reaction, but they may be helpful as a short 10-day course.

Prophylaxis for recurrence of herpes-associated erythema multiforme (HAEM) should be considered in patients with more than 5 attacks per year; oral acyclovir may be helpful in reducing recurrence (see Medications). Prophylaxis may be required for 6-12 months or longer. If the patient's condition is unresponsive, continuous therapy with valacyclovir has been reported to be effective.[27]

Tamoxifen may prevent premenstrual erythema multiforme.

Prophylactic antibiotics are not recommended because of the increased likelihood of selecting out resistant strains. However, evidence of infection should lead to prompt culturing and the selection of appropriate antimicrobial therapy based on culture and sensitivity results.

 

Medication

Medication Summary

Systemic corticosteroid therapy is controversial in erythema multiforme (EM), and some believe it may predispose to complications. If given, the course should be limited to 10 days to 2 weeks. Beneficial effects with hemodialysis, plasmapheresis, cyclosporin, immunoglobulin, levamisole, thalidomide, dapsone, apremilast,[28] adalimumab,[29] and cyclophosphamide have been documented in case reports.

Prophylaxis for recurrence of herpes-associated erythema multiforme (HAEM) should be considered in patients with more than 5 attacks per year. Low-dose acyclovir (200 mg qd to 400 mg bid) can be effective for recurrence of HAEM, even in subclinical herpes simplex virus (HSV) infection. In children, 10 mg/kg/d may be considered.[30, 31, 32] Prophylaxis may be required for 6-12 months or longer; if unresponsive, continuous therapy with valacyclovir (500 mg bid) has been reported to be effective.[27]

Alternative treatments for erythema multiforme include dapsone, antimalarials, azathioprine, cimetidine,[33] and thalidomide.

For ocular involvement, artificial wetting solutions, antibiotic solutions, or ointments may be helpful.

Prophylactic antibiotics are not recommended because of the increased likelihood of selecting out resistant strains. However, prompt culturing should be obtained with evidence of infection and then appropriate selection of antimicrobial therapy based on culture and sensitivity results. Some authors recommend routine alternate-day skin biopsy for culture to distinguish simple skin colonization from true infectious invasion and to guide antimicrobial therapy.

Antivirals

Class Summary

The goal in the use of antivirals is to shorten the clinical course, prevent complications, prevent development of latency and/or subsequent recurrences, decrease transmission, and eliminate established latency.

Acyclovir (Zovirax)

Acyclovir reduces the duration of symptomatic erythema multiforme lesions (EM). Patients on acyclovir experience less pain and faster resolution of cutaneous lesions.

This agent is indicated for patients who present within 48 hours of experiencing the rash.

Acyclovir demonstrates inhibitory activity directed against both herpes simplex virus type 1 (HSV-1) and HSV-2; infected cells selectively take it up.

Valacyclovir (Valtrex)

Valacyclovir is a prodrug that is rapidly converted to the active drug acyclovir. It produces greater serum concentrations of acyclovir with smaller oral dosing. Consider using this agent if lesions are unresponsive to acyclovir.

 

Questions & Answers

Overview

What is erythema multiforme (EM)?

What are the signs and symptoms of erythema multiforme (EM) minor?

What are the signs and symptoms of erythema multiforme (EM) major?

What is the consensus classification of erythema multiforme (EM) and Steven-Johnson syndrome?

What is the pathophysiology of erythema multiforme (EM)?

What evidence supports a cell-mediated immune reaction pathogenesis for erythema multiforme (EM)?

What is the role of HSV in the pathogenesis of erythema multiforme (EM)?

What is the role of drug hypersensitivity in the pathogenesis of erythema multiforme (EM)?

Which viral infections cause erythema multiforme (EM)?

What causes erythema multiforme (EM)?

What is the most common cause of erythema multiforme (EM) in children?

Which bacterial infections cause erythema multiforme (EM)?

Which fungal and parasitic infections cause erythema multiforme (EM)?

Which medications can cause erythema multiforme (EM)?

Which antibiotics can cause erythema multiforme (EM)?

Which antituberculoid agents can cause erythema multiforme (EM)?

Other than antibiotics and antituberculoids, which medications cause erythema multiforme (EM)?

What substances can cause erythema multiforme (EM) upon direct contract?

What are less common causes of erythema multiforme (EM)?

What is the incidence of erythema multiforme (EM) in the US and globally?

How does the incidence of erythema multiforme (EM) vary between males and females and among different age groups?

Which medical conditions increase the risk of developing erythema multiforme (EM)?

What is the prognosis of erythema multiforme (EM) minor?

What is the prognosis of erythema multiforme (EM) major?

What are poor prognostic factors for erythema multiforme (EM)?

What are the manifestations of continuous or persistent erythema multiforme (EM)?

What information about erythema multiforme (EM) should patients receive?

Presentation

What should be the focus of the history for suspected erythema multiforme (EM)?

What are the prodromal symptoms of erythema multiforme (EM) minor?

What are the prodromal symptoms of erythema multiforme (EM) major?

What are possible mucosal symptoms of erythema multiforme (EM) major?

What history is common in children with erythema multiforme (EM)?

What is the hallmark of erythema multiforme (EM)?

How are skin lesions characterized in erythema multiforme (EM)?

How are skin lesions distributed in erythema multiforme (EM)?

What are the characteristics of mucosal lesions in erythema multiforme (EM)?

What are nonspecific physical exam findings of erythema multiforme (EM)?

What causes dehydration in patients with erythema multiforme (EM)?

Which conditions complicate the course of erythema multiforme (EM)?

What are possible complications of erythema multiforme (EM) lesions?

What are ophthalmologic complications of erythema multiforme (EM)?

What are systemic complications of erythema multiforme (EM)?

DDX

What factors improve survival in erythema multiforme (EM)?

What measures should be taken if adverse drug reactions are suspected as a cause of erythema multiforme (EM)?

Which other conditions should be considered in the evaluation of suspected erythema multiforme (EM)?

What are the differential diagnoses for Erythema Multiforme?

Workup

What is the role of lab testing in the workup of erythema multiforme (EM)?

When are cultures indicated in the workup of erythema multiforme (EM)?

What is the role of imaging studies in the diagnosis of erythema multiforme (EM)?

Which complete blood count (CBC) results are characteristic of erythema multiforme (EM)?

What is the role of electrolyte values in the workup of erythema multiforme (EM)?

When are BUN and creatinine tests indicated in the workup of erythema multiforme (EM)?

What is the role of erythrocyte sedimentation (ESR) in the workup of erythema multiforme (EM)?

What is the role of immunofluorescence study and PCR amplification in the evaluation of erythema multiforme (EM)?

What is the role of histopathologic testing in the workup of erythema multiforme (EM)?

Which histologic findings are characteristic of erythema multiforme (EM)?

How are histology and immunochemistry used to differentiate erythema multiforme (EM) from Steven-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN)?

Treatment

What are the treatment options for erythema multiforme (EM)?

Why should all medications be discontinued during the treatment of erythema multiforme (EM)?

How are infections of erythema multiforme (EM) lesions treated?

What is the treatment for eye involvement in erythema multiforme (EM)?

What can prevent herpes simplex virus (HSV)-associated erythema multiforme (EM)?

How are mild cases of erythema multiforme (EM) treated?

What is the focus of treatment for severe cases of erythema multiforme (EM) major?

What does emergency care of erythema multiforme (EM) include?

When is hospitalization indicated in patients with erythema multiforme (EM)?

When is transfer indicated for patients with erythema multiforme (EM)?

Which treatment provides the greatest likelihood of survival in severe erythema multiforme (EM)?

What is the inpatient treatment for herpes simplex virus (HSV) or M pneumoniae-related erythema multiforme (EM)?

What is the duration of inpatient treatment for erythema multiforme (EM)?

When is fluid resuscitation and nutritional support indicated for the treatment of erythema multiforme (EM)?

How is fluid resuscitation and nutritional support administered in the treatment of erythema multiforme (EM)?

When is pulmonary support indicated in the treatment of erythema multiforme (EM)?

What inpatient supportive care should be provided in the treatment of erythema multiforme (EM)?

Which specialist consultations may be needed for diagnosis and management of erythema multiforme (EM)?

How should patients treated for erythema multiforme (EM) be monitored?

What is the treatment for erythema multiforme (EM) caused by medications?

When are topical corticosteroids indicated in the treatment of erythema multiforme (EM)?

When is prophylaxis for recurrence of herpes-associated erythema multiforme (HAEM) indicated?

How is premenstrual erythema multiforme (EM) prevented?

What is the role of antibiotics in the prevention and management of erythema multiforme (EM)?

Medications

What is the role of systemic corticosteroids in the treatment of erythema multiforme (EM)?

When should prophylaxis for recurrence of herpes-associated erythema multiforme (HAEM) be considered?

What are alternative medications for erythema multiforme (EM)?

What are the treatment options for ocular involvement in erythema multiforme (EM)?

How is antimicrobial therapy selected in erythema multiforme (EM)?

Which medications in the drug class Antivirals are used in the treatment of Erythema Multiforme?