Are You Confident of the Diagnosis?
Erythroderma is defined as inflammation of at least 90% of the total skin surface, characterized by generalized erythema with a highly variable degree of scaling or exfoliation. It is an important dermatological emergency as the systemic effects are potentially fatal.
What you should be alert for in the history
In a majority of cases there has been preexisting dermatosis, and the diagnosis may be quite clear from the history. Patients with dermatologic disorders recalcitrant to therapy may develop erythroderma during a flare-up. The patient should be asked about possible precipitating events, such as infection or exposure to sunlight and topical medicaments. A detailed drug history should include all over-the-counter and herbal remedies, such as St John’s wort. Severe pruritus may suggest eczema or lymphoma. Many patients complain of fever, shivering and malaise.
Characteristic findings on physical examination
Clinical examination may be entirely nonspecific (Figure 1). A patchy erythema may be progressive and may become generalized within 12-48 hours and be accompanied by pyrexia, malaise and shivering. Hypothermia can be a feature, particularly when erythema is increasing. Scaling appears 2-6 days later with variable degree and character. The scales may be fine in atopic dermatitis or dermatophytosis, bran-like in seborrheic dermatitis, crusted in pemphigus foliaceus, or exfoliative in drugs reactions. At this stage the skin is red, hot, dry and ,edematous. Irritation is sometimes severe but a sensation of tightness is more characteristic.
Lymphadenopathy is often present but is more often reactive than malignant. In difficult cases, a lymph node biopsy is recommended. However, the pathologist must be informed that the patient is erythrodermic for a reliable histopathological interpretation to be made.
Telogen effluvium and onychodystrophy may develop when erythroderma has been present for some weeks. Mucous membranes are usually spared although the periorbital skin is edematous, which can result in ectropion, with consequent epiphora. In very chronic cases, patients develop poikiloderma and dyspigmentation, with hyperpigmentation observed more frequently than hypo- or depigmentation. An eruption of warty papules resembling seborrheic keratoses, “Murray Williams warts” can occasionally occur following resolution of an inflammatory dermatosis.
Expected results of diagnostic studies
Investigation should involve hematology, urea and electrolytes, liver function tests and blood culture. Elevated erythrocyte sedimentation rate, raised IgE, anemia, hypoalbuminemia and hyperglobulinemia are frequent findings. Eosinophilia is generally a nonspecific finding, although a highly elevated count may be associated with malignancy, mainly T-cell lymphoma.
The clinicopathologic correlation is usually poor because the specific cutaneous changes of dermatoses of drug reactions are obscured by the nonspecific changes induced by the inflammatory process of erythroderma. The histology varies depending upon the severity and duration of the inflammatory process. In the acute stages, spongiosis and parakeratosis are prominent and there is a nonspecific inflammatory infiltrate. In the chronic stage, acanthosis and elongation of the rete ridges becomes more apparent.
Histopathological clues to the underlying disease are usually subtle but may be identified in 50% of the cases particularly with multiple skin biopsies. Immunofluorescent staining for immunoglobulin deposition should be performed if an immunobullous disease is suspected.
In erythroderma resulting from cutaneous T-cell lymphoma, the infiltrate may become increasingly pleomorphic and may eventually acquire diagnostic features. In other cases, it remains nonspecific throughout the course. Patients with Sézary syndrome often show features of chronic dermatitis, and benign erythroderma may occasionally show features suggestive of lymphoma. Immunophenotyping of the lymphoid infiltrate may not solve the problem as it generally shows features of mature T cells in both benign and malignant erythroderma. A skin biopsy for T cell receptor analysis to demonstrate clonal proliferation of lymphocytes may have some diagnostic value.
Genetic testing could be beneficial for certain congenital erythrodermas such as Netherton’s syndrome and Conradi-Hunermann syndrome. Erythroderma may be the first clinical manifestation of an immunodeficiency syndrome, especially in the presence of diarrhea and profound failure to thrive. Immunodeficiency screening must be considered in these cases.
Dermatophytosis rarely presents as erythroderma. Potassium hydroxide (KOH) preparation and fungal culture could be performed when there is clinical suspicion of dermatophytosis.
The indication for imaging studies (eg, computed tomography scanning, magnetic resonance imaging, chest radiography, mammography) is based on clinical context. Patch testing can be performed during periods of remission to identify any suspected contact allergen.
The diagnosis of erythroderma is made clinically. However, establishing the diagnosis of the underlying disease is often difficult due to the poor specificity of clinical and histological signs.
Eczema is a very common dermatosis. A severe generalized eczema may develop, either spontaneously or triggered by some factors such as a drug, infection, or intercurrent illness, and the patient becomes erythrodermic. The pruritus is intense and secondary excoriations or prurigo-like lesions can be seen. Psoriatic erythroderma is usually preceded by typically psoriatic plaques but when the exfoliative stage is reached, these specific features are lost. There may be clues such as bullae indicating the presence of bullous pemphigoid or pemphigus foliaceus. Severe scaling is suggestive of psoriasis.
Pityriasis rubra pilaris shows islands of uninvolved skin within erythrodermic regions with orange-colored palmoplantar keratoderma and follicular keratotic plugs on the knees, elbows and dorsae of the hands and toes. Sparing of flexures may suggest papuloerythroderma of Ofuji (“deck chair” sign). Hyperkeratosis of the palms and soles with subungual hyperkeratosis may suggest Norwegian scabies.
Who is at Risk for Developing this Disease?
Estimates of prevalence and incidence of erythroderma are based on several large series. A recent study from the Netherlands estimated the annual incidence at 0.9 per 100,000 population. Males are more commonly affected (male-female ratio of approximately 2:1 to 4:1) with the mean age between 40 and 60 years and, if the hereditary disorders and atopic dermatitis are excluded, most are over 45 years old.
What is the Cause of the Disease?
Erythroderma is commonly the result of generalization of a preexisting chronic dermatosis and systemic disease (Table I). These include genodermatoses and congenital disorders such as severe ichthyoses and ichthyosiform erythrodermas; severe cases of dermatoses such as psoriasis, atopic, seborrheic or contact allergic dermatitis; cutaneous T-cell lymphoma; allergic reactions to drugs (Table II); and manifestations of internal malignancies (especially lymphoma and other lymphoreticular malignancies). Up to 25% of cases develop without any apparent trigger and remain “idiopathic.”
|Contact allergic dermatitis|
|Cutaneous T-cell lymphoma|
|Graft Versus Host disease|
|Human immunodeficiency virus|
|Papuloerythroderma of Ofuji|
|Pityriasis rubra pilaris|
|Stasis dermatitis with autosensitization|
|Diaminodiphenyl sulfone (dapsone)|
Psoriatic erythroderma may precipitated by the withdrawal of potent topical or oral corticosteroids, use of medications such as lithium and antimalarials, phototherapy burns, infection including human immunodeficiency virus, pregnancy and systemic illness.
The mechanism of erythroderma is unknown. Adhesion molecules and their ligands (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-selectin and P-selectin) play a major role in endothelial-leucocyte interaction, which affect the binding, transmigration and infiltration of lymphocytes and mononuclear cells during inflammation, injury or immunologic reaction. The rise in adhesion molecule expression stimulates dermal inflammation, which leads to epidermal proliferation and increased production of inflammatory mediators. However, there is no difference in adhesion molecule expression on endothelial cells between different types of erythroderma.
Sézary Syndrome is a Th2 disorder with a selective expression of CCR4, whereas inflammatory erythroderma shares an overexpression of both Th1- and Th2- related chemokine receptors, suggesting a different pathophysiologic mechanism.
Systemic Implications and Complications
Persistent inflammation of the skin leads to marked peripheral vasodilation and increased cutaneous blood flow. In combination with increased percutaneous loss of fluid, these can lead to high-output cardiac failure, especially in elderly patients. Failure of the mechanical barrier will result in loss of normal temperature control with failure to maintain the core body temperature. Shivering and hypothermia may occur even though the skin feels deceptively warm.
Hypoalbuminemia is common and probably has several causes including increased plasma volume, decreased synthesis, increased metabolism, and protein loss via scaling and exudation.
Peripheral edema is common and can be due to a variety of causes, such as a shift of fluid into extracellular spaces, hypoalbuminaemia, concomitant cardiac failure and inflammation resulting from the primary skin disease. Occasionally, the increased permeability is severe enough to justify plasma infusions and parental steroids.
Severe pulmonary edema secondary to capillary leak syndrome and adult respiratory distress syndrome (ARDS) is a complication of erythroderma.
Colonization of the skin by Stahylococcus aureus is common and can lead to secondary cutaneous infections. Respiratory infections including pneumonia are common.
– Bed rest in hospital
– Continual surveillance of body temperature
– Monitoring and restoring electrolyte balance
– Control of nutrition
– Consider antibiotics for any secondary infection
Definitive treatment depends on the diagnosis and requires careful consideration (Table III).
|Psoriasis||Methotrexate, acitretin, azathioprine, biological agents|
|Drug||Withdrawal of offending drugs and nonessential drugs, systemic steroids, intravenous immunoglobulins|
|Inherited disorders of keratinization||Acitretin, isotretinoin|
|Pityriasis rubra pilaris||Retinoids, methotrexate|
|Papuloerythroderma of Ofuji||Retinoids, phototherapy|
|Cutaneous T cell lymphoma||PUVA, systemic retinoids, total body electron beam irradiation, topical nitrogen mustard, systemic chemotherapy, extracorporeal photophresis|
|Idiopathic||Mild topical steroids, systemic steroids and consider trial of other immunosuppressants, retinoid or phototherapy based on most probable cause|
PUVA, psoralen plus ultraviolet A.
Optimal Therapeutic Approach for this Disease
Patients with acute onset of erythroderma and unstable patients are best managed in a hospital setting, because frequent monitoring and intensive supportive care are required. The danger of this erythroderma is in the consequences of losing the cutaneous barrier; hence, many aspects of the management of a patient with erythroderma are similar regardless of the etiology, which include attention to nutrition, fluid balance, treatment of infection and thromboprophylaxis.
Treatment may be classified into general and specific measures; general measures include control of body temperature, fluid and electrolyte balance, heart failure, infection and nutrition.
The control of normal temperature is lost in erythroderma. The patient should be nursed at a steady ambient temperature around 30-32°C. Cooling and overheating must both be avoided by the use of extra blankets or fans respectively.
Careful attention must be paid to fluid balance to restore the dysmetabolism following erythroderma. Patients can dehydrate or go into cardiac failure. Hence, a strict input and output chart should be maintained. A reduction of urine volume may be an early indicator of hypovolemia or septicemia. If there is edema, diuretics and/or plasma infusion should be considered. Cardiac failure is difficult to diagnose as edema in erythrodermic patients is not a reliable sign of heart failure. However, cardiac failure must be treated if it develops.
The cutaneous inflammation should be treated empirically with bland emollients, bath emollient and low or moderate potency corticosteroids.Wet dressing can be applied to weeping and crusted areas. One variation of wet dressing is the use of tubular bandages (wet wrapping) as used in treatment of atopic dermatitis, for comfort, relief of pruritus, and sometimes to help to keep other topical medication in place. The majority of patients will improve over a week or two on this regimen, during which time the diagnosis of the underlying condition will often be established.
Care should be exercised in using more active topical treatment, such as coal tar, salicylic acid, vitamin D analogues and calcineurin inhibitors as they are more irritant than expected. In addition, systemic absorption of topical medication is increased as the barrier function of erythrodermic skin is greatly reduced. Antihistamines may be useful as sedatives.
Any secondary infections should be treated with antibiotics. Topical antibiotics are often adequate, although systemic antibiotics are instituted depending on the extent and severity of the secondary infection. The result of blood cultures should be interpreted with care as the specimens are easily contaminated with skin microflora. Colonization of the skin by Staphylococcus aureus may actually cause erythroderma which will clear with appropriate antibiotic therapy. Septicemia, often caused by Staphylococci, is a complication requiring urgent hospitalization, intravenous antibiotics and sometimes inotropic support.
Patients with erythroderma are in a hypercatabolic state with loss of protein through excessive desquamation and attention must be paid to nutrition. Preexisting malnutrition may become more marked and require nutritional intervention in older patients.
More specific measures depend on the etiology of the erythroderma. All nonessential and suspected drugs should be discontinued, and if the cause as been removed, erythroderma usually subsides in 2-6 weeks. However, in severe and recalcitrant cases, systemic prednisolone or even intravenous immunoglobulin may be justifiable. Acitretin, ciclosporin and methotrexate are useful in psoriatic erythroderma. However, withdrawal of systemic corticosteroid can exacerbate psoriasis into a generalized pustular form.
There is also increasing use of biological agents. In eczematous erythroderma, phototherapy and ciclosporin may be beneficial. Isotretinoin, acitretin and methotrexate are useful in erythroderma caused by pityriasis rubra pilaris. Idiopathic erythroderma may be treated with mild topical steroids and in refractory cases, ciclosporin and systemic steroids have been used successfully.
The use of systemic steroids in drug-induced and idiopathic erythroderma remains controversial. Many dermatologists prefer to avoid systemic steroid due to the dangers of fluid retention, secondary infection and diabetes. However, rapid and often persistent clearing of erythroderma has been achieved with an initial dose of 1-3mg/kg/day prednisolone and a maintenance dose of 0.5mg/kg/day. The use of acitretin in children with severe ichthyoses and erythroderma is safe and effective provided that the minimal effective dose is maintained and that side effects are carefully monitored.
The optimum treatment of erythrodermic cutaneous T-cell lymphoma remain debatable. Options include systemic steroids, psoralen plus ultraviolet A (PUVA), total body electron beam irradiation, topical nitrogen mustard and systemic chemotherapy. Extracorporeal photopheresis appears to be effective for selected patients although remission rates vary.
It is vital to establish a more precise diagnosis if possible for optimal long-term management . Drug-induced erythroderma invariably recovers completely with prompt initial management and removal of the offending drug. Patients should be educated to avoid any causative drugs.
The more common forms of erythroderma, such as eczema or psoriasis, may persists for months or years and tend to relapse. Treatment should be instituted for adequate control of the underlying dermatoses in the long term.
For the subgroup of patients with no obvious underlying disease, diligent follow-up and multiple serial biopsies can be helpful to exclude cutaneous T-cell lymphoma.
Unusual Clinical Scenarios to Consider in Patient Management
The most challenging issue is the management of erythrodermic patients without a diagnosis. It is often necessary to treat a case without knowing the cause.
Idiopathic erythroderma is defined as erythroderma in a patient without any history of previous skin disease, absence of atopic complaints, no family history of atopic disease, and nondiagnostic skin histopathologic and immunohistochemical results. The cutaneous changes may precede any other evidence of a lymphoma by many months or years. Repeated biopsies may be needed before infiltration of atypical lymphocytes become evident.
If these cases are excluded, the majority cases of idiopathic erythroderma are elderly men and the term “red-man syndrome” has been adopted for this group. It is characterized by marked palmoplantar keratoderma, dermatopathic lymphadenopathy and a raised serum IgE.
The three most common causes of idiopathic protracted erythroderma are probably atopic eczema of the elderly, intake of drugs overlooked by the patient, and prelymphomatous eruptions.
Idiopathic erythroderma carries an unpredictable outcome. The course of disease is marked by multiple exacerbations and prolonged use of corticosteroids is often necessary.
As the patients are often elderly, the prognosis must be guarded. The metabolic disturbances carry a serious risk of hypothermia, cardiac decompensation, peripheral circulatory failure, and thrombophlebitis. Cutaneous, subcutaneous, and respiratory infections are common, and the majority of patients who die do so as a result of pneumonia. Systemic antibiotics, inotropics and intensive support might be indicated for septicemia. The treatment can also be hazardous, especially when systemic steroids and immunosuppressants are required.
Many aspects of the management of a patient with erythroderma are similar regardless of the etiology. Individualized treatment based on the underlying etiologic cause should be combined with supportive skin care to ensure optimal outcomes.
What is the Evidence?
Beuchner, SA, Winkelmann, RK. “Pre-Sézary erythroderma evolving into Sézary syndrome”. Arch Dermatol. vol. 119. 1983. pp. 235-91. (This article reported the clinicopathological evolution of pre-Sézary erythroderma syndrome to Sézary erythroderma syndrome.
Zip, C, Murray, S, Walsh, NMG. “The specificity of histopathology in erythroderma”. J Cutan Pathol. vol. 20. 1993. pp. 393-8. (This article investigated the frequency with which a correct diagnosis can be based on histopathological assessment alone. It was concluded that despite the homogeneity of the clinical expression of erythroderma, diagnostic histopathological features of the underlying disease are retained in the majority of the cases.)
Sentis, HJ, WIllemze, R, Scheffer, E. “Histopathologic studies of Sézary syndrome and erythrodermic mycosis fungoides: a comparison with benign forms of erythroderma”. J Am Acad Dermatol. vol. 15. 1986. pp. 1217-26. (This study examined the histologic sections of Sézary syndrome, erythrodermic mycosis fungoides and benign forms of erythroderma such as chronic dermatitis, generalized drug eruption and psoriasis. The study suggested repeated skin biopsies, additional investigations of lymph nodes, peripheral blood and follow-up are required to establish a correct diagnosis.)
Abrahams, I, McCarthy, JT, Sanders, SL. “101 cases of exfoliative dermatitis”. Arch Dermatol. vol. 87. 1963. pp. 96-101. (This article reviewed the clinical and laboratory findings with correlation to the etiologic diagnosis of 101 cases of exfoliative dermatitis.)
Botella-Estrada, R, Sanmartin, O, Oliver, V, Febrer, I, Aliaga, A. “Erythroderma: a clinicopathological study of 56 cases”. Arch Dermatol. vol. 130. 1994. pp. 1503-7. (This article studied the frequency, etiology and evolution of 56 patients with a diagnosis of erythroderma over a period of 8 years. Erythroderma of unknown cause and protracted course may be secondary to senile atopic dermatitis, intake of drugs overlooked by patients and patients who are in slow progression to cutaneous T-cell lymphoma.)
Sigurdsson, V, Steegmans, PH, van Vloten, WA. “The incidence of erythroderma: a survey among all dermatologists in the Netherlands”. J Am Acad Dermatol. vol. 45. 2001. pp. 675-8. (This article investigated the incidence and causes of erythroderma and evaluates the referral pattern of erythrodermic patients by dermatologists in the Netherlands.)
Sigurdsson, V, de Vries, IJ, Toonstra, J, Bihari, IC, Thepen, T, Bruijnzeel-Koomen, CA. “Expression of VCAM-1, ICAM-1, E-selectin and P-selectin on endothelium in situ in patients with erythroderma, mycosis fundoides and atopic dermatitis”. J Cutan Pathol. vol. 27. 2000. pp. 436-40. (This study investigated the adhesion molecule expression on endothelial cells in erythroderma.)
Fierro, MT, Comessatti, A, Quaglino, P, Ortoncelli, M, Osella Abate, Ponti, R. “Expression pattern of chemokine receptors and chemokine release in inflammatory erythroderma and Sézary syndrome”. Dermatology. vol. 213. 2006. pp. 284-92. (This study evaluated the chemokine release and the expression pattern of Th1- and Th2-related chemokine receptors in inflammatory erythroderma and Sézary syndrome.)
Berth-Jones, J, Burns, T, Breathnach, S, Cox, N, Griffiths, C. “Rook's textbook of dermatology”. Eczema, lichenification, prurigo & erythroderma. 2010. pp. 23.46-23.51. (The author reviews the definition, incidence, etiology, histopathology, clinical features, complications, management and prognosis of erythroderma.)
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