Eosinophilic cellulitis (Wells syndrome)

In 1971, George Wells first described this syndrome as a recurrent granulomatous dermatitis with eosinophilia.¹ Wells and Smith renamed it eosinophilic cellulitis in 1979.²

Eosinophilic cellulitis (Wells syndrome) is an uncommon condition of unknown etiology. The presentation usually involves a mildly pruritic or tender cellulitislike eruption with typical histologic features characterized by edema, flame figures, and a marked infiltrate of eosinophils in the dermis.³ Papular and nodular eruptions at the clinical presentation have also been reported.^4,5 The condition can recur and may be preceded by a pruritic papular eruption. Although Wells syndrome is usually sporadic, some familial cases have been reported.

One study showed the successive occurrence of vasculitis, Wells syndrome, and Sweet syndrome in a patient. This finding suggests that an overlap between these diseases exists.⁶ Another report describes a dominant syndrome consisting of eosinophilic cellulitis, mental retardation, and abnormal body habitus in one family.⁷

Pathophysiology

The etiology is unknown. At least some cases may represent hypersensitivity to an arthropod bite or sting. A dermal infiltrate of histiocytes, eosinophils, and eosinophilic granules occurs between collagen bundles, which forms the classic flame figures. The eosinophilic infiltrate is almost always restricted to the epidermis and the dermis, but it has also been found in the subcutaneous tissue and the underlying muscle. The location of the infiltrate is correlated with the different clinical features.

In one study, immunophenotyping of peripheral T cells revealed an increased proportion of CD3⁺ and CD4⁺ T cells.⁸ These lymphocytes spontaneously release significant amounts of interleukin 5 (IL-5); this finding suggests that activated T cells may be involved in the pathogenesis of blood and tissue eosinophilia. The eosinophils then degranulate in the dermis, causing edema and inflammation.⁹

With immunofluorescent stains, eosinophil major basic protein is identified in the granules of the flame figures. On electron microscopy, the collagen fibers are intact; this finding suggests that an initial degeneration of collagen is not a factor in initiating the formation of flame figures.

Eosinophilic cellulitis may be due to drugs, various infections, and, possibly, nonhematological malignancies as trigger events.^10,11 Wells syndrome has also been reported to occur in patients with hypereosinophilic syndrome and Churg-Strauss syndrome.

History

Usually, the patient reports pruritus or a burning sensation, which is followed by erythema and edema. Occasionally, papular and nodular eruptions may be seen first. Typically, a tender or mildly pruritic cellulitislike eruption occurs. Systemic symptoms, including asthma, arthralgia, and fever, may be evident, although they usually do not occur.

The clinical presentation can vary widely and may include the following:

• Annular plaques
• Vesicles and bullae - Bullous Wells syndrome associated with non-Hodgkin lymphoma¹⁶
• Urticaria¹⁷
• Edema
• Papules or nodules

Physical

The lesions progress over a few days to become large, indurated plaques of edema and erythema, with violaceous edges and no calor. The lesions may last for several weeks, but they gradually darken from bright red to slate blue. Complete resolution with no scarring is typical, although scarring alopecia may occur.

The plaques can occur anywhere on the skin, and they may be solitary or multiple. Plaques on the affected areas are known to recur, and vesiculobullae may develop over the surface.

The clinical features seem to depend on the location of the infiltrates in the dermis. This observation suggests that a spectrum of eosinophilic dermatoses occurs in Wells syndrome.

Causes

The etiology is unknown. Wells syndrome is usually sporadic, but some familial cases have been described. Suggested precipitating factors include the following:

• Arthropod bites and stings, including those of the honeybee¹⁸
• Cutaneous viral infections
• Cutaneous parasitic infestations, including toxocariasis,^19,20 ascariasis,²¹ and onchocerciasis²²
• Leukemia
• Myeloproliferative disorders
• Atopic dermatitis
• Fungal infections
• Hypersensitivity reactions to medications
• Churg-Strauss syndrome: This syndrome has been associated in a few patients. These reports are noteworthy for the presence of bullae and of antineutrophil cytoplasmic antibodies.

Laboratory Studies

Peripheral blood and bone marrow eosinophilia are usually present. In peripheral blood, an increase in eosinophil cation protein (ECP) and IL-5 levels can be detected. Of note, the levels of ECP and IL-5 seem to be correlated with the severity of the disease.

Procedures

Eosinophilic cellulitis is usually diagnosed on the basis of the characteristic histopathologic findings in a skin biopsy specimen.

Histologic Findings

Skin biopsy specimens show a dermal infiltrate of eosinophils, histiocytes, and eosinophil debris between collagen bundles that forms flame figures. During the acute early phase, the dense infiltrate of degranulating eosinophils is usually located in the epidermis and the dermis, although it occasionally extends into the subcutaneous tissue and the underlying muscle.^24,25,26

Vesiculation can occur. The blisters contain eosinophils and are predominately subepidermal and, occasionally, multiloculated and spongiotic. The location of the infiltrate is correlated with the different clinical features.

After weeks, the flame figures are seen, along with a palisade of histiocytes and giant cells around some collagen fibers. With immunofluorescent stains, eosinophil major basic protein is identified in the granules of the flame figures.²⁷ On electron microscopy, the collagen fibers are intact; this finding suggests that an initial degeneration of collagen is not a factor in initiating the formation of flame figures.

Although the histopathologic findings of eosinophilia, histiocytes, and flame figures are characteristic of Wells syndrome, they are also found in other conditions, including bullous pemphigoid, eczema, tinea infection, and insect bites.

Medical Care

Numerous treatment options include the use of topical corticosteroids, griseofulvin, H1 antihistamines, cyclosporine, dapsone, and systemic corticosteroids.²⁹ Systemic corticosteroids are the most effective treatment, but they may lead to corticosteroid dependence.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antifungal

Mechanism of action usually involves inhibiting pathways (enzymes, substrates, transport) necessary for sterol/cell membrane synthesis or altering the permeability of the cell membrane (polyenes) of the fungal cell.

Griseofulvin (Fulvicin P/G, Grifulvin V)

Fungistatic activity. Fungal cell division is impaired by interfering with microtubules. Binds to keratin precursor cells. Keratin is gradually replaced by noninfected tissue, which is highly resistant to fungal invasions.

Antibiotics

Therapy must cover all likely pathogens in the context of this clinical setting.

Dapsone (Avlosulfon)

Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.

Immunosuppressants

These agents inhibit key factors in the immune system responsible for immune reactions.

Cyclosporine (Sandimmune, Neoral)

Demonstrated to be helpful in a variety of skin disorders.

Cortisone (Cortone)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Prednisone (Orasone, Meticorten, Sterapred, Deltasone)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Hydrocortisone topical (LactiCare-HC, Cortaid, Dermacort, Westcort, CortaGel)

An adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. Decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.

Dexamethasone (Alba-Dex, Dexone, Baldex, AK-Dex, Decadron)

For various allergic and inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Betamethasone (Topical) (Diprolene, Maxivate, Alphatrex)

For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.

H1 receptor antagonists

These agents act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal and flare reactions, bronchial constriction, mucous secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

Cyproheptadine (Periactin)

For the symptomatic relief of allergic symptoms caused by histamine released in response to allergens and skin manifestations.

Diphenhydramine (Benylin, Benadryl)

For symptomatic relief of symptoms caused by release of histamine in allergic reactions.

²⁸