Wells Syndrome

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Background

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]

Pathophysiology

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.

Etiology

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:

Epidemiology

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]

Prognosis

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.

History

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.

Physical Examination

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.

Approach Considerations

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.

Histologic Findings

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.[47, 48, 49]  See the images below.



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A superficial and deep perivascular and interstitial inflammatory pattern. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/p....



View Image

Superficial and deep perivascular and interstitial inflammatory pattern extending into the subcutaneous tissue. Courtesy of DermNet New Zealand (https....

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.[50] 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.[51, 52]

Approach Considerations

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.[53]

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

Medication Summary

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.[53] 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.[54] Since it tends to resolve, systemic treatment should be used cautiously.[55]

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

Griseofulvin (Fulvicin P/G, Grifulvin V)

Clinical Context:  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

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.

Dapsone

Clinical Context:  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

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

Cyclosporine (Sandimmune, Neoral, Gengraf)

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

Cortisone

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

Prednisone

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

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

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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

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

Cyproheptadine

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

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

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.

What is Wells syndrome (eosinophilic cellulitis)?What is the pathophysiology of Wells syndrome (eosinophilic cellulitis)?What causes Wells syndrome (eosinophilic cellulitis)?Which factors increase the risk for Wells syndrome (eosinophilic cellulitis)?What is the prevalence of Wells syndrome (eosinophilic cellulitis)?What is the prognosis of Wells syndrome (eosinophilic cellulitis)?What are the signs and symptoms of Wells syndrome (eosinophilic cellulitis)?Which physical findings are characteristic of Wells syndrome (eosinophilic cellulitis)?Which conditions should be included in the differential diagnoses of Wells syndrome (eosinophilic cellulitis)?What are the differential diagnoses for Wells Syndrome?How is Wells syndrome (eosinophilic cellulitis) diagnosed?Which histologic findings are characteristic of Wells syndrome (eosinophilic cellulitis)?How is Wells syndrome (eosinophilic cellulitis) treated?What is the role of medications in the treatment of Wells syndrome (eosinophilic cellulitis)?Which medications in the drug class Antihistamines, 1st Generation are used in the treatment of Wells Syndrome?Which medications in the drug class Immunosuppressants are used in the treatment of Wells Syndrome?Which medications in the drug class Antibiotics, Other are used in the treatment of Wells Syndrome?Which medications in the drug class Antifungals, Other are used in the treatment of Wells Syndrome?

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Justin Brown, MD, Dermatologist, The Dermatology Group

Disclosure: Received honoraria from Medicis for review panel membership; Received honoraria from Triax for review panel membership.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD Herman Beerman Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology and American Society of Dermatopathology

Disclosure: Lippincott Williams Wilkins Royalty Textbook editor; DLA Piper Consulting fee Consulting

Takeji Nishikawa, MD Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc

Disclosure: Nothing to disclose.

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A superficial and deep perivascular and interstitial inflammatory pattern. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/pathology/t/wellsfigure2.jpg).

Superficial and deep perivascular and interstitial inflammatory pattern extending into the subcutaneous tissue. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/pathology/t/wellsfigure3.jpg).

A superficial and deep perivascular and interstitial inflammatory pattern. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/pathology/t/wellsfigure2.jpg).

Superficial and deep perivascular and interstitial inflammatory pattern extending into the subcutaneous tissue. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/pathology/t/wellsfigure3.jpg).