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PAPULOSQUAMOUS AND ECZEMATOUS DERMATOSES SECTION 3

Erythroderma
Wolfram Sterry and Matthias Steinhoff
10
Synonyms: Exfoliative dermatitis Exfoliative erythroderma Red EPIDEMIOLOGY
man syndrome No precise data exist regarding the prevalence or incidence of erythro-
derma as most reports are retrospective and do not address the issue of
overall incidence. Large series of patients have focused on male-to-female
ratios, average age, and underlying diseases16. Men are more commonly
affected (male-to-female ratio from approximately 2:1 to 4:1). An even
Key features higher ratio can be found in the subset of idiopathic erythroderma, also
Erythroderma is defined clinically as generalized redness and referred to as red man syndrome (not to be confused with the cutane-
scaling of the skin ous reaction to rapid infusion of vancomycin). The average age at onset
of erythroderma was 52 years, with an average of 48 years in series
Systemic manifestations include peripheral edema, tachycardia,
including children, and 60 years in those excluding them1,3,4,6.
loss of fluid and proteins, and disturbances in thermoregulation
Of a total of 746 patients, dermatitis (24%), psoriasis (20%), drug
Erythroderma has multiple etiologies; the most common causes reactions (19%) and CTCL (8%) represented the most common under-
are psoriasis, drug reactions, atopic dermatitis and cutaneous T-cell lying causes of erythroderma1,3,4,6. When categories within the derma-
lymphoma (CTCL) titis group were examined, atopic dermatitis (9%) was the most common
Establishing the correct diagnosis requires consideration of initial type, followed by contact dermatitis (6%), seborrheic dermatitis (4%)
sites of involvement, additional clinical findings, histologic and and chronic actinic dermatitis (3%).
molecular features, and associated systemic abnormalities, as well For adults, unusual causes include ichthyoses, bullous dermatoses
as a complete medical history (usually pemphigus foliaceus), pityriasis rubra pilaris, Ofujis papulo-
Despite an intensive evaluation, the cause remains unknown erythroderma, and systemic lupus erythematosus (Table 10.1). Despite
(idiopathic) in 2530% of patients; some of these patients multiple skin biopsies, an in-depth clinical investigation and a detailed
eventually develop CTCL medical history, the underlying cause of erythroderma is not found in
at least 25% of patients.
Treatment strategies should address the dermatologic disease as
With regard to infants and neonates, ichthyoses, immunodeficien-
well as the underlying etiology and the systemic complications of
cies, dermatitides, psoriasis, and consequences of infection (e.g. staphy-
the erythroderma
lococcal scalded skin syndrome) represent the major causes of
erythroderma (Table 10.2)7. In addition, the possibility of drug-induced
erythroderma needs to be considered.

INTRODUCTION PATHOGENESIS
Erythroderma is defined as a generalized redness and scaling of the The pathogenetic mechanisms of the underlying diseases will be dis-
skin. However, it does not represent a defined entity, as it is the clinical cussed in the respective chapters. The pathways involved in the de novo
presentation of a variety of diseases. Most commonly, erythroderma is genesis of erythroderma or the generalization of pre-existing skin
due to generalization of pre-existing dermatoses (such as psoriasis or lesions are not well understood. The number of germinative cells as
atopic dermatitis), drug reactions or cutaneous T-cell lymphoma well as their mitotic rate is increased in erythrodermic skin, and the
(CTCL). Although up to 50% of the patients have a history of more transit time of cells through the epidermis is shortened. Consequently,
localized skin lesions prior to the onset of the erythroderma, identifica- scales consist of material normally retained by the skin (nucleic acids,
tion of the underlying disease process represents one of the most amino acids, soluble protein), and the daily loss of scales increases from
complex challenges in dermatology. Sustained efforts during longitudin 5001000mg to 2030g8. In acute erythroderma, the lost material
al evaluation may lead to the precise identification of the etiology. In usually has marginal metabolic significance.
approximately one-quarter of the patients, no specific etiology is found,
and these cases are called idiopathic erythroderma.
Attention should also be focused on the potential systemic compli-
cations of erythroderma. Hypothermia, peripheral edema, and loss of CLINICAL FEATURES
fluid, electrolytes and albumin with subsequent tachycardia and
cardiac failure are a serious threat to the erythrodermic patient. In Cutaneous Manifestations
addition, long-lasting erythrodermas may be accompanied by cachexia, Erythroderma is defined clinically by the presence of erythema and
diffuse alopecia, palmoplantar keratoderma, nail dystrophy and scaling involving more than 90% of the skin surface. Based upon its
ectropion. natural history, erythroderma can be classified into primary or second-
ary types. In the primary form, the erythema (often initially on the trunk)
extends within a few days or weeks to involve the entire skin surface,
HISTORY and this is followed by scaling (Fig. 10.1). The secondary form of eryth-
roderma is defined as a generalization of a preceding localized skin
The term erythroderma was introduced in 1868 by Hebra to describe disease for example, psoriasis or atopic dermatitis.
an exfoliative dermatitis involving more than 90% of the skin surface. With the exception of very slowly progressing secondary erythro-
Based upon the clinical course, erythroderma was classified into chronic derma, erythema precedes the development of exfoliation by 26 days.
ally relapsing (WilsonBrocq), chronically persisting (Hebra), and self- The associated scaling varies extensively in size and color depending
limiting epidemic (Savill) variants. However, these subdivisions are no upon the stage of the erythroderma and nature of the underlying 171
longer employed. disease. In more acute phases, scales are usually large and crusted,
SECTION

3 CAUSES OF ERYTHRODERMA IN ADULTS

Underlying disease Clinical clues Histologic clues Additional hints


Papulosquamous and eczematous dermatoses

COMMON
Psoriasis (Ch. 8) Pre-existing psoriatic plaques Confluent parakeratosis Personal or family history of psoriasis
Often spares the face Bottleneck-like rete ridges Withdrawal of corticosteroids,
Nail changes (oil-drop, pits, onycholysis) Tortuous vessels in papillary dermis methotrexate or cyclosporine (also
Subcorneal pustules Neutrophils within epidermis efalizumab prior to its removal from the
Inflammatory arthritis Often reduced granular layer market)

Atopic dermatitis (Ch. 12) Pre-existing lesions (flexures) Mild to moderate acanthosis Elevated serum IgE, eosinophilia
Severe pruritus Variable spongiosis Personal or family history of atopy (e.g.
Lichenification, including eyelids Dermal eosinophils asthma, allergic rhinitis)
Prurigo nodularis Parakeratosis Cataracts
Drug reactions (Ch. 21) Preceded by morbilliform or scarlatiniform Perivascular infiltrate with eosinophils No history of skin diseases
exanthem Lichenoid infiltrate Usually resolves within 26 weeks after
Facial edema Necrotic keratinocytes at all levels of withdrawal of responsible drug;
In dependent areas, may become epidermis possible exception is DIHS/DRESS
purpuric Vacuolar degeneration of basal layer
Idiopathic erythroderma Elderly men Nonspecific Consider less commonly associated
Chronic, relapsing drugs (see Table 10.3)
Severe pruritus Continue to re-evaluate for cutaneous
Palmoplantar keratoderma T-cell lymphoma
Dermatopathic lymphadenopathy
LESS COMMON
Cutaneous T-cell lymphoma Szary syndrome more common than Nuclear atypia in lymphocytes Elevated CD4+:CD8+ ratio (blood), with
(Ch. 120) erythrodermic mycosis fungoides Clustering of atypical cells within 10:1 ratio seen in Szary syndrome
Intense pruritus epidermis Detection of clonal T-cell population in
Deep purplered hue Often lichenoid infiltrate skin (and blood)
Painful, fissured keratoderma In Szary syndrome: 1000 Szary cells/
Alopecia mm3; 40% CD4+/CD7; or 30% CD4+/
Leonine facies CD26 (blood)

Pityriasis rubra pilaris (Ch. 9) Salmon-colored erythema Psoriasiform epidermal hyperplasia Flare after sun exposure
Islands of sparing (nappes claires) Alternating parakeratosis and Cephalocaudal progression
Waxy keratoderma orthokeratosis, both vertically and Appearance of erythema gyratum-like
Perifollicular keratotic papules horizontally lesions as erythroderma improves
Follicular plugs with shoulder
parakeratosis
Dermatitis (non-atopic), including Pre-existing localized disease Variable spongiosis Occupation and hobbies
contact (Chs 14 & 15) and stasis Distribution of initial lesions Patch testing
with autosensitization (Ch. 13) Review oral medications (systemic
contact dermatitis)
Paraneoplastic erythroderma Fine scaling Nonspecific changes Lymphoproliferative disorders,
Melanoerythroderma including other types of T-cell
Cachexia lymphoma
In the case of solid-organ malignancies,
usually late stage
BULLOUS DERMATOSES (CHS 29 & 30)
Pemphigus foliaceus Pre-existing lesions, often on upper trunk Acantholysis, superficial epidermis IIF, intercellular
Impetigo-like erosions and vesicles DIF, intercellular IgG
Moist scale-crust; cornflake scale
Bullous pemphigoid Urticarial plaques Subepidermal blister IIF, BMZ
Tense bulla Eosinophils
Elderly patients DIF, BMZ C3 and IgG
Paraneoplastic pemphigus Mucosal erosions and hemorrhagic crusts Interface dermatitis with necrotic IIF, intercellular and BMZ (+ IIF rat
Erythema multiforme-like lesions keratinocytes bladder)
Mucocutaneous lichenoid lesions Focal acantholysis
DIF, intercellular and BMZ IgG
Congenital ichthyoses (Ch. 57) Present from birth or early infancy (see See Table 10.2 See Table 10.2
Table 10.2)
RARE
Papuloerythroderma of Ofuji Widespread, pruritic, flat-topped Dense perivascular infiltrate of Multiple etiologies, including atopy,
redbrown papules that can become lymphocytes and eosinophils in the lymphomas (esp. CTCL), drugs (e.g. DDI,
confluent upper to mid dermis aspirin), infections (e.g. HIV, hepatitis C)
Sparing of skin folds (deck-chair sign) May have peripheral eosinophilia,
Favors elderly men lymphopenia
Table 10.1 Causes of erythroderma in adults. BMZ, basement membrane zone; DDI, dideoxyinosine; DIF, direct immunofluorescence; DIHS, drug-induced
hypersensitivity syndrome; DRESS, drug reaction with eosinophilia and systemic symptoms; IIF, indirect immunofluorescence. Continued

172
CHAPTER

CAUSES OF ERYTHRODERMA IN ADULTS 10


Underlying disease Clinical clues Histologic clues Additional hints

Erythroderma
Chronic actinic dermatitis (Ch. 87) Initial lesions in photodistribution Lichenoid infiltrate of lymphocytes and Drug history
exocytosis UVA, UVB and visible light phototesting
Possible lymphocyte nuclear Photopatch testing
pleomorphism
OTHER RARE CAUSES
Hypereosinophilic syndrome (Ch. 25) Dermatophyte infection
Crusted (Norwegian) scabies (Ch. 84) Primary immunodeficiencies (Ch. 60)
Lichen planus Sarcoidosis
GVHD (Ch. 52) Mastocytosis
Autoimmune connective tissue disease (e.g. acute or subacute cutaneous Hemophagocytic lymphohistiocytosis
lupus erythematosus, juvenile dermatomyositis [adolescents]) T-cell leukemia
Table 10.1 Causes of erythroderma in adults (contd).

CAUSES OF ERYTHRODERMA IN NEONATES AND INFANTS

Underlying disease Clinical clues Histologic clues Additional findings


INHERITED ICHTHYOSES (CH. 57)
Epidermolytic ichthyosis (previously Formation of superficial blisters and Classic epidermolytic hyperkeratosis Mutations in KRT1 and KRT10, which
referred to as bullous congenital erosions during the first days of life encode keratins 1 and 10
ichthyosiform erythroderma) Later, corrugated hyperkeratosis in
flexural areas
Congenital ichthyosiform Collodion baby Non-diagnostic Mutations in TGM1 (encodes
erythroderma (previously referred to Generalized scaling involving flexures transglutaminase 1), ALOXE3
as non-bullous congenital Cicatricial alopecia, nail dystrophy (lipoxygenase 3), ALOX12B (12[R]
ichthyosiform erythroderma) (subungual hyperkeratosis, ridging), rapid lipoxygenase), NIPAL4 (ichthyin),
nail growth ABCA12*, and CYP4F22*
Ectropion
Netherton syndrome Atopic-like dermatitis Routine histology non-diagnostic By electron microscopy: premature
Food allergies LEKT1 antibody secretion and abnormal lamellar bodies
Immune deficiency Elevated serum IgE levels
Erythroderma in neonates Mutations in SPINK5 (encodes serine
Erythroderma may persist or ichthyosis peptidase inhibitor, Kazal type 5)
linearis circumflexa develops
Examine eyebrows and eyelashes as well
as scalp hairs for trichorrhexis invaginata
(bamboo hair)
Failure to thrive
ConradiHnermannHapple Linear and swirled pattern Hyperkeratosis, reduced granular Mutations in EBP at Xp11 (encodes
syndrome (X-linked dominant Skeletal (chondrodysplasia punctata) and layer, follicular plugging emopamil binding protein [sterol
chondrodysplasia punctata) ocular anomalies (cataracts) isomerase])
IMMUNODEFICIENCIES (CH. 60)
Omenn syndrome Onset in neonatal period Necrosis of keratinocytes Leukocytosis, eosinophilia
Exfoliative erythroderma with diffuse Dense dermal infiltrate Hypogammaglobulinemia
alopecia (predominantly T cells) Elevated serum IgE levels
Lymphadenopathy and Acanthosis, parakeratosis Lymph nodes: disruption of germinal
hepatosplenomegaly centers and abundant S100+
Recurrent infections interdigitating reticulum cells
Diarrhea Mutations in RAG1 and RAG2
(see Ch. 60)
Other forms of SCID, Leiner phenotype of exfoliative Non-diagnostic See Ch. 60
agammaglobulinemia, complement dermatitis, chronic diarrhea and
deficiencies (e.g. C3, C5) recurrent infections
WiskottAldrich syndrome Primarily affects boys Non-diagnostic Microthrombocytopenia
Petechiae, ecchymoses Lymphopenia, eosinophilia
Atopic-like dermatitis Elevated serum IgE levels
Recurrent sinopulmonary infections Mutations in WAS
*ABCA12 and CYP4F22 encode ATP-binding cassette (ABC), sub-family A, member 12 and cytochrome P450, family 4, subfamily F, polypeptide 22, respectively.

Erythroderma can also occur secondary to GVHD (see Fig. 10.10).

Present from birth or early infancy.

Table 10.2 Causes of erythroderma in neonates and infants. SCID, severe combined immunodeficiency. Continued

173
SECTION

3 CAUSES OF ERYTHRODERMA IN NEONATES AND INFANTS

Underlying disease Clinical clues Histologic clues Additional findings


Papulosquamous and eczematous dermatoses

PRIMARY DERMATOSES
Atopic dermatitis Crusted eczematous lesions on extensor See Table 10.1 See Table 10.1
surfaces, face, scalp
Spares diaper area
Pruritus
Onset week 616
Seborrheic dermatitis Greasy, scaling plaques and satellite
papules on scalp and in skin folds
Diaper area involvement
Non-pruritic
Early onset (week 212)
Psoriasis Silvery white scaling and sharply See Table 10.1 Family history of psoriasis
demarcated plaques on face, elbows and
knees
Diaper area involvement
Nail pits
Usually later onset
DRUG REACTIONS (Table 10.1)
INFECTIONS
Staphylococcal scalded skin Temperature instability/low-grade fever Blister roof consists of the cornified Positive culture for Staphylococcus
syndrome Irritability layer and parts of the granular layer aureus (conjunctivae, nares, throat,
Skin-fold accentuation Subcorneal blisters contain a few rectum)
Large areas of tender erythema neutrophils and lymphocytes Identification of exfoliative toxins (ET-A
Superficial bulla formation followed by & ET-B) via slide latex agglutination,
desquamation double immunodiffusion, or ELISA (see
Radiating perioral scale-crusts Ch. 74)
Extracutaneous staphylococcal infections ET-A produced by S. aureus specifically
often responsible cleaves desmoglein 1

Neonatal toxic shock-like Generalized diffuse macular erythema or Colonization of umbilical stump,
exanthematous disease morbilliform eruption with confluence nasopharynx or skin with TSST-1-
Minimal scaling producing MRSA
Fever Thrombocytopenia
Occurs during first week of life
Congenital cutaneous candidiasis Maternal vaginal Candida infection with Yeast and pseudohyphae in the KOH examination, fungal culture
intrauterine spread stratum corneum (PAS)
Pustules, collarettes of scale Subcorneal and spongiform pustules
Oral cavity spared within the epidermis
May have paronychia and nail dystrophy
OTHERS
Pityriasis rubra pilaris (Ch. 9)
GVHD (e.g. maternalfetal or transfusion-related in the setting of SCID) (Ch. 52)
Diffuse cutaneous mastocytosis (Ch. 118)
Rare ichthyoses trichothiodystrophy, keratitisichthyosisdeafness (KID) syndrome, SjgrenLarsson syndrome, neutral lipid storage disease with ichthyosis (Ch. 57)
Ankyloblepharonectodermal dysplasiaclefting (AEC) syndrome (Ch. 63)
Nutritional dermatitis, including kwashiorkor (Ch. 51)
Table 10.2 Causes of erythroderma in neonates and infants (contd). ELISA, enzyme-linked immunosorbent assay; MRSA, methicillin-resistant Staphylococcus
aureus; SCID, severe combined immunodeficiency; TSST-1, toxic shock syndrome toxin 1.

whereas in chronic states they tend to be smaller and drier. Occasion- whereas a painful and fissured keratoderma can occur in Szary
ally, the cause of the erythroderma is suggested by the character of the syndrome.
scale for example, fine in atopic dermatitis or dermatophytosis, bran- In cases of pre-existing dermatoses, nail changes may precede the
like in seborrheic dermatitis, crusted in pemphigus foliaceus, and exfolia erythroderma (e.g. pits in psoriasis or horizontal ridging in atopic der-
tive in drug reactions. matitis), whereas others develop subsequently. Nail changes are said to
Despite the varied causes, erythrodermas have several common clini- be present in approximately 40% of patients. Most often shiny nails
cal features. Pruritus, the most frequent complaint, is observed in up are observed, but discoloration, brittleness, dullness, subungual hyper-
to 90% of patients. This symptom varies according to the underlying keratosis, Beaus lines, paronychia and splinter hemorrhages can be
cause, and it is most severe in patients with dermatitis or Szary syn- seen. The nails may even be totally shed. Due to their slower develop-
drome9. Given the itchscratch cycle, the skin may become thickened, ment, nail changes are of potential value in differentiating the underly-
and areas of lichenification are seen in one-third of cases. Especially ing cause. Diffuse non-scarring alopecia appears in 20% of patients with
in the case of chronic erythrodermas, patients develop dyspigmenta- chronic erythroderma, including that due to CTCL; the latter is also
tion, with hyperpigmentation (40/90 patients, 45%) observed more associated with cicatricial alopecia.
frequently than hypo- or depigmentation (18/90 patients, 20%)4. Patients with erythroderma due to a variety of causes can begin to
Palmoplantar keratoderma appears in approximately 30% of develop multiple seborrheic keratoses, and these papules may be pale
174 erythrodermic patients, and it is often an early sign in pityriasis rubra in color compared with the background erythema (Fig. 10.2). Coloniza-
pilaris9. A keratoderma with scale-crust can point to crusted scabies, tion of the skin with Staphylococcus aureus is common in the setting
CHAPTER

10
Fig. 10.1 Erythroderma Fig. 10.3 Psoriatic
with desquamation. erythroderma. The
Obvious exfoliation of disease flare correlated

Erythroderma
scale with underlying with the administration
erythema. of lithium. Courtesy, Jean L
Bolognia, MD.

persons. Furthermore, increased skin perfusion leads to thermoregula-


tory disturbances. Although hyperthermia (37%, 146/391 patients) is
Fig. 10.2 Eruptive more frequent than hypothermia (4%, 14/391), most patients describe
seborrheic keratoses in chilly sensations1,2,4,6. The chronic and excessive loss of heat leads
a patient with idiopathic to a compensatory hypermetabolism with subsequent development
erythroderma. Courtesy, of cachexia. Anemia, characterized by features of both iron deficiency
Jean L Bolognia, MD.
and anemia of chronic disease, is also observed in patients with chronic
erythroderma.
The most common extracutaneous manifestation of erythroderma
is generalized peripheral lymphadenopathy, which is found in approxi-
mately half of the patients. Even in the absence of an underlying
lymphoproliferative disorder, the lymphadenopathy may be prominent
and, if so, histologic and molecular examination of a lymph node
is recommended (in particular, flow cytometry and T-cell receptor
gene analysis)10. The major differential diagnosis is between lymphoma
tous involvement and reactive dermatopathic lymphadenopathy.
Hepatomegaly occurs in 20% of the cases (113/578), with a slight
predominance in erythroderma due to drug-induced hypersensitivity.
Splenomegaly is rarely seen and occurs most often in association with
lymphoma14,6.

Specific Findings of the Underlying Disease


In addition to the aforementioned general features, the clinical presen-
tations can have additional, sometimes specific, features suggesting the
underlying etiology (see Tables 10.1 & 10.2).
of erythroderma, and this can lead to secondary cutaneous infections.
Independent of the cause of the erythroderma, bilateral ectropion and
purulent conjunctivitis can develop as ocular complications. Lastly, an Psoriasis
exacerbation of the erythroderma can follow UV irradiation or drug Psoriasis is the most common underlying disorder in adults, whereas
ingestions, and this is not restricted to patients with photosensitive in children it represents the second most common cause of erythro-
eczema and drug-induced erythroderma, respectively4. derma, after drug eruptions. As a rule, psoriatic erythroderma is pre-
ceded by typical psoriatic plaques (see Ch. 8). Its onset is most often a
result of the withdrawal of potent topical or oral corticosteroids,
Systemic Manifestations cyclosporine or methotrexate; occasionally, widespread flares follow
An awareness of potential systemic complications of erythroderma is irritant contact dermatitis (e.g. tar), phototoxicity or systemic infection.
essential for proper patient management. Pedal or pretibial edema is After generalization of the erythema, the typical features of psoriatic
observed in approximately 50% of patients (182/380)1,35, and probably plaques are lost (Fig. 10.3), and disseminated sterile subcorneal pus-
results from a shift of fluid into extracellular spaces. In patients with tules may develop. Due to a slower turnover rate, nail changes, such
drug-induced erythroderma, facial edema may also develop. Because of as oil-drop changes, onycholysis or nail pits (Fig. 10.4), may still be
the markedly increased blood flow through the skin and an increased visible and provide valuable clues to the diagnosis of psoriatic erythro-
fluid loss by transpiration, tachycardia affects 40% of patients, and derma. Treatment of the erythroderma may result in the reappearance 175
there is a risk of high-output cardiac failure, particularly in elderly of more characteristic plaques of psoriasis.
SECTION

3 DRUGS ASSOCIATED WITH ERYTHRODERMA


Papulosquamous and eczematous dermatoses

COMMON
Allopurinol Phenytoins
Beta-lactam antibiotics Sulfasalazine
Carbamazepine/oxcarbazepine Sulfonamides*
Gold Zalcitabine
Phenobarbital
LESS COMMON
Captopril/lisinopril Lithium
Carboplatin/cisplatin Mercury compounds
Cytarabine Minocycline
Cytokines (IL-2/GM-CSF) Omeprazole/lansoprazole
Dapsone Ribavirin
Diflunisal Telaprevir
Fluindione Thalidomide
Hydroxychloroquine/chloroquine Tocilizumab
Isoniazid Vancomycin
Isotretinoin/acitretin
RARE
Abacavir Mitomycin C
Amiodarone Nifedipine/diltiazem
Fig. 10.4 Psoriatic erythroderma. Nail findings (pitting and onycholysis with a Aspirin (ASA) Other NSAIDs
proximal rim of inflammation) point to the diagnosis of psoriasis. Aztreonam Penicillamine
Beta-blockers Pentostatin
Chlorpromazine Pseudoephedrine
Cimetidine Rifampin
Ciprofloxacin St. Johns wort
Clofazimine Sulfonylureas
Atopic dermatitis Codeine Tear gas (CS gas)
Although occurring at any age, atopic erythroderma develops most Erythropoietin Terbinafine
frequently in patients with a history of moderate to severe atopic der- Fluorouracil Tobramycin
matitis. As a result, well-established pre-existing lesions can be found, Imatinib Tramadol
especially when the erythroderma is of recent onset. The pruritus is Indinavir Vinca alkaloids
intense, and secondary excoriations or prurigo-like lesions are fre- Lamotrigine Zidovudine
quently observed. Lichenification is often prominent and atrophy of the Methotrexate
skin due to topical corticosteroids may be seen. Increased serum IgE * Includes furosemide.

and eosinophilia may accompany other signs and symptoms of atopy. Not to be confused with red man syndrome due to rapid infusion of drug.

For additional drugs, see ref. 11.
Drug reactions
Table 10.3 Drugs associated with erythroderma.
The number of drugs that can cause erythroderma is staggering
(Table 10.3; see also Ch. 21). Whereas erythroderma resulting from
topical medications usually begins as dermatitis, eruptions due to sys-
temic drugs begin as a morbilliform or scarlatiniform exanthem. In
areas of greatest hydrostatic pressure (ankles and feet), the lesions may
become secondarily purpuric. Of the group of erythrodermas, those Fig. 10.5 Idiopathic
that are drug-induced have the shortest duration, usually resolving erythroderma. This is the
26 weeks after withdrawal of the responsible drug. However, it is type of patient that
imperative to exclude a drug reaction with eosinophilia and systemic requires longitudinal
symptoms (DRESS), nowadays often referred to as drug-induced hyper- evaluation to exclude the
development of
sensitivity syndrome (DIHS).
cutaneous T-cell
lymphoma.
Idiopathic erythroderma
In approximately one-third of erythrodermic patients, no underlying
disease is detectable. This group consists primarily of elderly men with
a chronic course of relapsing pruritic erythroderma in association with
dermatopathic lymphadenopathy and extensive palmoplantar kerato-
derma (Fig. 10.5); this constellation is referred to as red man syn-
drome or lhomme rouge (not to be confused with the red man
syndrome that accompanies rapid intravenous infusions of vancomy-
cin). When this group was compared with the entire group of erythro-
dermic patients, lymphadenopathy (68% vs 44%) and peripheral edema
(54% vs 40%) were found to be more common than in other types of
erythroderma, and hypothermia exceeded hyperthermia12. In one
series, atopic dermatitis, drug-induced and CTCL were the most
common etiologies not initially identified in patients with idiopathic
erythroderma2. In a second series, CTCL was the most common
underlying disease, using the detection of a cutaneous clonal T-cell
population as a diagnostic criterion13. However, it is important to note
that the presence of a T-cell clone in the peripheral blood of elderly
176 individuals may reflect a diminished T-cell receptor repertoire rather
than CTCL.
CHAPTER

10
Fig. 10.6 Erythroderma Fig. 10.7 Erythroderma
secondary to pityriasis due to pityriasis rubra
rubra pilaris. A few pilaris. Large thin scales

Erythroderma
islands of sparing are are seen as well as the
noted on the upper back characteristic orangered
(A), but are more color.
noticeable on the flank
and breast (B). Note the
salmon color.

papules on the knees, elbows and dorsal aspects of the fingers plus
nappes claires (islands of uninvolved skin within the erythroderma)
favors the diagnosis of PRP (Fig. 10.6B). When the classic histologic
A
features are present (see below), this is also helpful in distinguishing
PRP from psoriasis. Occasionally, CTCL can have an appearance
similar to PRP.

Paraneoplastic erythroderma
Paraneoplastic erythroderma is most commonly associated with lym-
phoproliferative malignancies, including types of T-cell lymphoma
other than Szary syndrome. In the case of solid-organ malignancies,
the erythroderma usually appears late in the course of the disease. Fine
scales and erythema can be accompanied by a brownish hue (i.e. melano
erythroderma). Additional signs of malignancy, such as cachexia or
fatigue, may be seen.

Bullous dermatoses
Among the bullous dermatoses, pemphigus foliaceus most commonly
presents as erythroderma; erythrodermic forms of paraneoplastic pem-
phigus and bullous pemphigoid are rare (see Table 10.1; see also Chs
29 & 30). In pemphigus foliaceus, impetigo-like blisters and erosions
B are followed by collarettes of scale and scale-like crusts (Fig. 10.8).
Usually, the erythroderma is preceded by localized lesions on the face
and upper trunk.

Ichthyoses
Erythroderma due to one of the inherited ichthyoses is usually present
Cutaneous T-cell lymphoma from birth or infancy. In neonates, one must consider congenital ich-
Erythroderma due to CTCL is subdivided into Szary syndrome and thyosiform erythroderma (CIE; previously referred to as non-bullous
erythrodermic mycosis fungoides (see Ch. 120). Szary syndrome is CIE), epidermolytic ichthyosis (previously referred to as bullous CIE),
defined by the triad of erythroderma, circulating malignant T lym- and Netherton syndrome (see Table 10.2; see also Ch. 57). As a rule,
phocytes, and generalized lymphadenopathy. Additional clinical fea- CIE presents as a collodion baby (90% of the cases)15. Within a few days
tures include a painful and fissured keratoderma, diffuse alopecia, and after birth, an erythroderma with fine white scaling appears. Epidermo-
leonine facies. The skin may be quite infiltrated or hyperpigmented lytic ichthyosis initially presents as generalized erythema with super-
(melanoerythroderma), and severe pruritus is common. To aid in dis- imposed superficial blisters and erosions. This disorder may be
tinguishing between Szary syndrome and erythrodermic mycosis fun- mistakenly diagnosed as staphylococcal scalded skin syndrome or as a
goides, revised criteria were recently proposed by the International form of epidermolysis bullosa. Later, children develop spiny, corrugated
Society of Cutaneous Lymphomas and the Cutaneous Lymphoma Task hyperkeratoses, particularly in flexural areas, and blisters and erosions
Force of the EORTC for the diagnosis of Szary syndrome erythro- become less prevalent. Netherton syndrome manifests as an ichthyosi-
derma and evidence of a T-cell clone in the blood plus one of the fol- form erythroderma in neonates. It is associated with trichorrhexis
lowing: (1) 1000 Szary cells/mm3; (2) a CD4:CD8 ratio of 10:1; or invaginata (bamboo hair), elevated serum levels of IgE, and an
(3) an increased percentage of CD4+ cells with an abnormal phenotype immune defect that can result in life-threatening infections, particu-
(40% CD4+/CD7 or 30% CD4+/CD26)14. larly within the first years of life. Later, either the ichthyosiform eryth-
roderma persists or ichthyosis linearis circumflexa develops, which is
Pityriasis rubra pilaris characterized by garland-like scaly eruptions.
Erythrodermic pityriasis rubra pilaris (PRP) can be observed in children
and adults (see Ch. 9). Usually, the lesions have a salmon to orangered Staphylococcal scalded skin syndrome
color (Fig. 10.6A). The degree of scaling varies, but it can be marked Staphylococcal scalded skin syndrome (SSSS; see Ch. 74) is seen pri- 177
with large scales (Fig. 10.7). The combination of follicular keratotic marily in children (<5 years of age), and it is due to a circulating
SECTION

3
Fig. 10.8 Erythroderma ridges, confluent parakeratosis, absence of the granular layer, elongated
due to pemphigus dermal papillae, and a sparse lymphohistiocytic infiltrate define the
foliaceus. Generalized fully developed plaque form of psoriasis, and appear in 30% of patients
Papulosquamous and eczematous dermatoses

erythema with with psoriatic erythroderma. Ten percent of patients with psoriatic
widespread scale-crusts
erythroderma exhibit findings of regressing psoriasis (i.e. slight epider-
and large areas of
erosion. mal hyperplasia, a normal or even thickened granular layer, and a
fibrotic papillary dermis)17.

Atopic dermatitis
A constant finding in atopic erythroderma is mild to moderate spongi-
osis, which is sometimes located in the follicular infundibulum.
However, spongiosis is found in other forms of dermatitis, including
contact dermatitis. Almost always, acanthosis and parakeratosis are
additional histologic features. A perivascular, rarely epidermotropic
infiltrate is observed in the upper dermis; it is accompanied by dermal
edema and prominent dermal vessels. In one series, numerous eosino
phils were found within the infiltrate in 77% of patients12.

Drug reactions
Histologically, changes vary considerably (see Ch. 21). Eosinophils may
or may not be present.

Idiopathic erythroderma
The findings in idiopathic erythroderma are generally nonspecific.
Subacute forms may have parakeratosis, acanthosis, spongiosis, papil-
lary edema and a superficial perivascular lymphohistiocytic infiltrate,
whereas chronic forms exhibit hyperkeratosis, psoriasiform acanthosis,
little (if any) spongiosis and a thickened papillary dermis9. In order to
identify the underlying disease in patients with idiopathic erythro-
exfoliative toxin produced by Staphylococcus aureus. Since desmoglein derma, the submission of multiple biopsies from untreated affected
1 is cleaved by exfoliative toxin A, pemphigus foliaceus and SSSS skin (taken either simultaneously or sequentially) is advocated. Clinico
exhibit clinical similarities, with the latter often becoming erythroder- pathologic correlation is important as sometimes there is evidence of
mic. Common foci for the initial infection include the nares, nasophar- two disorders, e.g. dermatitis superimposed upon psoriasis.
ynx, conjunctivae and umbilicus. After a period of 12 days of a
low-grade fever, large areas of tender erythema develop. The skin
appears tense and subcorneal blisters appear, which subsequently desq-
Cutaneous T-cell lymphoma
uamate. A very similar syndrome, the toxic shock syndrome, can be The histologic features of typical erythrodermic CTCL consist of a
caused by staphylococcal or streptococcal exotoxins. It favors adults, band-like infiltrate in the papillary dermis containing small to medium-
but acral exfoliation has a delayed appearance, usually 2 weeks later. sized (and occasionally large) mononuclear cells with hyperchromatic,
cerebriform nuclei as well as a variable number of admixed inflamma-
Omenn syndrome tory cells. Neoplastic cells, or sometimes groups of neoplastic cells,
colonize the basal layer of the epidermis, and the cells are either evenly
Omenn syndrome represents an autosomal recessive form of severe
distributed or form Pautriers microabscesses; the latter are pathogno-
combined immunodeficiency (see Ch. 60), and it is characterized by
monic but occur in a minority of cases. In contrast to circumscribed
failure to thrive, leukocytosis with prominent eosinophilia, hypogam-
forms of mycosis fungoides, there is often less epidermotropism and
maglobulinemia, and elevated serum IgE levels. Cutaneous findings,
the morphology of the neoplastic cells is sometimes more monotonous
which appear in neonates, are generally the first sign of the syndrome
in erythrodermic mycosis fungoides and Szary syndrome18.
and include an erythroderma with diffuse alopecia. Systemic manifesta-
tions include prominent lymphadenopathy, hepatosplenomegaly and
recurrent diarrhea. In the absence of hematopoietic stem cell or bone Pityriasis rubra pilaris
marrow transplantation, the disease is rapidly fatal with recurrent The characteristic histologic finding in PRP is foci of orthokeratosis
infections. alternating with parakeratosis in both vertical and horizontal direc-
tions. These features are also found in the follicular infundibula. A
slight psoriasiform hyperplasia may be present, but the granular layer
PATHOLOGY is normal and the rete ridges do not become thinned. In addition, a
Although sometimes subtle, histopathologic features of the underlying superficial and sparse interstitial infiltrate of lymphocytes is observed,
disease are present in about two-thirds of patients. Diagnostic findings and neutrophils are absent17.
were frequently found in psoriasis (81% of 16 patients in one series)16,
but less often in PRP or CTCL (50% of 6 and 8 patients, respectively). Ichthyoses
Erythroderma due to drug hypersensitivity and dermatitis had typical
pathologic findings in 67% (4 of 6) and 64% (9 of 16) of patients, With the exception of epidermolytic hyperkeratosis in epidermolytic
respectively16. Specific histopathologic clues to the underlying disease ichthyosis (bullous CIE), the histopathologic findings in ichthyosiform
are discussed below. erythrodermas are generally non-diagnostic. In the non-bullous inflam-
matory type, psoriasiform hyperplasia, focal spongiosis and focal
Psoriasis parakeratosis are found to a variable extent; a sparse perivascular lym-
phocytic infiltrate may be present.
In 60% of erythroderma patients diagnosed as having psoriasis, changes
associated with early psoriasis are found17. These findings include
slight epidermal hyperplasia, a reduced or absent granular layer, focal Bullous dermatoses
parakeratosis, an edematous papillary dermis, and a perivascular and The major histologic features of the bullous dermatoses are outlined
178 interstitial lymphohistiocytic infiltrate. Sometimes, extravasated erythro in Table 10.1, as are the immunofluorescence microscopy findings. The
cytes can be observed. Epidermal hyperplasia with bottleneck-like rete latter are required for precise diagnosis (see Chs 29 & 30).
CHAPTER
Staphylococcal scalded skin syndrome
Subcorneal blisters typically contain sparse acantholytic keratinocytes
A comprehensive clinical examination may reveal additional clues to
the underlying disease. Once the number of possible underlying dis- 10
eases is reduced, further laboratory investigation can aid in establishing
and few inflammatory cells.

Erythroderma
the final diagnosis.
Omenn syndrome
The histologic features of Omenn syndrome can resemble GVHD, with
vacuolar degeneration of the basal layer and keratinocyte necrosis, but TREATMENT
the former disorder is characterized by a denser dermal infiltrate of
lymphocytes (as well as macrophages and eosinophils), acanthosis Erythroderma can represent a serious medical threat to the patient,
and parakeratosis. Degeneration of subcutaneous fat lobules may be therefore hospitalization may be required. Regardless of the underlying
observed. Examination of the enlarged lymph nodes shows an absence disease, the initial management consists of nutritional assessment,
of lymph node architecture with massive infiltration of histiocytes and correction of fluid and electrolyte imbalances, prevention of hypother-
eosinophils. mia, and treatment of secondary infections. Sedating oral antihista-
mines may ease the often severe pruritus9. Systemic corticosteroids
may be necessary in idiopathic erythroderma and drug reactions. With
DIFFERENTIAL DIAGNOSIS an initial dose of 12mg/kg/day of prednisone, and a maintenance dose
of 0.5mg/kg/day or less, rapid and often continued clearing of the
Erythroderma is a clinical presentation for a variety of diseases, and erythroderma can be achieved. Caution must be exercised upon taper-
identification of the underlying etiology represents one of the most ing, as rebound may occur. Topical therapy includes open wet dressings
complex challenges in dermatology (Figs 10.9 & 10.10; see Tables 10.1 and bland emollients or low-potency corticosteroid ointments. High-
& 10.2). The evaluation starts with a complete medical history: up to potency topical corticosteroids should be reserved for lichenified areas,
45% of the patients will have a prior history of a more localized skin and chronic, extensive application should be avoided. Coal tar oint-
disease, and approximately 20% of cases represent drug reactions16. ments may aggravate the condition.

APPROACH TO THE DIFFERENTIAL DIAGNOSIS OF ADULT ERYTHRODERMA

Approach to the adult patient with erythroderma

Medical history

History or clinical Exposure to


evidence of medications,
characteristic chemicals
pre-existing skin (Table 10.3)
lesions or + for MF
Complete physical
+ examination
Histologic examination
Search for + (multiple skin
additional clinical + biopsies; lymph node
manifestations of Discontinue biopsy if obvious and/or
primary dermatosis offending agents lymphadenopathy)
Laboratory evaluation
(e.g. flow cytometry*)

Confirmation via Improvement


histologic within 26 weeks
examination and (except + + +
laboratory DRESS/DIHS)
evaluation (may Cutaneous T-cell Rare causes, e.g.
Idiopathic Paraneoplastic
include patch lymphoma hypereosinophilic
testing) syndrome,
autoimmune
connective tissue
Reconsider disease
Primary other drugs
dermatosis, Continue to
e.g. psoriasis, re-evaluate for
atopic dermatitis, + cutaneous T-cell
pityriasis rubra lymphoma Erythrodermic
pilaris, pemphigus Check for risk Solid organ, mycosis fungoides
Drug-induced Lymphoma Szary syndrome
foliaceus factors for HIV usually end stage (MF)

Fig. 10.9 Approach to the differential diagnosis of adult erythroderma. *Of peripheral blood and/or tissue. DRESS/DIHS, drug reaction with eosinophilia and 179
systemic symptoms/drug-induced hypersensitivity syndrome.
SECTION

3 APPROACH TO THE DIFFERENTIAL DIAGNOSIS OF INFANTILE ERYTHRODERMA


Papulosquamous and eczematous dermatoses

Onset at birth or during the neonatal period Later onset

Most likely
(non-bullous)
congenital Blistering and/ Recurrent Preceding or Preceding Periorificial
Prominent
ichthyosiform or erosions Pustules infections coexistent exanthematous and acral
generalized
erythroderma lesions eruption accentuation of
scaling
(see Ch.57) characteristic scaly and/or
of a primary erosive
dermatosis dermatitis
Common History of
collodion
membrane
Rare

Involvement Diarrhea Histologic Exposure to


Assess for: Assess for:
of palms & FTT confirmation medication
soles (if required) Improvement
Maternal within 26
vaginal weeks upon
Trichorrhexis Periorificial & Keratinocyte
candidiasis discontinuation
invaginata* + intertriginous necrosis on
Netherton of offending
Elevated IgE accentuation skin biopsy
agent
FTT, electrolyte
syndrome Temperature + Staphylococcal
abnormalities instability/fever scalded skin
Irritability syndrome
Extracutaneous
+ Staphylococcus
Tiger tail Trichothio- aureus infection +
hairs** dystrophy

+
Vacuolated Neutral lipid Hyperkeratosis + Cutaneous Relatively
leukocytes storage Epidermolytic
(+/) induration, thin
disease ichthyosis
EHK on skin alopecia epidermis,
(bullous CIE)
biopsy Prominent macrophage >
LAD & HSM T-cell
Streaks & swirls + Conradi- Marked infiltrate
of feathery scale Hnermann- peripheral on skin
Stippled epiphyses Happle eosinophilia, biopsy
Unilateral cataracts syndrome elevated IgE
Primary
Acanthosis,
dermatosis
parakeratosis
e.g. atopic
+ & primarily
Perifoveal + Sjgren- 'Leathery' Diffuse dermatitis,
T-cell infiltrate
glistening Larsson cutaneous cutaneous seborrheic
on skin biopsy
white dots syndrome induration mastocytosis dermatitis,
Spasticity + Darier sign psoriasis
Increased mast (see Table
cells on skin 10.2)
+ biopsy
Sensorineural KID
deafness syndrome
Consider
Keratitis (+/ )
other forms of
Later discrete
immuno-
hyperkeratotic
+ deficiency
plaques, PPK
AEC Omenn (see Table 10.2
Cleft lip &
syndrome syndrome and Ch.60)
palate
+ Ankylo-
Severe CNS Gaucher blepharon
disease, HSM disease Prominent Congenital GVHD Nutritional
WBC acid scalp cutaneous in the setting dermatitis
-glucosidase Drug eruption
involvement candidiasis of SCID (see Ch.51)

* Often not evident during infancy; hairs should be clipped from the eyebrows as well as the scalp to maximize yield.
** Detected in virtually all hairs in patients with trichothiodystrophy.
The differential diagnosis includes pustular psoriasis.
Maternal-fetal or transfusion-related GVHD can also occur outside the setting of SCID.
Progression of a morbilliform eruption to erythroderma can also characterize neonatal toxic shock-like exanthematous disease and GVHD.
Earlier onset is occasionally observed.

AEC, ankyloblepharon-ectodermal dysplasia-clefting; CIE, congenital ichthyosiform erythroderma; CNS, central nervous system; EHK, epidermolytic hyperkeratosis; EHK, epidermolytic hyperkeratosis;
FTT, failure to thrive; GVHD, graft-versus-host disease; HSM, hepatosplenomegaly; KID, keratitis-ichthyosis-deafness; LAD, lymphadenopathy; PPK, palmoplantar keratoderma; SCID, severe combined
immunodeficiency

Fig. 10.10 Approach to the differential diagnosis of infantile erythroderma.


180
CHAPTER
In neonates and children with erythroderma, management of fluid
and electrolyte balance is critical in order to prevent hypernatremic
non-essential drugs and all suspected drugs, erythroderma usually
improves within 26 weeks (with the exception of some patients with 10
dehydration. Emollients, topical antibiotics and, depending upon the DRESS/DIHS). However, systemic prednisone (12mg/kg/day) or even

Erythroderma
extent and severity of the secondary infections, systemic antibiotics are the administration of IVIg may be useful in severe cases. After careful
administered. Due to increased transcutaneous absorption, topical sali- exclusion of any underlying cause, idiopathic erythroderma may be
cylic and lactic acid should be avoided19. treated with low-potency topical corticosteroids and oral antihista-
Treatment of specific underlying diseases is outlined in the respective mines. In refractory cases, cyclosporine has been used successfully, with
chapters (see Tables 10.1 & 10.2). In the case of psoriatic erythroderma, an initial dosage of 5mg/kg/day, and subsequent reduction to 13mg/
administration of methotrexate, acitretin, cyclosporine or targeted kg/day. Additional steroid-sparing agents include methotrexate, aza-
immunomodulators (biologic agents) is preferred over systemic corti- thioprine and mycophenolate mofetil, all of which have been used
costeroids, given the risk of a pustular flare when corticosteroids are anecdotally, with dosages similar to those for recalcitrant atopic der-
tapered20. For drug reactions, following the discontinuation of all matitis. There are a few case reports of the use of etanercept.

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181