Chapter 249: Generalized Skin Disorders

This chapter describes selected serious generalized skin disorders in adults and discusses their dermatologic diagnosis and treatment. Covered are erythema multiforme, toxic epidermal necrolysis, exfoliative erythroderma, the toxic infectious erythemas, disseminated viral infections, Rocky Mountain spotted fever, disseminated gonococcal infection, purpura fulminans, and pemphigus vulgaris. Staphylococcal scalded skin syndrome and meningococcemia are discussed in the pediatric section, in chapter 141, "Rashes in Infants and Children." Staphylococcal and streptococcal toxic shock syndrome are also discussed in chapter 150, "Toxic Shock Syndromes." Disseminated viral infections are discussed in chapter 153, "Serious Viral Infections" and in chapter 141.

The disorders erythema multiforme, toxic epidermal necrolysis, exfoliative erythroderma, staphylococcal and streptococcal toxic shock syndrome, and staphylococcal scalded skin syndrome share some features in common. Table 249–1 can help in differentiating these disorders.

Erythema multiforme (EM) is an acute inflammatory skin disease (Figure 249–1) with a broad range of severity, from a minimal, nuisance-level event to a severe multi-system illness. It is divided into two distinct sub-types, considering the extent of involvement, presence of epidermal detachment, and the development of mucous membranes lesions. Erythema multiforme minor, the less severe form of the illness, is a localized papular eruption of the skin, with an acral distribution and involving target lesions and/or raised, edematous papules. Erythema multiforme major is the more severe form of EM with multi-system involvement and widespread vesiculobullous lesions and erosions of the mucous membranes; specifically, EM major includes involvement of one or more mucous membrane areas and epidermal detachment less than 10% of total body surface area.

Some authorities include Stevens-Johnson syndrome (SJS) as a severe form of EM major while others consider it a less severe form of toxic epidermal necrolysis. Perhaps the most appropriate classification approach for the emergency physician is as follows: Stevens-Johnson syndrome noted with less than 10% of the body surface area with epidermal detachment; the “overlap” presentation of Stevens-Johnson syndrome and toxic epidermal necrolysis noted with 10% to 30% epidermal detachment; and toxic epidermal necrolysis noted with greater than 30% epidermal detachment.¹ In either consideration, SJS is a serious dermatologic illness with significant, widespread skin involvement, more extensive epidermal detachment, and mucous membrane lesions. This taxonomic controversy has no meaning for the emergency physician; what is important for the emergency physician is the recognition of a significant, potentially life-threatening, multi-system dermatologic condition.

Morbidity and mortality rise with the amount of epidermal detachment.² The highest incidence is in young adults (age range, 20 to 40 years), and erythema multiforme occurs commonly in the spring and fall. Common precipitating factors are infection, especially with Mycoplasma and herpes simplex virus; drugs, especially antibiotics and anticonvulsants; and malignancies. However, the cause is often unknown.³ Most likely, erythema multiforme is the result of a hypersensitivity reaction, with immunoglobulin and complement components demonstrated in the cutaneous microvasculature on immunofluorescent studies of skin biopsy specimens, circulating immune complexes found in the serum, and mononuclear cell infiltrate noted on histologic examination.^3,4

Symptoms include malaise, fever, myalgias, and arthralgias. Diffuse pruritus or a generalized burning sensation can occur before the skin lesions develop. The morphologic configuration of the lesions is variable, hence the descriptor multiforme. Maculopapular (Figure 249–2) and target, or iris (Figure 249–3), lesions are the most characteristic. Erythematous papules appear symmetrically on the dorsum of the hands and feet and on the extensor surfaces of the extremities. The maculopapule evolves into the classic target lesion during the next 24 to 48 hours. As the maculopapule enlarges, the central area becomes cyanotic, occasionally accompanied by central purpura or a vesicle. Urticarial plaques also may occur with or without the iris lesion in a similar distribution. Vesiculobullous lesions, which may be pruritic and painful, develop within preexisting maculopapules or plaques, usually on the extensor surface of the arms and legs and less frequently on the trunk. Vesiculobullous lesions are found most often on mucosal surfaces, including the mouth, eyes, vagina, urethra, and anus; they may also be seen on the trunk. Ocular involvement rarely occurs in erythema multiforme minor, whereas ophthalmologic lesions are seen in almost 70% of patients with Stevens-Johnson syndrome.⁵ The various lesions (Table 249–2) develop in successive crops during a 2- to 4-week period and heal over 5 to 7 days. The differential diagnosis of erythema multiforme includes herpetic (herpes simplex virus and varicella-zoster virus) infection, vasculitis, toxic epidermal necrolysis, various primary blistering disorders (pemphigus and pemphigoid), urticaria, Kawasaki's disease, and the toxic and infectious erythemas.

Recurrence may be noted on repeat exposure to the etiologic agent, a special concern in cases associated with herpes simplex virus infection or medication use.⁶ The rate of erythema multiforme recurrence is very high in children with herpes simplex virus infection. For example, 75% of children with a history of herpes simplex virus–related erythema multiforme developed erythema multiforme recurrence after herpes simplex virus reactivation.⁶ Fluid and electrolyte disorders and secondary infection from cutaneous sites are the most frequent complications.

Systemic steroids are commonly used for localized disease and provide symptomatic relief but are of unproven benefit in influencing the duration and outcome of erythema multiforme.⁷ Many authorities recommend a short, intensive steroid course of prednisone, 60 to 80 milligrams PO once a day, particularly in drug-related cases, with abrupt cessation in 3 to 5 days if no favorable response is noted. Systemic analgesic agents and antihistamines provide symptomatic relief. Stomatitis is treated with diphenhydramine and viscous lidocaine mouth rinses. Do not swallow oral viscous lidocaine because it causes neurotoxicity. Treat blisters with cool compresses of Burow solution (5% aluminum acetate). Ocular involvement should be monitored by an ophthalmologist. Unfortunately, burst steroid therapy does not reduce the chance of development or significance of existing ocular lesions.

Disposition is admission to an intensive care or burn unit. Acyclovir may reduce recurrence of herpes simplex virus infection and therefore lessen the potential for another bout of erythema multiforme; prolonged prophylactic acyclovir therapy may reduce the chance of recurrent erythema multiforme related to herpes simplex virus.⁶

Toxic epidermal necrolysis (Figure 249–4) is an explosive dermatosis characterized by tender erythema, bullae formation, mucous membrane lesions, and subsequent exfoliation. Patients are systemically ill. Many authorities consider Stevens-Johnson syndrome to be a less severe form of toxic epidermal necrolysis while others consider SJS to be a more severe form of EM major; in either case, SJS and toxic epidermal necrolysis are severe dermatologic illnesses, whether they are distinct entities or two forms of the same syndrome.⁴

Toxic epidermal necrolysis is found in all age groups without predilection for either sex. The syndrome has multiple causes, with medications being the most common cause.^3,4,8 Sulfa and penicillin antibiotics, anticonvulsants, and oxicam nonsteroidal anti-inflammatory drugs are the most frequent drug triggers for toxic epidermal necrolysis.^9,10 Other causes include malignancy and human immunodeficiency virus infection.⁸ In many cases, a cause is not found. The pathogenesis is poorly understood and may be partly immunologic and partly genetic.¹¹

Symptoms include a 1- to 2-week prodrome of malaise, anorexia, arthralgias, fever, or symptoms of upper respiratory tract infection. Skin tenderness, pruritus, tingling, or burning may be found at this time. Skin signs (Table 249–2) begin with a warm erythema, initially involving only the eyes, nose, mouth, and genitalia, but later becoming generalized. The erythematous areas become tender and confluent within hours. Flaccid, ill-defined bullae then appear within the areas of erythema. Lateral pressure with a finger on normal skin adjacent to a bullous lesion dislodges the epidermis, producing denuded dermis and demonstrating Nikolsky sign. Nikolsky sign is slippage of the epidermis from the dermis when slight rubbing pressure is applied to the skin. The bullae form along the cleavage plane between the epidermis and the dermis. The epidermis is then shed in large sheets, which leaves raw, denuded areas of exposed dermis. The average time until onset after exposure to the inciting agent is 2 weeks. Cutaneous extension follows an unpredictable time course, ranging from 24 hours to 15 days, with some severe cases demonstrating rapid, extensive involvement within 24 hours.

Perilabial blistering and erosive lesions are disfiguring and often impair adequate oral intake, contributing to hypovolemia. Ocular complications include purulent conjunctivitis, painful erosions, and potential blindness. Anogenital lesions are common. Additional mucous membrane involvement includes the GI, urinary, and respiratory tracts. The two major complications and leading causes of death in toxic epidermal necrolysis are infection and hypovolemia with electrolyte disorders. A broad range of pathogens is usually found, with staphylococcal and pseudomonal species predominating. The mortality rate has been reported as being between 25% and 35%.^8,11 The clinical characteristics associated with poor prognosis include advanced age, extensive disease, idiopathic nature, use of multiple medications, steroid therapy, azotemia, hyperglycemia, leukopenia, and thrombocytopenia.⁹ The differential diagnosis of toxic epidermal necrolysis is presented in Table 249–1 and also includes primary blistering disorders (pemphigus and pemphigoid) and Kawasaki's disease in children.

Management of toxic epidermal necrolysis requires hospitalization in an intensive care or burn unit.⁹ Immediate concerns center on the airway, because sloughing of airway and respiratory epithelium can occur. Hypovolemia and electrolyte abnormalities should be corrected. Prompt, aggressive antibiotic administration is necessary in suspected or documented infection; initial prophylactic antibiotics are not recommended by most. Solicit the advice of the burn center regarding any topical dressings that are applied before transfer.

Pemphigus vulgaris is a generalized, mucocutaneous, autoimmune, blistering eruption with a grave prognosis characterized by intraepidermal acantholytic blistering (Table 249–3). The primary lesions of pemphigus vulgaris are vesicles or bullae (Figure 249–5) that vary in diameter from <1 cm to several centimeters. They commonly first affect the head, trunk, and mucous membranes. The blisters are usually clear and tense, originating from normal skin or atop an erythematous or urticarial plaque. Within 2 to 3 days, the bullae become turbid and flaccid. Rupture soon follows, producing painful, denuded areas. These erosions are slow to heal and prone to secondary infection. The Nikolsky sign is present in pemphigus vulgaris. Mucous membranes are affected in most patients, and in some, the mucous membranes are the primary sites of involvement. Blisters on mucous membranes are more transitory than blisters on the skin in that they are more vulnerable to rupture; this is particularly true in the mouth, where ragged ulcerative lesions readily develop after inadvertent biting of the tissues.

Limited oral intake and accelerated protein, fluid, and electrolyte losses through the involved skin can rapidly lead to hypovolemia and electrolyte disturbances. Admission and aggressive fluid and electrolyte resuscitation, as well as treatment with corticosteroids and immunosuppressive agents, are needed to prevent mortality. Plasmapheresis and IV immunoglobulins may also be needed.

Exfoliative dermatitis is a condition in which most or all of the skin surface is involved with a scaly erythematous dermatitis. It is a cutaneous reaction in response to a drug or a chemical agent or to an underlying systemic or cutaneous disease, Most patients are >40 years old. The cause is unknown.

Exfoliative dermatitis can have an abrupt onset, particularly when related to a drug, contact allergen, or malignancy; exacerbations related to an underlying cutaneous disorder usually evolve more slowly. Exfoliative dermatitis tends to be a chronic condition, with a mean duration of 5 years, when related to a chronic illness; the course is often shorter after suppression of the underlying dermatosis, discontinuation of causative drugs, or avoidance of allergen. Idiopathic and chronic disease–related exfoliative dermatitis can continue for ≥20 years; death is rare.

Generalized erythema and warmth are noted, but skin tenderness is usually lacking. Erythema is accompanied by scaling or flaking, and the patient often complains of pruritus and skin tightness (Figure 249–6). The process generally begins on the face and upper trunk with progression to other skin surfaces. The patient usually has a low-grade fever. Excessive heat loss and hypothermia can complicate exfoliative dermatitis. Widespread cutaneous vasodilation may result in high-output congestive heart failure. The disruption of the epidermis results in increased transepidermal water loss, and continued exfoliation can result in significant protein loss and negative nitrogen balance. Chronic inflammatory exfoliation produces many changes, such as dystrophic nails, thinning scalp and body hair, and patchy or diffuse pigmentation changes.

The differential diagnosis of exfoliative dermatitis in adults is found in Table 249–1. Patients generally require admission. Correct hypothermia and hypovolemia. Obtain dermatology consultation before giving systemic corticosteroids.

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug reaction that usually develops within 8 weeks of initiation of drug therapy. Aromatic anticonvulsants (such as phenytoin and phenobarbital), allopurinol, and sulfa medications are the most common culprits; however, other causes include nonsteroidal anti-inflammatory drugs, antiretroviral medications, angiotensin-converting enzyme inhibitors, calcium channel blockers, and other antibiotics.¹²

It is believed that there is a genetic predisposition if exposed to the appropriate medication.¹² Because of the potential genetic risk, DRESS syndrome should be discussed with the family members of any patient in whom it is diagnosed.

DRESS syndrome is defined by fever, rash, and internal organ involvement, with the liver, kidneys, and hematologic system being most commonly affected.¹² Rash and fever are typically the first signs of the syndrome, and they may have associated lymphadenopathy (Figure 249–7). The rash itself can take multiple forms, ranging from an erythematous scaly rash similar to that of exfoliative dermatitis, to a blistering/bullous rash similar to that of Stevens-Johnson syndrome, with varying degrees of severity. Abnormal laboratory findings include eosinophilia, which occurs in about 30% of DRESS syndrome patients,¹³ and hepatic and renal dysfunction. Because of the variety of clinical presentations, early diagnosis of DRESS syndrome is difficult and requires a high level of clinical suspicion. The current standard of care involves immediate stoppage of the suspected culprit medication, administration of systemic steroids in severe cases (those with evidence of hepatitis, pneumonitis, or extensive exfoliative dermatitis), supportive care including antipyretic and antipruritic medications, and hospital admission.^13,14

MENINGOCOCCEMIA

Meningococcemia is a potentially fatal infectious illness caused by the gram-negative diplococcus Neisseria meningitidis. Meningococcal disease presents across a wide clinical spectrum in the acute and chronic forms. The acute entities include pharyngitis, meningitis, and bacteremia. Meningococci are present in mucosal samples from approximately 5% to 10% of the general population (the carrier state).^15,16 In high-risk populations, such as military recruits, the organism may be found in almost half of people without evidence of active disease.¹⁷

The illness usually strikes patients <20 years of age, with the vast majority of cases occurring in children and infants <5 years old. A rash is frequently noted on presentation and is an invaluable clue to the correct diagnosis early in the disease course. The dermatologic manifestations include petechiae, urticaria, hemorrhagic vesicles, macules, and/or maculopapules (Figure 249–8). The classic petechial lesions are found on the extremities and trunk but also are noted on the palms, soles, head, and mucous membranes. The petechiae evolve into palpable purpura with gray necrotic centers, a pathognomic finding for meningococcal infection. The skin findings result from the organism's invasion and destruction of the endothelium. Histopathologic analysis shows an infectious vasculitis. For further discussion, see chapters 141, "Rashes in Infants and Children," and 117, "Meningitis in Infants and Children."

PURPURA FULMINANS

Purpura fulminans is a rare vascular disorder characterized by fever, shock, multiorgan failure, and the rapid development of hemorrhagic skin necrosis. It is associated with dermal vascular thrombosis, vascular collapse, and disseminated intravascular coagulation. Purpura fulminans can result from hereditary or acquired protein C deficiency, activated protein C resistance, or protein S deficiency. It may also result from any condition that causes disseminated intravascular coagulation.

Purpura fulminans presents with the dermatologic triad of widespread ecchymoses, hemorrhagic bullae (Figure 249–9), and epidermal necrosis. Cyanosis with initial ecchymoses and ultimate necrosis of the tip of the nose, ears, and genitalia frequently occur; in general, distal tissue areas with end circulation are affected. Large confluent ecchymoses can develop, often on the extremities, from distal to proximal, and on the perineum, buttocks, and abdomen. The extremities are often involved symmetrically. Treatment is directed at the underlying cause.