AUTHOR INFORMATION

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Authored by Therese I Mendenhall, DO, Staff Physician, Department of Emergency Medicine, University of Arkansas for Medical Sciences

Coauthored by Barry Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, and Professor of Anatomy and Neurobiology, Research Director, Department of Emergency Medicine, University of Arkansas for Medical Sciences; Jonathan R Pilcher, MD, Staff Physician, Department of Emergency Medicine, University of Arkansas Medical Center; Selwyn Waterton, MD, Assistant Professor, Department of Emergency Medicine, State University of New York Health Sciences Center at Brooklyn

Therese I Mendenhall, DO, is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and American Medical Association

Edited by Mark Louden, MD, FACEP, Consulting Staff, Emergency Department, Duke Health Raleigh Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Mark W Fourre, MD, Program Director, Department of Emergency Medicine, Maine Medical Center, Associate Clinical Professor, Department of Surgery, University of Vermont School of Medicine; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Barry Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, and Professor of Anatomy and Neurobiology, Research Director, Department of Emergency Medicine, University of Arkansas for Medical Sciences

Author's Email:	Therese I Mendenhall, DO
Editor's Email:	Mark Louden, MD, FACEP

eMedicine Journal, September 28 2005, VOLUME 6, Number 9

INTRODUCTION

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Background: Exfoliative dermatitis, or erythroderma, is an erythematous, scaly dermatitis involving most, if not all, of the skin. This generalized scaling eruption of the skin is drug induced, idiopathic, or secondary to underlying cutaneous or systemic disease.

Appreciation for this condition requires an understanding of the skin's normal epithelial layer. Normal epidermis has a continual turnover of epithelial cells. Cell division occurs near the basal layer. As cells move toward the periphery, they become well keratinized. This process requires approximately 10-12 days. Cells subsequently remain in the stratum corneum for another 12-14 days prior to being sloughed off.

In exfoliative dermatitis, the mitotic rate in the basal layer increases and overall transit time decreases; therefore, more cells are lost from the surface. The mechanism responsible for this is not known, although an immunologic basis has been suggested.

Pathophysiology: Exfoliative dermatitis may occur in response to drug therapy, systemic disease, or an idiopathic entity. As many as 40% of cases involve preexisting cutaneous disease. Approximately 10% of cases are the result of drug reactions. As many as 40% are caused by underlying systemic disease. The remaining cases are idiopathic.

Histopathologic patterns observed for drug-induced and idiopathic causes of exfoliative dermatitis are nonspecific. Biopsy findings in individuals with preexisting cutaneous or systemic disease during an exfoliative stage may reveal, inconsistently, the underlying skin lesion or pathology. Through multiple-biopsy histologic analysis, the diagnosis may be confirmed in as many as 45% of patients.

Frequency:

• In the US: An estimated 1% of hospitalizations are for skin disease.

• Internationally: The ratio of hospitalized patients experiencing adverse drug reactions is 3 in 1000. According to 1 large Finnish study, approximately 1% of these instances involve exfoliative dermatitis.

Mortality/Morbidity: Mortality approaches 30%. In a report of 108 patients with exfoliative dermatitis who were autopsied, 87 died from the underlying disease. No cause other than exfoliation was found for the remaining 17 patients.

Race: Exfoliative dermatitis occurs in all races. In the young black male population, recent research suggests exfoliative dermatitis may be a marker for HIV infection.

Sex: The male-to-female ratio is 2:1.

Age: Individuals older than 40 years are affected most frequently.

CLINICAL

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History:

• Prior dermatologic illnesses

• Treatment with new medications

• Underlying systemic diseases

• Swelling or adenopathy

• Recurrent infections

• Cough or change in bowel or urinary habits

• Constitutional symptoms of low-grade fever, chills, and malaise (more commonly, patients complain of skin erythema, tightness, and scaling)

Physical:

• Gynecomastia is a common finding in almost all patients with exfoliative dermatitis of several weeks' duration; it is believed to be secondary to hyperestrogenism, but the precise mechanism is unknown.

• Additional findings include alopecia, dystrophic nails, and hypopigmentation and/or hyperpigmentation.

• More than 40% of patients were febrile to more than 38°C; a relative tachycardia also was noted.

• Firm, rubbery lymphadenopathy, referred to as dermatopathic lymphadenitis, is a common finding.

• Hepatomegaly was noted in more than 50% of patients in 1 series, and splenomegaly was noted in approximately 30% of patients, all of whom had lymphoma.

• Steatorrhea also may develop and tends to resolve when exfoliative dermatitis clears.

• Patients with exfoliative dermatitis also have increased cutaneous blood flow, transcutaneous fluid losses, and radiation and convective heat losses.

• A number of cases of hypothermia have been reported.

• Fluid shifts increase cardiac output, causing dyspnea, dependent edema, and cardiac failure (possibly) in some patients.

• Prostate or thyroid glands may be enlarged or nodular.

Causes:

• Systemic diseases (10-40%)

• Lymphoma - Primarily cutaneous T-cell lymphoma (CTCL)

• Leukemia

• Multiple myeloma

• Carcinoma of the lung, prostate, colon, and thyroid

• Graft versus host disease

• Immunodeficiency, including HIV

• Hodgkin disease

• Cutaneous diseases (10-40%)

• Psoriasis

• Seborrheic dermatitis

• Atopic dermatitis

• Stasis dermatitis

• Contact dermatitis

• Pityriasis rubra pilaris

• Pemphigus foliaceus

• Mycosis fungoides

• Dermatophytosis

• Lichen planus

• Drugs (3-10%)

• Dimercaprol (British antilewisite [BAL])

• Codeine

• Captopril

• Diphenylhydantoin

• Gold

• Iodine

• Antimicrobials - Sulfas, penicillin (PCN), cephalosporins, minocycline, isoniazid

• Granulocyte colony-stimulating factor (GCSF)

• Phenytoin

• Allopurinol

• Mercury

• Arsenic

• Quinidine

• Barbiturates

• Trimethadione

• Aspirin

• Carbamazepine

• Idiopathic (15-45%)

DIFFERENTIALS

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Erythema Multiforme
Pediatrics, Kawasaki Disease
Staphylococcal Scalded Skin Syndrome
Toxic Epidermal Necrolysis
Toxic Shock Syndrome

WORKUP

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Lab Studies:

• Perform laboratory studies based on clinical suspicion or history that may help to establish the primary cause of exfoliative dermatitis. Other laboratory studies include the following:

• Evaluation for cardiac failure and renal and intestinal dysfunction

• CBC with differential, liver enzymes level, creatinine level, and urinalysis

• Serum albumin level

• Erythrocyte sedimentation rate (ESR)

• Most common laboratory abnormalities are anemia, hypoalbuminemia, eosinophilia, and an elevated sedimentation rate

Imaging Studies:

• Order imaging studies based on suspicion of underlying systemic disease or when other causes are excluded.

Procedures:

• Biopsy

• Perform skin biopsy and lymph node biopsy if significant lymphadenopathy is noted.

• Histologic findings generally are nonspecific and include hyperkeratosis, parakeratosis, acanthosis of the epidermis, and perivascular infiltrate consisting of histocytes, lymphocytes, and some eosinophils.

TREATMENT

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Emergency Department Care: Hospitalize most patients suffering from acute exfoliative dermatitis in the intensive care unit or burn center for supportive care, fluid replacement, laboratory studies, and contact isolation for protection against secondary bacterial and fungal infections. No studies have suggested a better outcome for patients treated in burn centers.

• General measures

• Withdraw implicated medications or treatment of identified underlying infection and/or disease.

• Protect patient from development of hypothermia.

• Prescribe cool oatmeal baths.

• Advise local moisturizing ointments and/or lotions.

• Advise high-protein diet with folic acid supplementation, since protein losses may be increased as much as 30% above normal.

Consultations: Urgent dermatology consultation is recommended.

MEDICATION

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Treatment of the underlying illness is key since exfoliative dermatitis resists treatment until the basic disease is treated. Frequent tub baths with emollients are indicated to provide symptomatic relief.

Drug Category: Corticosteroids -- These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli. Also used to treat idiopathic and acquired autoimmune disorders.

Drug Name	Prednisone (Deltasone, Orasone, Meticorten) -- Glucocorticoid that readily is absorbed from GI tract. Used primarily for anti-inflammatory effects in disorders of many organ systems.
Adult Dose	40-60 mg PO qd; daily dose may be increased by 20 mg if no improvement observed in 3-4 d; taper over 2 wk as symptoms resolve
Pediatric Dose	1-2 mg/kg PO; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral infection, PUD, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, PUD, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Antihistamines -- These agents are used to treat minor allergic reactions and anaphylaxis. Used for relief of pruritus.

Drug Name	Diphenhydramine (Benadryl, Benylin) -- For symptomatic relief of symptoms caused by release of histamine in allergic reactions. May control itching by blocking effects of endogenously released histamine.
Adult Dose	25-50 mg PO q6-8h prn; not to exceed 400 mg/d 10-50 mg IV/IM q6-8h prn; not to exceed 400 mg/d
Pediatric Dose	12.5-25 mg PO tid/qid, or 5 mg/kg/d, or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d 5 mg/kg/d IV/IM or 150 mg/m2/d, divided qid; not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; MAOIs
Interactions	Potentiates effects of CNS depressants; due to alcohol content, do not administer syr dosage form to patients taking medications that can cause disulfiramlike reactions
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur

Drug Category: Immunosuppressives -- These agents interfere in the immune processes that promote inflammation. Used to relieve chronic severe dermatitis.

Drug Name	Cyclosporine (Neoral, Sandimmune) -- Demonstrated to cause remission in some patients. Has improved overall prognosis of exfoliative dermatitis.
Adult Dose	2.5-5 mg/kg/d PO in divided doses; specialized dosing
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UV-B radiation in psoriasis since it may increase risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Drug Category: Antirheumatic, disease modifying -- These agents modulate inflammatory and immune responses.

Drug Name	Etanercept (Enbrel) -- Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses. Has been reported to be effective. No current FDA approval/indication for the use of this drug with exfoliative dermatitis.
Adult Dose	25 mg SC 2 times/wk
Pediatric Dose	0.4 mg/kg SC; maximum single dose 25 mg
Contraindications	Documented hypersensitivity; sepsis; concurrent live vaccination
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Empiric case reports for effectiveness; no current FDA approval/indication for use with exfoliative dermatitis Serious infections may develop, and the therapy should be discontinued if they occur; possible adverse effects include injection site pain, redness and swelling at injection site, and headaches; rare cases of lupuslike symptoms and heart failure have been reported (discontinue treatment if symptoms develop)

FOLLOW-UP

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Complications:

• Bacterial or fungal superinfection

• Hypothermia

• Dehydration and/or electrolyte imbalance

• Heart failure

Prognosis:

• In general, long-term prognosis is good for patients with drug-induced disease after the offending agent is withdrawn and proper supportive measures are undertaken.

• For patients with idiopathic exfoliative dermatitis, the prognosis is poor. Frequent recurrences or chronic symptoms require long-term steroid therapy and its attendant sequelae.

• For patients with underlying disease or malignancy, prognosis rests on the outcome and course of the disease process.

Patient Education:

• Avoid known etiologic agents.

• Educate patients with underlying disease about symptomatic treatment and advise that many cases spontaneously remit.

• Advise patients on protection from hypothermia.

• Advise patients to follow a high-protein diet as symptoms persist.

• Encourage patients to be diligent in watching for signs of infection.

MISCELLANEOUS

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Special Concerns:

• In neonates, thoroughly investigate severe immunodeficiency as a possibility.

• Elderly patients are at risk of cardiac complications. Fluid losses and shifts often are significant, and decreased compensatory mechanisms in members of the elderly population make them particularly vulnerable.

• Use corticosteroids with caution. This syndrome has a clinically similar appearance to that of toxic epidermal necrolysis for which steroids have shown no benefit or increased morbidity or mortality.

TEST QUESTIONS

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CME Question 1: Which of the following is the proper treatment of elderly patients with new-onset exfoliative dermatitis?

A: Hospitalization for evaluation, fluid management, and treatment
B: Referral to a dermatology clinic
C: Administration of oral steroids and discharge
D: Referral to an oncology clinic for evaluation
E: None of the above

The correct answer is A: Elderly patients are at risk of cardiac complications. All patients with new-onset exfoliative dermatitis should be hospitalized and the etiology investigated.

CME Question 2: Which of the following is not part of the medical treatment of exfoliative dermatitis?

A: Intravenous fluids
B: Tub baths with emollients
C: Systemic corticosteroids
D: Oral antihistamines
E: Prophylactic antibiotics

The correct answer is E: Antibiotics are not indicated unless secondary bacterial infection is noted.

Pearl Question 1 (T/F): Exfoliative dermatitis most commonly affects women older than 40 years.

The correct answer is False: An estimated 75% of cases affect men older than 40 years.

Pearl Question 2 (T/F): Skin erythema, tightness, and scaling are the most common dermatologic complaints that cause patients to seek medical attention for exfoliative dermatitis.

The correct answer is True: Skin erythema, tightness, and scaling are the most common dermatologic complaints. Constitutional symptoms include low-grade fever, chills, and malaise.

Pearl Question 3 (T/F): Cardiac failure is not a concern in patients with exfoliative dermatitis.

The correct answer is False: Cardiac failure is a concern because of fluid shifts that can place susceptible patients at risk of such problems.

Pearl Question 4 (T/F): The best treatment of exfoliative dermatitis is to treat the underlying cause.

The correct answer is True: The underlying cause or disease must be treated since exfoliative dermatitis resists treatment until the basic disease is treated.

BIBLIOGRAPHY

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• Pruszkowski A, Bodemer C, Fraitag S, et al: Neonatal and infantile erythrodermas: a retrospective study of 51 patients. Arch Dermatol 2000 Jul; 136(7): 875-80[Medline].
• Querfeld C, Guitart J, Kuzel TM, Rosen S: Successful treatment of recalcitrant, erythroderma-associated pruritus with etanercept. Arch Dermatol 2004 Dec; 140(12): 1539-40[Medline].
• Quiceno GA, Cush JJ: Iatrogenic rheumatic syndromes in the elderly. Clin Geriatr Med 2005 Aug; 21(3): 577-88, vii[Medline].
• Rothe MJ, Bialy TL, Grant-Kels JM: Erythroderma. Dermatol Clin 2000 Jul; 18(3): 405-15[Medline].
• Shuster S, Brown JB: Gynaecomastia and urinary oestrogens in patients with generalised skin disease. Lancet 1962 Dec 29; 2: 1358[Medline].
• Sommer S, Henderson CA: Papuloerythroderma of Ofuji responding to treatment with cyclosporin. Clin Exp Dermatol 2000 Jun; 25(4): 293-5[Medline].
• Voigt GC, Kronthal HL, Crounse RG: Cardiac output in erythrodermic skin disease. Am Heart J 1966 Nov; 72(5): 615-20[Medline].
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