A 14-year-old boy presents to the emergency department with a 1-day history of fever associated with lip swelling and peeling (Figure 185-1A). Within 48 hours he developed involvement of his ocular (Figure 185-1B) and urethral mucosa along with an erythematous papular rash on his trunk that spread to his extremities. In Figure 185-1C, target lesions can be seen on his back. He was diagnosed with Stevens-Johnson syndrome and admitted to the hospital.
Stevens-Johnson syndrome in a 14-year-old boy who received penicillin for pneumonia. A. Lips and mouth are involved. B. Eye involvement. C. Target lesions on his back. (Reproduced with permission from Dan Stulberg, MD.)
Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are skin disorders thought to be types of hypersensitivity reactions (undesirable reactions produced by a normal immune system in a presensitized host) that occur in response to medication, infection, or illness. Both SJS and TEN are severe cutaneous reactions thought to describe the same disorder, differing only in severity (TEN more severe); however, there is debate as to whether these three fall into a spectrum of disease that includes EM.
EM has also been called EM minor.
SJS has been called EM major in the past but is now thought to be a distinct entity different from all types of EM.
TEN is also known as Lyell syndrome.
The incidence of EM has been estimated to range from 1 in 1000 persons to 1 in 10,000 persons.1 The true incidence is unknown.1
SJS and TEN are rare severe cutaneous reactions often caused by drugs. Reports of incidence vary from 1.2 to 6 per 1 million for SJS and from 0.4 to 1.2 per 1 million for TEN.2-4
EM is rare in children under age 3 years and adults over age 50 years: 20% of cases occur in children and adolescents.5
With respect to EM, males are affected more often than females (3:2 to 2:1).5
ETIOLOGY AND PATHOPHYSIOLOGY
Numerous factors have been identified as causative agents for EM:
Herpes simplex virus (HSV) I and HSV II are the most common causative agents, having been implicated in at least 60% of cases (Figure 185-2).6,7 The virus has been found in circulating blood,8 as well as on skin biopsy of patients with EM minor.6
Bacterial causes are numerous and include cat-scratch disease, chlamydial infections, hemolytic streptococci, legionellosis, Neisseria meningitidis, Mycoplasma pneumoniae, pneumococci, and rickettsial infections.5
Other causes include foods and food preservatives, immunologic disorders, mechanical factors (e.g., tattooing), and malignancy.5 Some cases are thought to be related to medications (e.g., sulfa drugs), although no test reliably proves the link to a specific drug, and half of EM cases are considered idiopathic.5
Erythema multiforme in a 43-year-old woman that recurs every time she breaks out with genital herpes. A. Target lesions on hand. B. Target lesions on elbow. (Reproduced with permission from Richard P. Usatine, MD.)
For SJS and TEN, most cases are drug induced.
Drugs most commonly known to cause SJS and TEN are sulfonamide antibiotics, allopurinol, NSAIDs, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine.9
Mycoplasma pneumoniae has been identified as the most common infectious cause for SJS7; in 2013, an outbreak of 8 pediatric cases of SJS was reported at Children's Hospital Colorado associated with M. pneumoniae infection.10 Clinical presentation of cases of SJS following mycoplasma infection were different from non-associated SJS cases in having less extensive skin disease, an elevated erythrocyte sedimentation rate, and preceding respiratory symptoms.
Other less-common causative agents for EM, SJS, and TEN include:
Infectious agents such as Mycobacterium tuberculosis, group A streptococci, hepatitis B, Epstein-Barr virus, Francisella tularensis, Yersinia, enteroviruses, Histoplasma, and Coccidioides.1
Neoplastic processes, such as leukemia and lymphoma.1
Antibiotics, such as penicillin, isoniazid, tetracyclines, cephalosporins, and quinolones.
Anticonvulsants, such as phenobarbital and valproic acid.1,7
Other drugs including captopril, etoposide, aspirin, and allopurinol.
Immunizations such as bacillus Calmette-Guérin, diphtheria-tetanus toxoid, hepatitis B, measles-mumps-rubella, and poliomyelitis.6
Other agents or triggers including radiation therapy, sunlight, pregnancy, connective tissue disease, and menstruation.1
Although the pathogenesis of EM, SJS, and TEN remains unknown, recent studies show that it may be as a result of a host-specific cell-mediated immune response to an antigenic stimulus that activates cytotoxic T cells and results in damage to keratinocytes.6,9
Recent evidence shows individuals with certain human leukocyte antigen (HLA) alleles may be predisposed to developing SJS/TEN, and to SJS-associated ocular involvement, when taking certain drugs.2,11 In addition, IKZF1 has been identified as a susceptibility gene for cold medicine–induced SJS/TEN with severe mucosal involvement in Japanese, Korean, and Indian subjects.12
Certain diseases such as HIV/AIDS (Figure 185-3), malignancy, or autoimmune disease, also predispose individuals to SJS/TEN.2,13
Stevens-Johnson syndrome that evolved into toxic epidermal necrolysis in a human immunodeficiency virus–positive man with a CD4 of 6. He presented to the emergency department with fever and rash on face, eyes, and mouth. Chest X-ray suggested pneumonia, so he was started on azithromycin, ceftriaxone, and trimethoprim-sulfamethoxazole. He developed bullae on skin, and a skin biopsy confirmed toxic epidermal necrolysis, possibly secondary to one of the antibiotics. He was transferred to a burn unit and given intravenous gamma-globulin 1 g/kg for 3 days. The patient survived. A. Oral lesions. B. Eye and facial involvement. C. Trunk and upper extremities involved so that greater than 30% of the skin was affected. (Reproduced with permission from Robert T. Gilson, MD.)
In these conditions, there is a rapid onset of skin lesions. EM is a disease in which patients present with the following lesions:
Classic lesions begin as red macules and expand centrifugally to become target-like papules or plaques with an erythematous outer border and central clearing (iris or bull's-eye lesions) (Figures 185-4, 185-5, 185-6, 185-7). Target lesions, although characteristic, are not necessary to make the diagnosis. The center of the lesions should have some epidermal disruption, such as vesicles or erosions.
Lesions can coalesce and form larger lesions up to 2 cm in diameter with centers that can become dusky purple or necrotic.
Unlike urticarial lesions, the lesions of EM do not appear and fade; once they appear they remain fixed in place until healing occurs many days to weeks later.
Patients are usually asymptomatic, although a burning sensation or pruritus may be present.
Lesions typically resolve without any permanent sequelae within 2 weeks.
Recurrent outbreaks are often associated with HSV infection (see Figure 185-2).6,7
Erythema multiforme on the palm with target lesions that have a dusky red and white center. (Reproduced with permission from Richard P. Usatine, MD.)
Erythema multiforme with target lesions on the palms secondary to an outbreak of oral herpes. (Reproduced with permission from Richard P. Usatine, MD.)
Erythema multiforme with vesicles and blistering of the target lesions on the hand. (Reproduced with permission from Richard P. Usatine, MD.)
Erythema multiforme on the dorsum of the hand showing targets with small, eroded centers. There should be some epidermal erosion to diagnose erythema multiforme. (Reproduced with permission from Richard P. Usatine, MD.)
In both SJS and TEN, patients may have blisters that develop on dusky or purpuric macules. SJS is diagnosed when less than 10% of the body surface area is involved, SJS/TEN overlap when 10% to 30% is involved, and TEN when greater than 30% is involved.
Lesions may become more widespread and rapidly progress to form areas of central necrosis, bullae, and areas of denudation (see Figure 185-1).
Fever higher than 39°C (102.2°F) is often present.
In addition to skin involvement, there is involvement of at least 2 mucosal surfaces, such as the eyes, oral cavity, upper airway, esophagus, GI tract, or the anogenital mucosa (see Figures 185-1 and 185-3).
New lesions occur in crops and may take 4 to 6 weeks to heal.
Large areas of epidermal detachment occur (Figures 185-8, 185-9, 185-10).
Severe pain can occur from mucosal ulcerations, but skin tenderness is minimal.
Skin erosions lead to increased insensible blood and fluid losses, as well as an increased risk of bacterial superinfection and sepsis.
These patients are at high risk for ocular complications (e.g., conjunctivitis, lid-margin and conjunctival ulceration, corneal opacification) that may lead to blindness. Additional risks include bronchitis, pneumonitis, myocarditis, hepatitis, enterocolitis, polyarthritis, hematuria, and acute tubular necrosis.
Toxic epidermal necrolysis with desquamation of skin on the hand. (Reproduced with permission from Richard P. Usatine, MD.)
Toxic epidermal necrolysis with large areas of desquamation on the leg. (Reproduced with permission from Richard P. Usatine, MD.)
Toxic epidermal necrolysis secondary to amoxicillin. A. Face with large areas of desquamation and loss of pigmentation. B. Skin detaching from leg in large sheets and bullae. (Reproduced with permission from Richard P. Usatine, MD.)
The distribution of the rash in EM can be widespread.
The distal extremities, including the palms and soles, are most commonly involved.
Extensor surfaces are favored.
Oral lesions may be present, especially in SJS (see Figures 185-1 and 185-3).
Severe lesions with exfoliation and extensive mucosal lesions occur in SJS and TEN (see Figures 185-8, 185-9, 185-10).
There are no consistent laboratory findings with these conditions. The diagnosis is usually made based on clinical findings.
Routine blood work may show leukocytosis, elevated liver transaminases, and an elevated erythrocyte sedimentation rate.
In TEN, leukopenia may occur.
A cutaneous punch biopsy can be performed to confirm the diagnosis or to rule out other diseases.
Histologic findings of EM will show a lymphocytic infiltrate at the dermal–epidermal junction. There is a characteristic vacuolization of the epidermal cells and necrotic keratinocytes within the epidermis.1
Bullous pemphigoid—Can be either subacute or acute with tense widespread blisters that can occur after persistent urticaria; mucosal involvement is rare. Significant pruritus can be present. As with EM, SJS, and TEN, bullous pemphigoid can occur after certain exposures such as UV radiation or certain drugs (Chapter 192, Bullous Pemphigoid).
Urticaria—A skin reaction characterized by red wheals that are usually pruritic. Unlike EM, individual lesions rarely last more than 24 hours (Chapter 156, Urticaria and Angioedema).
Kawasaki disease—Fever persists at least 5 days and there must be at least four of the five following features to diagnose complete (or classic) Kawasaki disease.14
Changes in extremities—Acute: erythema and edema of the hands and feet; or subacute: periungual desquamation (peeling of fingers and toes).
Rash: maculopapular, diffuse erythroderma, or erythema multiforme–like.
Bilateral bulbar conjunctival injection without exudate.
Changes in lips and oral cavity—Erythema, lips cracking, strawberry tongue (see Chapter 36, Scarlet Fever and Strawberry Tongue), and/or erythema of the oral and pharyngeal mucosae.
Cervical lymphadenopathy (>1.5 cm diameter), usually unilateral.
Cutaneous vasculitis—Also caused by a hypersensitivity reaction, lesions are palpable papules or purpura. Blisters, hives, and necrotic ulcers can occur on the skin. Lesions are usually located on the legs, trunk, and buttocks (see Chapter 187, Vasculitis).
Erythema annulare centrifugum—A hypersensitivity reaction caused by a variety of agents. Lesions look similar with erythematous papules of a few to several centimeters that enlarge and clear centrally and may be vesicular. Lesions tend to appear on the legs and thighs, but may occur on upper extremities, trunk, and face; palms and soles are spared (see Chapter 215, Erythema Annulare Centrifugum).
Staphylococcal scalded skin syndrome—Rash may also follow a prodrome of malaise and fever but is macular, brightly erythematous, and initially involves the face, neck, axilla, and groin. Skin is markedly tender. Like SJS and TEN, large areas of the epidermis peel away. Unlike TEN, the site of the staphylococcal infection is usually extracutaneous (e.g., otitis media, pharyngitis) and not the skin lesions themselves (Chapter 122, Impetigo).
Treat the infectious cause if known (e.g., herpes or mycoplasma).
Withdraw the suspected drug (new medication within 2 months of onset).5
Treatment is mainly supportive. Symptomatic relief may be provided with topical emollients and eye lubricants, mouthwashes (e.g., xylocaine), systemic oral antihistamines, and acetaminophen. These do not, however, alter the course of the illness.
The use of corticosteroids has not been well studied but is thought to prolong the course or increase the frequency of recurrences in HSV-associated cases.7
Prophylactic acyclovir has been used to control recurrent HSV-associated EM with some success.7
Treatment is mainly supportive and may require intensive care or placement in a burn unit. Early diagnosis is imperative so that triggering agents can be discontinued.
Oral lesions can be managed with mouthwashes and glycerin swabs.
Skin lesions should be cleansed with saline or Burow solution (aluminum acetate in water).
IV fluids should be given to replace insensible losses.
Daily examinations for secondary infections should occur, and systemic antibiotics should be started as needed.
Consultation with an ophthalmologist is important because of the high risk of ocular sequelae.
Pharmacologic therapy is widely debated in the literature. Intravenous immunoglobulin (IVIG) at doses of 2 to 3 g/kg may help shorten the course and improve outcome if started early during the disease.15
Systemic corticosteroids have been the mainstay of treatment for SJS/TEN. Authors of a meta-analysis found that glucocorticosteroids and cyclosporine were the most promising therapies, although steroids were of statistically significant survival benefit in only one analysis, and cyclosporine was of significant benefit only in a feasible analysis of individual patient data.16 In this review, IVIGs were not found to be helpful.
Agents that have been tried with limited success include thalidomide, tumor necrosis factor α inhibitors, cyclophosphamide, granulocyte colony-stimulating factors, and plasmapheresis.16
A tear-exchangeable limbal contact lens was found to improve vision and quality of life in patients with ocular sequelae.17
Screening populations known to carry HLA alleles prior to starting medications with higher risks for SJS/TEN has been suggested by some researchers2 but, in one study, was not found to be cost effective.18
EM usually resolves spontaneously within 1 to 2 weeks.
Recurrence of EM is common, especially when preceded by HSV infection.
Prognosis is poorer for patients with SJS and TEN, especially if they are older, have a large percentage of body surface area involved, or have intestinal or pulmonary involvement.
About one quarter of patients with TEN require ventilator assistance; in one study, the need for a ventilator was associated with a higher percentage of epidermal-detached body surface area (especially greater than 30%), serum bicarbonates less than 20 mmol/L, serum urea greater than 10 mmol/L, WBCs more than 12,000/mm3, and hemoglobin less than 8 g/dL, in addition to more extensive pulmonary infiltrates.19
Mortality for SJS/TEN can be predicted based on the severity of illness score for TEN (SCORTEN).20 One point is given for each of the following: serum blood urea nitrogen greater than 10 mmol/L; serum bicarbonate less than 20 mmol/L; serum glucose greater than 14 mmol/L; age older than 40 years; malignancy present; heart rate greater than 120 beats per minute; percentage of body surface area involved greater than 10%. Scores of 0 to 1 are associated with a mortality rate of 3.2%, whereas scores of 5 or higher are associated with a mortality rate of 90%.
For patients with SJS, mortality rates have been reported of 5% to 10% and up to 30% for TEN.9,21
For uncomplicated cases, no specific follow-up is needed.
For patients with EM major and any of the complications listed above, follow-up should be arranged with the appropriate specialist.
If an offending drug is found to be the cause, it should be discontinued immediately.
Patients with HSV-associated EM should be made aware of the risk of recurrence.
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