Background
Wells syndrome (eosinophilic cellulitis) is an uncommon condition of unknown etiology. In 1971, George Wells first described this syndrome as a recurrent granulomatous dermatitis with eosinophilia.[1] In 1979, he and Neil Smith renamed it eosinophilic cellulitis.
The presentation of Wells syndrome 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.[2] Papular and nodular eruptions at the clinical presentation have also been reported. The condition can recur and may be preceded by a pruritic papular eruption. Although the syndrome is usually sporadic, some familial cases have been reported.
In a small retrospective study (N = 9), vasculitis, Wells syndrome, and Sweet syndrome occurred in succession in one patient, suggests that these diseases may overlap each other.[3] Another report described a dominant syndrome consisting of eosinophilic cellulitis, intellectual disability, and abnormal body habitus in one family.[4]
Of the numerous treatment options available for Wells syndrome,[5] systemic corticosteroids are the most effective, though they carry a risk of corticosteroid dependence. Other options include topical corticosteroids, calcineurin inhibitors, griseofulvin, H1-receptor antagonists, cyclosporine, and dapsone.
Pathophysiology
At least some cases of Wells syndrome may involve 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 this syndrome.[6] 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.
Type 2 T helper cell (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.[7] 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 (IL)-5, suggesting 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 the flame figures.
Etiology
The etiology of Wells syndrome is unknown. Drugs, various infections, and, possibly, nonhematologic malignancies may act as as trigger events.[10, 11] Medications linked include antibiotics, anticholinergic agents, anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), thyroid medications, chemotherapeutic agents, thiomersal-containing vaccinations, anti–tumor necrosis factor (TNF) agents, and thiazide diuretics.[12, 13] Vaccines implicated include hepatitis B vaccine, influenza vaccine, tetanus vaccine, tetanus-diphtheria vaccine, human papillomavirus (HPV) vaccine, and triple-antigen vaccine.[14, 13, 15, 16]
Although some familial cases have been described, eosinophilic cellulitis is usually sporadic. Suggested precipitating factors include the following:
Arthropod bites and stings, including those of the honeybee[17]
Cutaneous viral infections - There may be a link between parvoviral infection and Wells syndrome[18]
Cutaneous parasitic infestations, including toxocariasis,[19, 20] ascariasis,[21] and onchocerciasis[22]
Leukemia[23]
Myeloproliferative disorders
Atopic dermatitis
Fungal infections
Giardiasis[24]
Hypersensitivity reactions to medications or metals, including metallic alloy implants[25]
Churg-Strauss syndrome - This association has been noted in a few patients[26] ; the reports are noteworthy for the presence of bullae and antineutrophil cytoplasmic antibodies[27] ; only a few other autoimmune diseases have been associated with Wells syndrome, including a case report of systemic lupus erythematosus (SLE)[28]
Differentiating Wells syndrome from Churg-Strauss syndrome can be challenging.[29] Both syndromes may be characterized by eosinophils and flame figures. It has been postulated that Wells syndrome might represent the initiation of a pathogenetic process that is fully developed as Churg-Strauss syndrome.[30] Thus, the two syndromes may occur together or appear to do so, possibly in association with the hypereosinophilic syndrome.[31]
Epidemiology
Wells syndrome is rare, with only a couple of hundred reported cases in the literature.[1]
Wells syndrome usually affects adults but has been known to occur in children.[32, 33, 34] In one case series of 19 patients, the classic plaque-type presentation was the most common variant in children, whereas the annular granuloma–like variant was the most common variant in adults.[35]
Prognosis
The prognosis for patients with Wells syndrome is excellent. The condition tends to resolve in weeks or months, usually without scarring; however, it occasionally recurs, and in these recurrent cases, it can take years to resolve.
History
Usually, a 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.[36, 37] Typically, a tender or mildly pruritic cellulitislike eruption occurs. The clinical presentation may also include annular plaques, vesicles and bullae (bullous Wells syndrome associated with non-Hodgkin lymphoma[38] ), and urticaria.[39] This rare linkage of Wells syndrome with lymphoma may even be the latter’s initial manifestation, though that is usually not the case.[40]
Systemic symptoms, including asthma, arthralgia, and fever, may be evident, though they usually do not occur. In most cases, there are no long-term sequelae, but in some, reticular pigmentation and scarring alopecia may occur. Rarely, Wells syndrome is associated with life-threatening diseases such as leukemia and lymphoma.[23, 41, 42] It remains to be determined whether these are coincidental findings or real associations.
Physical Examination
The lesions in patients with Wells syndrome 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, gradually darkening from bright red to slate blue. Complete resolution with no scarring is typical, though scarring alopecia may occur in some cases.
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, increases in eosinophil cation protein (ECP) and interleukin (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
In Wells syndrome, 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, though it occasionally extends into the subcutaneous tissue and the underlying muscle.[51, 52, 53] (See the images below.)
View Image | Superficial and deep perivascular and interstitial inflammatory pattern. Image from DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/path.... |
View Image | Superficial and deep perivascular and interstitial inflammatory pattern extending into subcutaneous tissue. Image from DermNet New Zealand (https://ww.... |
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.[54] 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.[55, 56]
Medical Care
There are numerous treatment options for Wells syndrome (eosinophilic cellulitis), including the following (see Medication):
Topical corticosteroids
Systemic corticosteroids
Calcineurin inhibitors
Antifungals (eg, griseofulvin)
Antibiotics (eg, dapsone)
Immunosuppressants (eg, cyclosporine[57] )
H1-receptor antagonists (eg, cyproheptadine and diphenhydramine)
Systemic corticosteroids are the most effective treatment, but they may lead to corticosteroid dependence.
First-generation antihistamines should be used with caution; they have poor receptor selectivity, cross the blood-brain barrier, reduce rapid eye movement (REM) sleep, and interfere with histaminergic transmission.[58]
Because Wells syndrome tends to resolve, systemic treatment should be used cautiously.[5]
Some case reports have described successful treatment of Wells syndrome with Janus kinase (JAK) inhibitors (eg, abrocitinib and ruxolitinib).[59, 60] Others have described successful use of dupilumab[61, 62] and other monoclonal antibodies.[63]
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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