Exfoliative Erythroderma Syndrome (EES) ICD-9: 695.9
EES is a serious, at times life-threatening, reaction pattern of the skin characterized by a uniform redness, infiltration, and scaling involving practically the entire skin.
It is associated with fever, malaise, shivers, and generalized lymphadenopathy.
Two stages, acute and chronic, merge one into the other. In the acute and subacute phases, there is rapid onset of generalized vivid red erythema and fine branny scales; the patient feels hot and cold, shivers, and has fever. In chronic EES, the skin thickens, and scaling continues and becomes lamellar.
There may be loss of scalp and body hair, and the nails become thickened and separated from the nail bed (onycholysis).
There may be hyperpigmentation or patchy loss of pigment in patients whose normal skin color is brown or black.
The most frequent preexisting skin disorders are (in order of frequency) psoriasis, atopic dermatitis, adverse cutaneous drug reaction, lymphoma, allergic contact dermatitis, and pityriasis rubra pilaris.
[See “Sézary Syndrome” in Section 21 for a special consideration of this form of EES.]
Age of Onset. Usually >50 years; in children, EES usually results from atopic dermatitis.
Sex. Males > females.
Some 50% of patients have history of preexisting dermatosis. Most frequent are psoriasis, atopic dermatitis, adverse cutaneous drug reactions, cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis, and pityriasis rubra pilaris (Table 8-1). Drugs most commonly implicated in EES are shown in Table 8-2. In 20% of patients, it is not possible to identify the cause.
TABLE 8-1 ETIOLOGY OF EXFOLIATIVE DERMATITIS IN ADULTS
TABLE 8-2 DRUGS THAT CAUSE EXFOLIATIVE DERMATITIS
The metabolic response to EES may be profound. Large amounts of warm blood are present in the skin due to the dilatation of capillaries, resulting in considerable heat dissipation. Also, there may be high-output cardiac failure; the loss of scales (and thus proteins) through exfoliation can be considerable, up to 9 g/m2 of body surface per day.
Depending on the etiology, the acute phase may develop rapidly, usually in a drug reaction, or psoriasis. At this early acute stage, it is still possible to identify the preexisting dermatosis. There is fever, pruritus, fatigue, weakness, anorexia, weight loss, malaise, feeling cold, and shivers.
Appearance of Patient. Frightened, red, “toxic,” may be malodorous.
Skin lesions. Skin is red, thickened, scaly. Dermatitis is uniform involving the entire body surface (Figs. 8-1 to 8-3), except for pityriasis rubra pilaris, where EES spares sharply defined areas of normal skin (see Fig. 3-17). Thickening leads to exaggerated skin folds (Figs. 8-2 and 8-3); scaling may be fine and branny and may be barely perceptible (Fig. 8-2) or large, up to 0.5 cm, and lamellar (Fig. 8-1).
Figure 8-1. Exfoliative dermatitis: psoriasis There is universal erythema, thickening of the skin, and heavy scaling. This patient had psoriasis as suggested by the large silvery white scales and the scalp and nail involvement not seen in this illustration. The patient had fatigue, weakness, malaise, and was shivering. It is quite obvious that such massive scaling can lead to protein loss and the maximal dilatation of skin capillaries to considerable heat dissipation and high-output cardiac failure.
Figure 8-2. Exfoliative dermatitis: drug induced This is generalized erythroderma with thickening of skin resulting in increased skin folds, universal redness, a fine brawny scaling. This patient had developed erythroderma following the injection of gold salts for rheumatoid arthritis.
Figure 8-3. Exfoliative dermatitis: cutaneous T-cell lymphoma There is universal erythema, thickening, and scaling. Note that in contrast to erythroderma shown in Figs. 8-1 and 8-2, the degree of erythema and thickness is not uniform and the redness has a brownish hue. In addition, this elderly patient had hair loss, massive involvement of palms and soles with diffuse hyperkeratoses, cracks, and fissures. Generalized lymphadenopathy was also present.
Palms and Soles. Usually involved, with massive hyperkeratosis and deep fissures in pity-riasis rubra pilaris, Sézary syndrome, and psoriasis.
Hair. Telogen effluvium, even alopecia, except for EES arising in eczema or psoriasis.
Nails. Thickening of nail plates, onycholysis, shedding of nails.
Pigmentation. In chronic EES, there may be hyperpigmentation or patchy loss of pigment in patients whose normal skin is brown or black.
Lymph nodes generalized, rubbery, and usually small; enlarged in Sézary syndrome. Edema of lower legs and ankles.
Chemistry. Low serum albumin and increase in gammaglobulins; electrolyte imbalance; acute-phase proteins increased.
Bacterial Culture. Skin: rule out secondary Staphylococcus aureus infection. Blood: rule out sepsis.
Dermatopathology. Depends on type of underlying disease. In all there is parakeratosis, inter- and intracellular edema, acanthosis with elongation of the rete ridges, and exocytosis of cells, edema of the dermis, and an inflammatory infiltrate.
Imaging. CT scans or MRI should be used to find evidence of lymphoma.
Lymph Node Biopsy. When there is suspicion of lymphoma.
The history of the preexisting dermatosis may be the only clue. Also, pathognomonic signs and symptoms of the preexisting dermatosis may help, e.g., dusky-red color in psoriasis (Fig. 8-1) and yellowish red in pityriasis rubra pilaris (see Fig. 3-17); typical nail changes of psoriasis; lichenification, erosions, and excoriations in atopic dermatitis and eczema; diffuse, relatively nonscaling palmar hyperkeratoses with fissures in CTCL and pityriasis rubra pilaris; sharply demarcated patches of noninvolved skin within the erythroderma in pityriasis rubra pilaris; massive hyperkeratotic scale of scalp, usually without hair loss in psoriasis and with hair loss in CTCL and pityriasis rubra pilaris; in the latter and in CTCL, ectropion may occur.
Course and Prognosis
Guarded, depends on underlying etiology. Patients may succumb to infections or, if they have cardiac problems, to cardiac failure (high-output failure) or, as was unfortunately often the case in the past, to the effects of prolonged glucocorticoid therapy.
This important medical problem should be dealt with in a modern inpatient dermatology facility with experienced personnel. The patient should be hospitalized in a single room, at least for the beginning workup and during the development of a therapeutic program. The hospital room conditions (heat and cold) should be adjusted to the patient’s needs; most often, these patients need a warm room with many blankets.
Topical. Water baths with added bath oils, followed by application of bland emollients.
Systemic. Oral glucocorticoids for remission induction but not for maintenance; systemic and topical therapy as required by underlying condition.
Supportive. Supportive cardiac, fluid, electrolyte, protein replacement therapy as required.
Rashes in the Acutely III Febrile Patient
The sudden appearance of a rash and fever causes anxiety for the patient and medical advice is sought immediately. About 10% of all patients seeking emergency medical care have a dermatologic problem.
The diagnosis of an acute rash with a fever is a clinical challenge (Figs. 8-4 and 8-5). If a diagnosis is not established promptly in certain patients [e.g., those having septicemia (Fig. 8-6)], lifesaving treatment may be delayed.
The cutaneous findings alone are often diagnostic before confirmatory laboratory data are available. On the basis of a careful differential diagnosis, appropriate therapy—whether antibiotics or glucocorticoids—may be started. Furthermore, prompt diagnosis and isolation of the patient with a contagious disease, which may have serious consequences, prevent spread to other persons. Contagious diseases presenting with rash and fever as the major findings include viral infections (Fig. 8-6).
The diagnosis of skin eruptions is based mainly on precise identification of the type of skin lesions and additional morphologic clues such as the configuration (annular? iris?) of the individual lesion, the arrangement(zosteriform? linear?) and the distribution pattern (exposed areas? centripetal or centrifugal? mucous membranes?).
In the differential diagnosis of exanthems, it is important to determine, by history, the site of first appearance and temporal evolution [the rash of Rocky Mountain spotted fever characteristically appears first on the wrists and ankles], in measles (see Fig. 8-5) it spreads from head to toes in a period of 3 days, while in rubella it spreads rapidly in 24–48 h from head to toes and then sequentially clears—first face, then trunk, and then limbs. Contrasting this evolution, drug eruptions usually start simultaneously on the whole body (Fig. 8-4) or as fixed drug eruption at preferential sites (see Fig. 23-6).
Although there may be some overlap, the differential diagnostic possibilities may be grouped into five main categories according to the type of lesion (Table 8-3).
Figure 8-4. Generalized fixed drug eruption: tetracycline. Prostrated, 59-year-old woman with fever. Multiple confluent violaceous red erythematous areas, some of which later became bullous.
Figure 8-5. Generalized rash with fever: measles Young woman with high fever, cough, conjunctivitis, and a confluent maculopapular eruption in the edematous face. The rash also involves the trunk and the extremities. The patient has measles.
Figure 8-6. Generalized purpura necrosis and fever: DIC A 54-year-old woman with fever, prostration, and extensive geographic infarctions on the face, the trunk, and the extremities. This is disseminated intravascular coagulation: purpura fulminans following sepsis after abdominal surgery.
TABLE 8-3 GENERALIZED ERUPTIONS IN THE ACUTELY ILL PATIENT: DIAGNOSIS ACCORDING TO TYPE OF LESIONa
Laboratory Tests Available for Quick Diagnosis
The physician should make use of the following laboratory tests immediately or within 8 hours:
1. Direct smear from the base of a vesicle. This procedure, known as the Tzanck test, is described in the “Introduction.” Smears are examined for acantholytic cells, giant acanthocytes, and/or multinucleated giant cells.
2. Viral culture, negative stain (electron microscopy), polymerase chain reaction for infections with herpes viruses, direct fluorescence (DIF) technique.
3. Gram stain of aspirates or scraping of pustules. Organisms can be seen in the lesions of acute meningococcemia, rarely in the skin lesions of gonococcemia and ecthyma gangrenosum.
4. Touch preparation. Helpful in deep fungal infections and leishmaniasis. The dermal part of a skin biopsy specimen is touched repeatedly to a glass slide, which is immediately fixed in 95% ethyl alcohol. Special stains will reveal organisms.
5. Biopsy of the skin lesion. All purpuric lesions, inflammatory dermal nodules, and most ulcers should be biopsied (at base and margin) and a portion of tissue minced and cultured for bacteria and fungi. In gangrenous cellulitis (see Section 25), frozen sections of a deep biopsy will verify the diagnosis in minutes.
6. Blood and urine examinations. Blood culture, rapid serologic tests for syphilis, and serology for lupus erythematosus. Examination of urine sediment may reveal red cell casts in renal involvement in allergic vasculitis.
7. Dark-field examination. In the skin lesions of secondary syphilis, repeated examinations of papules show Treponema pallidum. Not reliable in the mouth because of resident nonpathogenic organisms but a lymph node aspirate can be subjected to dark-field examination.
Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (ten) ICD-9: 695.1 ICD-10: L51.1/51.2
SJS and TEN are acute life-threatening mucocutaneous reactions characterized by extensive necrosis and detachment of the epidermis.
They are variants of the same disease and differ only in the percentage of body surface involved.
Either “idiopathic” or drug induced.
Pathomechanism is widespread apoptosis of keratinocytes induced by a cell-mediated cytotoxic reaction.
Confluent erythematous purpuric and target-like macules evolve into flaccid blisters and epidermal detachment mostly on the trunk and extremities, and there is associated mucous membrane involvement.
Histopathologically: full-thickness necrosis of the epidermis and a sparse lymphocytic infiltrate.
Treatment is symptomatic. Systemic treatment with glucocorticoids and high-dose intravenous immunoglobulin is advocated by some but still controversial.
There is now consensus that SJS and TEN are different from erythema multiforme (EM).
TEN is a maximal variant of SJS differing only in the extent of body surface involvement. Both can start with macular and target-like lesions; however, about 50% of TEN cases do not, and in these, the condition evolves from diffuse erythema to immediate necrosis and epidermal detachment.
SJS: <10% epidermal detachment.
SJS/TEN overlap: 10–30% epidermal detachment.
TEN: >30% epidermal detachment.
Age of Onset. Any age, but most common in adults >40 years. Equal sex incidence.
Overall Incidence. TEN: 0.4–1.2 per million person-years. SJS: 1.2–6 per million person-years.
Risk Factors. Systemic lupus erythematosus, HLA-B12, HLA-B1502, and HLA-B5801 in Han Chinese, HIV/AIDS.
Etiology and Pathogenesis
Polyetiologic reaction pattern, but drugs are clearly the leading causative factor. TEN: 80% of cases have strong association with specific medication (Table 8-4); <5% of patients report no drug use. SJS: 50% are associated with drug exposure. Also chemicals, Mycoplasma pneumoniae, viral infections, immunization. Etiology often not clear.
TABLE 8-4 MEDICATIONS AND THE RISK OF TOXIC EPIDERMAL NECROLYSIS
Pathogenesis of SJS-TEN is only partially understood. It is viewed as a cytotoxic immune reaction aimed at the destruction of keratinocytes expressing foreign (drug-related) antigens. Epidermal injury is based on the induction of apoptosis. Fas and Fas-ligand interactions and/or the proapoptotic protein granulysin are implicated.
Time from first drug exposure to onset of symptoms: 1–3 weeks. Occurs more rapidly with rechallenge, often after a few days; newly added drug is most suspect. Prodromes: fever, malaise, arthralgias 1–3 days prior eruption. Mild to moderate skin tenderness, conjunctival burning or itching, then skin pain, burning sensation, tenderness, paresthesia. Mouth lesions are painful, tender. Impaired alimentation, photophobia, painful micturition, anxiety.
Skin lesions. Prodromal Rash. Is morbilliform, can be target-like lesion, with/without purpura (Fig. 8-7); rapid confluence of individual lesions; alternatively, can start with diffuse erythema and no rash (Fig. 8-8).
Figure 8-7. TEN, exanthematic presentation There is a widespread confluent macular rash with crinkling of the epidermis in some areas. There is detachment of the epidermis at the site of pressure (Nikolsky sign) resulting in a red erosion. This eruption was due to allopurinol.
Figure 8-8. TEN, exanthematic presentation A macular rash is starting to coalesce. Dislodgment and shedding of the necrotic epidermis has led to large, oozing, extremely painful erosions. The eruption was due to a sulfonamide.
Early. Necrotic epidermis first appears as macular areas with crinkled surface that enlarge and coalesce (Fig. 8-7). Sheetlike loss of epidermis (Fig. 8-8). Raised flaccid blisters that spread with lateral pressure (Nikolsky sign) on erythematous areas. Full-thickness epidermal detachment yields exposed, red, oozing dermis (Fig. 8-9) resembling a second-degree thermal burn.
Figure 8-9. TEN, non-exanthematic diffuse presentation This 60-year-old man developed diffuse erythema over almost the entire body, which then resulted in epidermal crinkling, detachment, and shedding of epidermis leaving large erosions. This is reminiscent of extensive scalding.
Distribution. Initial erythema on face, extremities, becoming confluent over a few hours or days. Epidermal sloughing may be generalized, resulting in large denuded areas (Figs. 8-8 and 8-9). Scalp, palms, soles may be less severely involved.
Mucous Membranes. Invariably involved, i.e., erythema, painful erosions: lips, buccal mucosa, conjunctiva, genital, and anal skin.
Eyes. 85% have conjunctival lesions: hyperemia, pseudomembrane formation; keratitis, corneal erosions; later synechiae between eyelids and bulbar conjunctiva.
Recovery. Regrowth of epidermis begins within days; completed in >3 weeks. Pressure points and periorificial sites exhibit delayed healing. Skin that is not denuded acutely is shed in sheets, especially palms/soles. Nails and eyelashes may be shed.
• Fever usually higher in TEN than in SJS.
• Usually mentally alert. Distress due to severe pain.
• Cardiovascular: pulse may be >120 beats/min. Blood pressure.
• Renal: tubular necrosis may occur. Acute renal failure.
• Respiratory and GI tracts: sloughing of epithelium with erosions.
Hematology. Anemia, lymphopenia; eosinophilia uncommon. Neutropenia correlates with poor prognosis. Serum urea increased, serum bicarbonate decreased.
Dermatopathology. Early. Vacuolization/necrosis of basal keratinocytes and throughout the epidermis.
Late. Full-thickness epidermal necrosis and detachment with subepidermal split above basement membrane. Sparse lymphocytic infiltrate in dermis. Immunofluorescence studies unremarkable, ruling out other blistering disorders.
Diagnosis and Differential Diagnosis
Early. Exanthematous drug eruptions, EM major, scarlet fever, phototoxic eruptions, toxic shock syndrome, graft-versus-host disease (GVHD).
Fully Evolved. EM major (typical target lesions, acute GVHD (may mimic TEN; less mucosal involvement), thermal burns, phototoxic reactions, staphylococcal scalded-skin syndrome (in young children, rare in adults and no mucosal involvement), generalized bullous fixed drug eruption, exfoliative dermatitis.
Course and Prognosis
Average duration of progression is <4 days. A prognostic scoring system is shown in Table 8-5. Course similar to that of extensive thermal burns. Prognosis related to extent of skin necrosis. Transcutaneous fluid loss is large and varies with area of denudation; associated electrolyte abnormalities. Prerenal azotemia is common. Bacterial colonization is common and associated with sepsis. Other complications include hypermetabolic state and diffuse interstitial pneumonitis. Mortality rate for TEN is 30%, mainly in elderly; for SJS, 5–12%. If the patient survives the first episode of SJS/TEN, reexposure to the causative drug may be followed by recurrence within hours to days, more severe than the initial episode.
TABLE 8-5 SCORTEN: A PROGNOSTIC SCORING SYSTEM FOR PATIENTS WITH EPIDERMAL NECROLYSIS
Skin. Scarring, hypo- and hyperpigmentation, abnormal regrowth of nails.
Eyes. Common, including Sjögren-like sicca syndrome with deficiency of mucin in tears; entropion, trichiasis, squamous metaplasia, neovascularization of conjunctiva and cornea; synblepharon, punctate keratitis, corneal scarring; persistent photophobia, burning eyes, visual impairment, blindness.
Anogenitalia: Phimosis, vaginal synechiae.
• Early diagnosis and withdrawal of suspected drug(s).
• Patients are best cared for in an intermediate or intensive care unit.
• Manage replacement of IV fluids and electrolytes as for patient with extensive thermal burn. However, less fluid usually required as for thermal burn of similar extent.
• Systemic glucocorticoids early in the disease and in high doses are reported helpful in reducing morbidity or mortality (as is also the experience of the authors), but this has been questioned. Late in the disease, they are contraindicated.
• High-dose IV immunoglobulins halt progression of TEN if administered early. This is questioned by some authors; the discrepancy may be explained by the different products and batches used.
• With oropharyngeal involvement, suction to prevent aspiration pneumonitis.
• Surgical debridement not recommended.
• Diagnose and treat complicating infections, including sepsis (fever, hypotension, change in mental status).
• Treat eye lesions early with erythromycin ointment.
Prevention. The patient must be aware of the likely offending drug and that other drugs of the same class can cross-react. These drugs must never be readministered. Patient should wear a medical alert bracelet.