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]

Wells syndrome (eosinophilic cellulitis) is an uncommon condition of unknown etiology. The presentation usually involves a mildly pruritic or tender cellulitis-like 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 there is an overlap between these diseases.[6] Another report describes a dominant syndrome consisting of eosinophilic cellulitis, mental retardation, and abnormal body habitus in one family.[7]

At least some cases of Wells syndrome (eosinophilic cellulitis) may represent hypersensitivity to an arthropod bite or sting. An impressive response of peripheral lymphocytes to mosquito salivary gland extracts has been documented in some patients with Wells syndrome.[8] 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.

Th2-skewing immune dysregulation may be evident, as may a strong CD4+ T-cell proliferation in response to mosquito salivary gland extracts, probably reflecting a significant association between Wells syndrome and mosquito bites in some patients.[9] In one study, immunophenotyping of peripheral T cells revealed an increased proportion of CD3+ and CD4+ T cells.[10] 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.[11]

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.

The etiology of Wells syndrome (eosinophilic cellulitis) is unknown. Wells syndrome may be due to drugs, various infections, and, possibly, nonhematologic malignancies as trigger events.[12, 13] Medications linked include antibiotics, anticholinergic agents, anaesthetics, nonsteroidal anti-inflammatory agents, thyroid medications, chemotherapeutic agents, thiomersal-containing vaccinations, antitumor necrosis factor agents, and thiazide diuretics.[14, 15] Vaccines implicated include hepatitis B vaccine, influenza vaccine, tetanus vaccine, tetanus-diphtheria vaccine, human papillomavirus vaccine, and triple-antigen vaccine.[15, 16, 17]

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 honeybee[18]

• Cutaneous viral infections; there is a possible link between parvoviral infection and Wells syndrome[19]

• Cutaneous parasitic infestations, including toxocariasis,[20, 21] ascariasis,[22] and onchocerciasis[23]

• Leukemia[24]

• Myeloproliferative disorders

• Atopic dermatitis

• Fungal infections

• Giardiasis[25]

• Hypersensitivity reactions to medications or metals, including metallic alloy implants[26]

• Churg-Strauss syndrome: This syndrome has been associated in a few patients[27] ; these reports are noteworthy for the presence of bullae and of antineutrophil cytoplasmic antibodies[28] ; only a few other autoimmune diseases have been associated, including a case report of systemic lupus erythematosus[29] ; sometimes, differentiating between these disorders can be challenging[30] Both Wells syndrome and Churg-Strauss syndrome may have eosinophils and flame figures. It has been postulated that Wells syndrome could represent the initiation of a pathogenetic process fully developed as Churg-Strauss syndrome.[31]

Wells syndrome (eosinophilic cellulitis) is rare. Only about 80 cases have been reported worldwide.

Wells syndrome usually affects adults, but it has been known to occur in children.[32, 33, 34, 35] In one case series of 19 patients, the classic plaque-type presentation was the most common variant found in children, whereas the annular granuloma–like variant was the most common variant in adults.[36]

The prognosis for patients with Wells syndrome (eosinophilic cellulitis) is excellent. It tends to resolve in weeks or months, usually without scarring. It occasionally recurs. In these recurrent cases, it can take years to ultimately resolve.

Usually, the patient with Wells syndrome (eosinophilic cellulitis) 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 cellulitis-like eruption occurs. The clinical presentation may also include annular plaques, vesicles and bullae (bullous Wells syndrome associated with non-Hodgkin lymphoma[37] ), and urticaria.[38]

Systemic symptoms, including asthma, arthralgia, and fever, may be evident, although they usually do not occur. Although long-term sequelae usually do not result, reticular pigmentation and scarring alopecia may occur. Rarely, Wells syndrome is associated with life-threatening diseases such leukemia and lymphoma.[24, 39, 40] However, at this point, determining if these are coincidental findings or real associations is impossible.

The lesions in patients with Wells syndrome (eosinophilic cellulitis) progress over a few days to become large, indurated plaques of edema and erythema, with violaceous edges and no collar. 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 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.

Wells Syndrome (eosinophilic cellulitis) is usually diagnosed on the basis of the characteristic histopathologic findings in a skin biopsy specimen.

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. The levels of ECP and IL-5 seem to be correlated with the severity of the disease.

Skin biopsy specimens of Wells Syndrome (eosinophilic cellulitis) 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.[49, 50, 51]  See the images below.

Vesiculation can occur. The blisters contain eosinophils and are predominantly 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.[52] 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, dermatitis herpetiformis, scabies, and insect bites.[53, 54]

There are numerous treatment options for Wells Syndrome (eosinophilic cellulitis), including the use of topical corticosteroids, calcineurin inhibitors, griseofulvin, H1 antihistamines, cyclosporine, dapsone, and systemic corticosteroids.[55]

Systemic corticosteroids are the most effective treatment, but they may lead to corticosteroid dependence.

The medications used for the treatment of eosinophilic cellulitis include antifungals, such as griseofulvin; antibiotics, such as dapsone; immunosuppressants, such as cyclosporine and cortisone; and H1 receptor antagonists, such as cyproheptadine and diphenhydramine.[55] First-generation antihistamines should be used with caution, as they have poor receptor selectivity, cross the blood-brain barrier, reduce rapid eye movement (REM) sleep, and interfere with histaminergic transmission.[56] Since it tends to resolve, systemic treatment should be used cautiously.[57]

Systemic corticosteroids are the most effective treatment, but they may lead to corticosteroid dependence.

Class Summary

The mechanism of action of antifungals 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)

Griseofulvin has fungistatic activity. Fungal cell division is impaired by interfering with microtubules. It binds to keratin precursor cells. Keratin is gradually replaced by noninfected tissue, which is highly resistant to fungal invasions.

Class Summary

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

Dapsone

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

Class Summary

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

Cyclosporine (Sandimmune, Neoral, Gengraf)

Cyclosporine has been demonstrated to be helpful in a variety of skin disorders.

Cortisone

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

Prednisone

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear activity.

Hydrocortisone topical (Cortaid Advanced, Dermacort, Westcort, Ala-Cort, HydroSKIN)

Hydrocortisone is an adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. It decreases inflammation by suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.

Dexamethasone (Baycadron)

Dexamethasone is used for various allergic and inflammatory diseases. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Betamethasone (Diprolene, Celestone, Celestone Soluspan, Luxiq)

Betamethasone is used for inflammatory dermatoses responsive to steroids. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. It affects production of lymphokines and has an inhibitory effect on Langerhans cells.

Class Summary

H1 receptor antagonists 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. These first-generation antihistamines should be used with caution, as they have poor receptor selectivity, cross the blood-brain barrier, reduce rapid eye movement (REM) sleep, and interfere with histaminergic transmission. Histamine is a vital neurotransmitter that increases arousal in the circadian sleep-wake cycle and reinforces learning and memory.

Cyproheptadine

Cyproheptadine is used for the symptomatic relief of allergic symptoms caused by histamine released in response to allergens and skin manifestations.

Diphenhydramine (AllerMax, Aller-Cap, Anti-Hist, Benadryl)

Diphenhydramine is used for the symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Chlorpheniramine (Chlor-Trimeton, Teldrin, Aller-Chlor, Chlor-Hist)

Chlorpheniramine is used to treat intense, localized allergic reactions. This agent competes with histamine or H1-receptor sites on effector cells in blood vessels and the respiratory tract.

Hydroxyzine hydrochloride (Vistaril)

Hydroxyzine hydrochloride antagonizes H1 receptors in the periphery. It may suppress histamine activity in the subcortical region of the central nervous system (CNS).