Erythema Multiforme

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 various other triggers.^[1]  It has a wide spectrum of severity and occurs in both minor and major forms. 

EM 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 first image below). 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 EM may follow, with many affected individuals experiencing several recurrences per year.

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Target lesion of erythema multiforme.

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Raised atypical targets and arcuate lesions.

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

Erythema multiforme vs Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been considered severity variants of a single entity that has been divided into the following two broad categories: (1) EM, including both minor and major forms, and (2) SJS/TEN. Clinical descriptions are as follows:

• EM minor - Typical targets or raised edematous papules distributed acrally
• EM major - Typical targets or raised edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involving less than 10% of total body surface area (TBSA)
• SJS/TEN - Widespread blisters predominating on the trunk and face, presenting with erythematous or pruritic macules and one or more mucous membrane erosions; epidermal detachment involving less than 10% TBSA for SJS/TEN but 30% or more for TEN

More recent clinical data favor the view that EM and SJS, though sometimes confused with each other, are separate disorders.^[1]

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

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Pathophysiology

The pathophysiology of EM has not been fully elucidated, 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).

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 (for < 30 d) demonstrate a T-helper cell type 1 (Th1) cytokine response (interferon [IFN] gamma, tumor necrosis factor [TNF]-α, 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 three 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

HSV is a major cause of EM^[2] ; in fact, recent or recurrent herpes has been reported as the principal risk factor for EM. Herpes-associated EM (HAEM) appears to represent the result of a cell-mediated immune reaction associated with HSV antigen. 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 EM.^[3] In particular, HLA-DQ3 is specifically related to recurrent EM and may be a helpful marker for distinguishing HAEM from other cutaneous diseases.^[4]

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.

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Etiology

Many suspected etiologic factors have been reported to cause EM. Both EM and SJS may be induced by medications, but infectious agents are also considered to be a major cause of EM. Approximately 50% of cases are idiopathic, with no precipitating factor identified. Other reported risk factors include male sex and a previous history of EM; pregnancy may contribute to the development of EM 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 EM.

EM minor is regarded as being commonly triggered by HSV types 1 and 2, and HSV is the most common cause in young adults; in fact, many instances of idiopathic EM minor may be precipitated by subclinical HSV infection. Mycoplasmal infection is another common cause.

Bacterial

Bacterial infections that may trigger EM include the following:

• Borreliosis
• Catscratch disease
• Diphtheria
• Hemolytic streptococci
• Legionellosis
• Leprosy
• Neisseria meningitidis
• Mycobacterium avium complex
• Mycoplasma pneumoniae^{[5, 6]}
• Pneumococci
• Tuberculosis
• Proteus/Pseudomonas/Salmonella/Staphylococcus/Yersinia species
• Treponema pallidum^[7]
• Tularemia
• Vibrio parahaemolyticus
• Vincent disease
• Rickettsial infections

Chlamydial infectious causes include lymphogranuloma venereum and psittacosis.

Viral

Viral infections that may trigger EM include the following:

• Adenovirus
• Coxsackievirus B5
• Cytomegalovirus (CMV)
• Echovirus
• Enterovirus
• EBV
• Hepatitis A/B/C viruses (HAV/HBV/HCV)
• HSV
• Influenza^[8]
• Measles
• Mumps
• Paravaccinia
• Parvovirus B19
• Poliomyelitis
• Varicella-zoster virus (VZV)
• Variola

An association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been described.^[9]  It has also been suggested that EM may be a potential adverse consequence of COVID-19 vaccination.^[10]

Other virus-related causes include the virus-drug interactions CMV infection–terbinafine^[11] and EBV infection–amoxicillin.^[12]

Other

EM may also be triggered by fungal infections (eg, coccidioidomycosis, dermatophytosis, and histoplasmosis) and some parasitic infections (eg, Trichomonas species and Toxoplasma gondii).

Drugs

More than 50% of cases of EM major are related to medication use, but no test has conclusively established the link between a single case and a specific drug.

The most common pharmacologic triggers are the sulfa drugs (30% of cases). The second most commonly involved agents are the anticonvulsants, including the following:

• Barbiturates^[13]
• Carbamazepine^[13]
• Hydantoin
• Phenytoin^[13]
• Valproic acid

Causative antibiotics include the following:

• Penicillin
• Ampicillin
• Tetracyclines
• Amoxicillin
• Cefotaxime
• Cefaclor
• Cephalexin
• Ciprofloxacin^[14]
• Erythromycin
• Minocycline
• Sulfonamides
• Trimethoprim-sulfamethoxazole
• Vancomycin

Antituberculoid agents (eg, rifampin, isoniazid, thiacetazone, and pyrazinamide) are also known offenders. Antipyretic agents as triggers include analgesics (especially aspirin), as well as phenylbutazone, oxyphenbutazone, and phenazone.

Others agents that may cause EM include the following:

• Acarbose
• Albendazole
• Alendronate^[15]
• Allopurinol^[13]
• Arsenic
• Bromofluorene
• Quinine
• Cimetidine
• Clofibrate
• Corticosteroids
• Diclofenac
• Didanosine
• Dideoxycytidine
• Dihydrocodeine phosphate^[16]
• Diphosphonate
• Estrogen
• Etretinate
• Fluconazole
• Griseofulvin^[17]
• Gabapentin
• Granulocyte-macrophage colony-stimulating factor (GM-CSF)
• Hydralazine
• Indapamide
• Imiquimod^[18]
• Indinavir
• Lamotrigine^[13]
• Methazolamide
• Mefloquine
• Methotrexate
• Meprobamate
• Mercurials
• Minoxidil
• Nifedipine
• Nevirapine^[13]
• Nivolumab^{[19, 20]}
• Nystatin
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Phenolphthalein
• Piroxicam^[13]
• Pyritinol
• Progesterone
• Potassium iodide
• Secukinumab^[21]
• Sulindac
• Suramin
• Saquinavir
• Thiabendazole
• Thiouracil
• Terbinafine
• Theophylline
• Tramadol^[22]
• Vandetanib^[23]
• Verapamil

Contact exposure

Contactants that may induce an EM-like eruption include the following:

• Ammoniated mercury
• Budesonide
• Bufexamac
• Capsicum
• Chloromethylnaphthalene
• Desoximetasone
• Dinitrochlorobenzene (DNCB)
• Disperse blue 124
• Diphenylcyclopropenone
• Fire sponge (Tedania ignis)
• Herbal medicines (eg, Alpinia galanga)^[24]
• Isopropyl-p-phenylenediamine of rubber
• Nickel
• Nitrogen mustard
• Oxybenzone
• Phenylbutazone
• Poison ivy^[25]  
• Proflavin
• Resin
• Rosewood
• Triamcinolone acetonide

Other etiologic factors

The following have also been reported as causes of EM:

• Flavorings and preservatives (eg, benzoic acid and cinnamon^[26] )
• Immunologic disorders (eg, transient selective C4 deficiency of infancy,^[27] collagen diseases, vasculitides, sarcoidosis, non-Hodgkin lymphoma, leukemia, multiple myeloma, myeloid metaplasia, and polycythemia)
• Physical or mechanical factors (eg, tattooing, radiotherapy, cold, and sunlight)
• Foods (eg, salmon berries and margarine)
• Malignancy
• Hormonal factors

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Epidemiology

The exact incidence of EM in the United States is not defined; however, as many as 1% of dermatologic outpatient visits are for EM. Globally, the frequency of EM has been estimated to be in the range of 1.2-6 cases per million individuals per year.

Before the HIV epidemic among young males, EM showed a slight female predominance; however, it has since become more common in younger males (male-to-female ratio, 2-3:1), mainly seen in the second to fourth decades but sometimes also in children and adolescents (20%).^[28]  EM 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 EM:

• HIV infection
• Corticosteroid exposure
• Bone marrow transplant
• Systemic lupus erythematosus (SLE)
• Graft-versus-host disease (GVHD)
• Inflammatory bowel disease (IBD)

Individuals undergoing radiation therapy, chemotherapy, or neurosurgery for brain tumors are also at higher risk.

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Prognosis

Most cases of EM are self-limited. In EM minor, the lesions evolve over 1-2 weeks and ultimately subside within 2-3 weeks without scarring. However, recurrence of EM minor is common, developing in as many as one third of cases, and is mostly preceded by apparent or subclinical HSV infection.

EM major has a mortality of less than 5%, which is directly proportional to the TBSA of sloughed epithelium. It usually has a more protracted course than EM minor, and clearing may require 3-6 weeks. Skin lesions usually heal with hyperpigmentation, hypopigmentation, or both. Scarring is usually absent, except after secondary infection. Sepsis secondary to loss of the cutaneous barrier is the principal cause of death.

Advanced age, visceral involvement, increased serum urea nitrogen level, and previous bone marrow transplantation are poor prognostic factors. Surprisingly, although people with HIV infection have an increased incidence of EM (approaching one case per 1000 individuals per year), they do not appear to have a higher mortality.

Continuous and persistent erythema multiforme

Two additional rare clinical forms of EM have been reported: continuous EM and persistent EM. Continuous EM manifests as a prolonged course with overlapping attacks and may be associated with systemic administration of glucocorticoids. Persistent EM 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 IBD, occult renal carcinoma, persistent or reactivated EBV infection, and HSV infection.

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Patient Education

Patients with EM should be educated regarding appropriate symptomatic treatment and reassured that the condition is usually self-limited. In addition, patients should be advised regarding the significant risk of recurrence and the possible need for suppressing recurrent HSV infection with appropriate antiviral therapy. (See Monitoring and Prevention.)

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History

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

Prodromal symptoms are usually absent or mild in persons with EM 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 EM 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 EM minor (ie, they are usually symmetrical and extend from the face and torso to the trunk and proximal extremities).

Prominent mucosal involvement may also occur in EM 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 (GU) tract ulceration may also occur. Shortness of breath or difficulty in breathing may occur due to tracheobronchial epithelial involvement.

A localized form of EM has been reported at the site of marrow aspiration. About 50% of children with EM have a history of herpes labialis or genitalis. Although the onset of herpes usually precedes EM by 3-14 days, it may still be present at the onset of EM.

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Physical Examination

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 (see the image below).

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Target lesion of erythema multiforme.

Some lesions consist of only two concentric rings. Polycyclic or arcuate lesions may occur (see the image below). Some lesions appear at areas of previous trauma (Koebner phenomenon). Postinflammatory hyperpigmentation or hypopigmentation may occur. The Nikolsky sign is negative (ie, the top layers of the skin do not slip away from the lower layers when slightly rubbed).

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Raised atypical targets and arcuate lesions.

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 (SJS) is more severe and more extensive than that of EM major. Generalized lymphadenopathy often accompanies EM 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

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Complications

Most patients with 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. Vaginal and urethral erosions may cause urinary retention and phimosis. Hematocolpos is the result of genital lesions in teenage females. Severe scarring of the GU tract may cause vaginal and urethral stenosis.

Severe eye complications (eg, purulent conjunctivitis, anterior uveitis, panophthalmitis, scarring of the conjunctivae, and symblepharon) may occur in 20% of cases and 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, and visual impairment

Additional potential complications include the following:

• Patchwork appearance of the skin, with hypopigmented regions and possible hypertrophic scarring
• Pneumonia or acute respiratory distress syndrome (ARDS)
• Dehydration and electrolyte disturbances
• Possible GI hemorrhage, nephritis, and acute kidney injury (AKI)

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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.

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Laboratory Studies

The complete blood count (CBC) 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 higher than 1000/μL may also be seen. Neutropenia (30% of patients) may occur and indicates a poor prognosis. A severely elevated total white blood cell (WBC) count indicates infection. Mild anemia may be present, and thrombocytopenia is found in 15% of patients.

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

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

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

Specific herpes simplex virus (HSV) antigens have been detected within keratinocytes by means of immunofluorescence study. 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 or immunoglobulin A [IgA] linear dermatosis).

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Procedures

A cutaneous punch biopsy may be performed to allow histopathologic examination to confirm the diagnosis of EM and rule out alternative diagnoses (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 the absence of target lesions.

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Histologic Findings

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 image below). 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.

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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; CD8 T cells and macrophages predominant in the epidermis) and macrophages, with a few neutrophils and occasional eosinophils (particularly in those cases associated with medications).

Erythema multiforme vs SJS/TEN and SSSS

Histology and immunochemistry studies have shown that inflammatory infiltrates of EM and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are strikingly different in density and nature. EM 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)-α 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.

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Approach Considerations

Mild cases of erythema multiforme (EM) 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 (eg, saline gargles, viscous lidocaine, and diphenhydramine elixir).

In the severe cases of EM major, aggressive monitoring and replacement of fluids and electrolytes as necessary are of paramount importance. Supportive respiratory care, including suctioning and postural drainage, should be provided as necessary.

The cause of EM 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. All unnecessary medications should be discontinued.

Infections should be appropriately treated after cultures or serologic tests have been performed. The use of liquid antiseptics (eg, 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 EM, but antiviral treatment started after the eruption of EM has no effect on the course of EM.

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Medical Care

Analgesics should be administered as needed to control pain, which may be severe. Topical corticosteroids are useful for outpatient treatment of patients with limited disease. Systemic corticosteroid therapy is controversial in EM, and some believe it may predispose to complications. If given, the course should be limited to 10 days to 2 weeks.

Prophylaxis for recurrence of herpes-associated EM (HAEM) should be considered in patients with more than five attacks per year. Oral acyclovir in a dosage of 200 mg qd to 400 mg bid can be effective for recurrence of HAEM, even in subclinical herpes simplex virus (HSV) infection.^[30] In children, 10 mg/kg/day may be considered.^[31]  Prophylaxis may be required for 6-12 months or longer. If the patient's condition is unresponsive, continuous therapy with valacyclovir (500 mg bid) has been reported to be effective.^[32]  Famciclovir 250 mg bid has also been recommended.^[1]

Alternative treatments for erythema multiforme include dapsone, antimalarials, azathioprine, cimetidine,^[33] and thalidomide. Beneficial effects with hemodialysis, plasmapheresis, cyclosporin, immunoglobulin, levamisole, thalidomide, dapsone, apremilast,^[34]  adalimumab,^[35]  and cyclophosphamide have been documented in case reports.

Tamoxifen may prevent premenstrual erythema multiforme. For ocular involvement, artificial wetting solutions, antibiotic solutions, or ointments may be helpful.

Empiric antibiotics are indicated if clinical evidence of secondary infection exists. 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.

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Hospitalization

EM major may warrant hospitalization for the treatment of complications and sequelae (eg, in cases of severe mucous membrane involvement, 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 units (ICUs) 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 in much the same way as thermal burns, though debridement is best avoided while lesions are still progressing. Eroded areas may be bathed every day or every other day with saline or Burrow solution and dressed with nonadherent dressings.

HSV- or M pneumoniae–related EM should be treated as appropriate. Intravenous (IV) antibiotics may be necessary to treat secondary infections. Barrier isolation should be implemented to decrease the risk of infection.

All potentially causative drugs should be discontinued immediately.

During the healing process, which usually takes about 2 weeks, proper skin care is essential. Aseptic handling should be practiced and adhesive materials avoided. Topical agents such as 0.5% silver nitrate solution or 0.05% chlorhexidine solution should be used to cleanse the skin; they should be warmed before being applied. Silver sulfadiazine should not be used, because of its causative association with EM.

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

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

Supportive measures

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, a soft, flexible feeding tube should be passed into the stomach or small bowel and appropriate feedings initiated. Oral antacids may be helpful for discrete oral ulcers.

Profuse diarrhea may result from gastrointestinal (GI) involvement, making oral or enteral feeding difficult. Parenteral nutrition may be appropriate. Increased energy expenditure (eg, from increased core body temperature) must be recognized and treated appropriately. Nitrogen balance and other nutritional parameters are useful for estimating nutritional needs and evaluating the efficacy of nutritional therapy.

Fluid and electrolyte resuscitation are approximately 66-75% of that required for a similarly sized burn wound. Warmed fluids should be administered through a peripheral IV angiocatheter at a site removed from the skin eruptions. Central venous access should be avoided if at all possible in order to decrease the risk of line infection. All catheters, whether peripheral or central, should be changed at regular intervals.

The adequacy of fluid resuscitation should be monitored by using a urinary bladder catheter. Minimum urine output for adults is 0.5 mL/kg/hr; for children, it is 1 mL/kg/hr.

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 measures

Thermoregulation may be maintained by keeping the environmental temperature at 30-32°C, administering only warmed fluids, and making use of 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. Antacids, proton pump inhibitors (PPIs), or histamine-2 blockers may be given to prevent stress ulceration.

Ssubcutaneous heparin may be administered to prevent the development of deep venous thrombosis (DVT).

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Monitoring and Prevention

If the patient was hospitalized, the medical professional(s) who provided treatment during that time should see the patient regularly and provide symptomatic relief as needed. Such practitioners may include burn or trauma surgeons, ophthalmologists, nephrologists, infectious disease specialists, or 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, the patient should be advised to use sunscreens for 1 year after the incident has resolved.

Once 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.

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Consultations

Consultation with one or more of the following specialists may be necessary:

• Dermatologist - For diagnosis and management and for performance of skin biopsies, if indicated
• Internal medicine specialist or 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, administration of wetting or antibiotic eyedrops for disruption of synechiae 
• Burn or trauma surgeon - For expertise in caring for critically ill patients who have burn wounds or open wounds
• Infectious disease specialist - For evaluation of intercurrent infections and treatment recommendations
• Respiratory therapist - For tracheobronchial involvement
• Physical or occupational therapist
• Psychologist, psychiatrist, or social worker.

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Acyclovir (Zovirax)

• Dosing, Interactions, etc.

Clinical Context: 

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Famciclovir (Famvir)

• Dosing, Interactions, etc.

Clinical Context: 

• References

Valacyclovir (Valtrex)

• Dosing, Interactions, etc.

Clinical Context: 

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