Eosinophilic cellulitis (Wells syndrome)

INTRODUCTION — Eosinophilic cellulitis (EC) is a rare inflammatory skin disorder of unknown etiology first described by Wells in 1971 as "recurrent granulomatous dermatitis with eosinophilia" [1]. EC is characterized clinically by pruritic, erythematous plaques resembling infectious cellulitis and histologically by the presence of edema, infiltration of eosinophils, and "flame figures" in the dermis. The exact nature of EC remains controversial. Most authors considered EC to be a specific disorder with a unique constellation of clinical and histopathologic signs, although many of the clinical and histologic features of EC are not specific, as they can be found in other inflammatory disorders [2,3].

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and treatment of EC. Hypereosinophilic syndromes and other disease associated with eosinophilia are reviewed separately. Angiolymphoid hyperplasia with eosinophilia and Kimura disease are also discussed separately.

●(See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

●(See "Eosinophil biology and causes of eosinophilia".)

●(See "Approach to the patient with unexplained eosinophilia".)

●(See "Angiolymphoid hyperplasia with eosinophilia and Kimura disease".)

EPIDEMIOLOGY — The epidemiology of eosinophilic cellulitis (EC) is not well defined. The prevalence and incidence of EC are unknown. EC is thought to predominantly occur in adults, with peak incidence in the second and third decades of life [4,5]. However, EC occurs in patients of all ages, and a case of congenital EC has even been reported [6].

There is no sex predilection for EC in adults, but there may be a male predilection for EC in children [7]. There is no known racial or ethnic predilection for EC.

PATHOGENESIS — The pathogenesis of eosinophilic cellulitis (EC) is unclear. It appears to be a reaction pattern to a variety of stimuli, rather than a disease with a single etiology. Most of our understanding of the pathogenetic mechanisms underlying EC is derived from single case reports. Some have suggested that EC is caused by a delayed type (type IV) hypersensitivity reaction, similar to allergic contact dermatitis [8,9].

A case report examined peripheral blood T cell receptor gamma gene rearrangements and found several clonal populations of circulating T cells; in addition, interleukin (IL)-5 expression was significantly increased in in vitro assays of the patient's peripheral blood mononuclear cells [10]. Another case report found elevated levels of peripheral CD4⁺CD7^- cells expressing mRNA for IL-5, which decreased with successful treatment [11].

Eosinophil degranulation leads to the release of eosinophil cationic and major basic proteins, which may have toxic effects on tissue and further activate other immune cells [12-15] (see "Eosinophil biology and causes of eosinophilia"). Elevated levels of IL-5 and eosinophil cationic protein in serum and fluid extracted from bullous lesions, which fluctuated and correlated with disease activity and recurrence, were described in one patient [16]. Eosinophilic major basic protein has been found surrounding collagen fibers using immunofluorescence and is thought to contribute to the formation of flame figures [17].

Eliciting factors — A variety of different stimuli for EC have been proposed, including:

●Infections:

•Viral (varicella, mumps, parvovirus, coxsackievirus, coronavirus disease 2019 [COVID-19]) [7,18-21]

•Fungal (Trichophyton rubrum)

•Bacterial (Mycoplasma) [22]

●Parasitic infestations (giardiasis, toxocariasis, onchocerciasis) [23,24]

●Insect bite or sting (bees, ticks, fleas, spiders) [7,25,26]

●Vaccines (hepatitis B; diphtheria, tetanus, and pertussis [DTaP]; tetanus; COVID-19) [27-31]

●Drugs (adalimumab, infliximab, ustekinumab, penicillins, lincomycin, tetracycline, minocycline, ampicillin, erythromycin, bleomycin, chlorambucil, anticholinergics, anesthetics, danazol, acetylsalicylic acid, tenoxicam, diclofenac sodium and amoxicillin, thiazides) [3,10,32-36]

●Delayed type (type IV) hypersensitivity (thimerosal in vaccines [8,37], aluminum in vaccines [38], paraphenylenediamine in a temporary tattoo [9])

●Malignancy (metastatic renal carcinoma [39], chronic lymphocytic leukemia [40,41])

●Atopic dermatitis [42]

●In utero exposure to medications [6]

Reactions may be delayed and have been reported to occur as long as 15 days after the exposure [8]. A case report of three family members with short stature and developmental delay suggested that EC may have an underlying genetic predisposition [43].

None of the above-mentioned triggers or mechanisms have been definitively proven. Many cases have been reported with no relevant prior exposures or etiologies [33,34].

CLINICAL MANIFESTATIONS — Eosinophilic cellulitis (EC) is characterized by the sudden onset of single or multiple pruritic, erythematous plaques, most often located on the extremities, that resemble infectious cellulitis (picture 1). However, the clinical presentation may be heterogeneous, with morphologically different lesions coexisting in the same patient. In a review of 32 published cases of EC, all patients presented with large, erythematous plaques; in some, other types of lesions were also present, including vesicles (19 percent), bullae (34 percent), papules (22 percent), and nodules (16 percent) [44]. Seven clinical variants have been described: plaque-type, annular granuloma-like, urticaria-like, papulovesicular, bullous, papulonodular, and fixed drug eruption-like [33]. An erysipelas-like presentation of Wells syndrome has been reported [45].

Lesions typically develop over a two- to three-day period and resolve without scarring in two to eight weeks [34]. Lesions may be localized or diffuse and are most commonly located on the trunk and limbs, but can also occur on the face, eyelids, ears, scalp, axillae, and groin, and even involve the tongue and throat [44].

Itching and burning may precede or occur simultaneously with visible lesions. Lesions may be warm to touch, but generally are not tender and do not respond to antimicrobial therapy as in bacterial cellulitis [44].

Approximately one in five patients may present with systemic symptoms, including fever, malaise, and/or arthralgias [44]. The presence of systemic symptoms in EC may indicate a more severe or progressive course [46].

Laboratory abnormalities may include peripheral eosinophilia (50 to 67 percent), leukocytosis (41 percent), and elevated erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, and serum immunoglobulin E (IgE) [34,44,47,48]. However, none of these findings are required for diagnosis.

Clinical course and complications — In most cases, lesions resolve in two to eight weeks without scarring [49]. However, in some patients the course may be prolonged, with lesions lasting for months or years. Lesions may recur in the same location, even after a complete and prolonged remission.

Superinfection with Staphylococcus aureus, Pseudomonas aeruginosa, and other bacteria may occur [49,50]. Atrophic scarring, scarring alopecia, and dyspigmentation have been reported in complicated cases [49,50].

PATHOLOGY — Eosinophilic cellulitis (EC) is histologically characterized by the presence of edema, infiltration of eosinophils, and "flame figures" in the dermis in virtually all cases [44]. A superficial and deep, perivascular, chronic, inflammatory infiltrate may be present [51]. Flame figures are composed of eosinophil major basic protein surrounding collagen fibers [17]. Of note, they may be detected in other eosinophilic dermatoses associated with cutaneous eosinophilia, such as bullous pemphigoid, eczema, prurigo, pemphigoid gestationis, drug eruptions, and scabies [2,52,53].

Some authors have described different stages of lesions, with dermal edema and infiltration of eosinophils occurring early on in lesions ("acute stage"), followed by later formation of flame figures ("subacute stage") [54]. As EC lesions resolve ("resolving stage"), there can be phagocytic histiocytes palisading around the flame figures, foreign-body giant cells, and granuloma formation [54]. Intense edema in the dermis and/or epidermis may result in bullae formation [53,55].

Vasculitis is absent [32,51,54]. Direct immunofluorescence and special stains for microorganisms are negative [51,54]. The stratum corneum is typically normal, though mild compact orthokeratosis or focal parakeratosis has been observed [53].

DIAGNOSIS — The diagnosis of eosinophilic cellulitis (EC) is difficult and often delayed, as most patients are initially misdiagnosed with bacterial cellulitis and treated with antibiotic therapy. The diagnosis of EC should be suspected in patients with a clinical history of recurrent, pruritic, cellulitic plaques that are nontender and do not respond to antibiotic treatment. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

A skin biopsy showing characteristic histopathologic findings (eosinophilic dermal infiltrate, "flame figures," and a blood cell count demonstrating peripheral eosinophilia) support the clinical diagnosis. However, as the clinical, histologic, and laboratory findings of EC are not specific, a careful clinicopathologic correlation is necessary for the definitive diagnosis.

Additional diagnostic workup may be needed to identify potential triggers and rule out other disorders that share similar features [32]. (See 'Eliciting factors' above and 'Differential diagnosis' below.)

Skin biopsy — A punch biopsy with standard hematoxylin and eosin staining is typically adequate for identification of the characteristic histologic findings of EC. (See 'Pathology' above.)

Immunohistochemistry and special stains are generally not required for the diagnosis of EC. However, in resolving lesions with phagocytic palisading histiocytes, special stains for microorganisms and tissue culture may be required to rule out deep fungal or mycobacterial infections [51]. Direct and/or indirect immunofluorescence may be performed to rule out bullous pemphigoid.

Laboratory tests and imaging — A complete blood cell count with differential should be performed to detect peripheral eosinophilia. Additional testing (eg, skin bacterial cultures, potassium hydroxide [KOH] preparation, stool examination for parasites, serologic testing) may be needed to exclude other conditions with or without associated eosinophilia that may mimic EC. (See 'Differential diagnosis' below.)

Occasionally, magnetic resonance imaging (MRI) has been used to rule out osteomyelitis, computed tomography (CT) scan to rule out an underlying abscess, as well as magnetic resonance venography or venous Doppler examination to rule out deep vein thrombosis [51].

Proposed diagnostic criteria — A series of clinical and pathologic criteria have been proposed to help in the diagnosis of EC [3]. However, they have not been validated in large series of patients:

●Major criteria (two of four are required):

•Clinical presentation consistent with EC:

-Plaque-type

-Annular granuloma-like

-Urticaria-like

-Papulovesicular

-Bullous

-Papulonodular

-Fixed drug eruption-like

•Relapsing, remitting course

•No evidence of systemic disease

•Histologic features of dermal eosinophilic infiltration and no vasculitis

●Minor criteria (at least one is required):

•Flame figures

•Histologic features of granulomatous change

•Peripheral eosinophilia, not persistent and not >1500/microL

•Triggering factor (eg, drug)

DIFFERENTIAL DIAGNOSIS — A wide range of disorders present with clinical and/or histopathologic findings that overlap with those of eosinophilic cellulitis (EC); most, but not all, of them are associated with peripheral eosinophilia [2,18,44,56] (see "Eosinophil biology and causes of eosinophilia"). These include:

●Infections and infestations:

•Bacterial cellulitis – Bacterial cellulitis presents with erythema, edema, and warmth of well-demarcated skin areas, usually associated with systemic symptoms, including fever, chills, and malaise. Lesions are most often located on the lower extremities and are typically unilateral (picture 2). An elevated white blood cell count with neutrophilia supports the diagnosis. On histology, there is dermal edema and a nonspecific neutrophilic and lymphocytic infiltrate. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

•Tinea corporis – Tinea corporis is a dermatophytic infection that usually presents with pruritic, circular or oval, erythematous, scaling patch or plaque that spreads centrifugally (picture 3A-C). A potassium hydroxide (KOH) preparation will show the segmented hyphae characteristic of dermatophyte infections (picture 4). (See "Dermatophyte (tinea) infections".)

•Toxocariasis – Toxocariasis (visceral larva migrans) is an infestation with the larvae of the dog ascarid Toxocara canis. Heavy infestation may present with fever, anorexia, malaise, hepatomegaly, and a pruritic, urticaria-like cutaneous eruption. The diagnosis can be confirmed by enzyme-linked immunosorbent assay (ELISA) demonstrating immunoglobulin G (IgG) antibodies to Toxocara antigens. (See "Toxocariasis: Visceral and ocular larva migrans".)

•Scabies – Scabies presents with an intensely pruritic eruption of multiple small, erythematous papules, which are often excoriated (picture 5); severe infestation may cause peripheral blood eosinophilia. The diagnosis is based on clinical history, physical examination, and demonstration of scabies mites in skin scrapings. In difficult cases, a skin biopsy may be needed. (See "Scabies: Epidemiology, clinical features, and diagnosis".)

•Erythema migrans (EM) – EM is the most common manifestation of Borrelia burgdorferi infection (early localized Lyme disease). It presents as an erythematous plaque at the site of the tick bite that typically expands slowly over the course of days or weeks, often with central clearing (picture 6 and picture 7). As EM appears before the development of an immune response, the diagnosis of early Lyme disease is clinical in a patient who lives in or has recently traveled to an area that is endemic for Lyme disease. (See "Clinical manifestations of Lyme disease in adults" and "Diagnosis of Lyme disease".)

●Arthropod bites:

•Large local reaction to insect bites − Hypersensitivity reactions to mosquito and other insects bites present with itchy, red, warm swellings sometimes accompanied by low-grade fever and malaise. Clues to the diagnosis include a history of exposure to insect bites and the rapid development of lesions, typically within hours of the exposure. (See "Allergic reactions to mosquito bites" and "Insect and other arthropod bites".)

●Autoimmune dermatoses:

•Bullous pemphigoid (BP) – The prodromal phase of BP is characterized by pruritic, inflammatory plaques that may resemble EC (picture 8). In this phase, histology shows eosinophilic spongiosis with a superficial dermal infiltrate of lymphocytes, eosinophils, and neutrophils. Direct immunofluorescence on a biopsy sample taken from the perilesional skin shows an IgG and/or C3 linear staining along the basement membrane zone. The diagnosis of BP is further confirmed by ELISA for antibodies to the BP antigen BP180 NC16A domain. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

•Pemphigoid gestationis − Pemphigoid gestationis (formerly called herpes gestationis) is a rare autoimmune bullous disease that occurs during the second or third trimester of pregnancy. It presents with intensely pruritic plaques typically located on the abdomen (picture 9). The diagnosis is confirmed by direct immunofluorescence on a biopsy of perilesional skin showing a linear deposit of IgG and/or C3 at the basement membrane zone and detection of circulating antibodies to BP180. (See "Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.)

●Drug reactions:

•Maculopapular drug eruptions – Maculopapular (morbilliform) drug eruptions are characterized by erythematous macules and papules that predominantly involve the trunk and proximal extremities occurring 5 to 14 days after drug exposure (picture 10A-B). Symptoms include pruritus, low-grade fever, and mild eosinophilia. Histologically, there is a superficial perivascular and interstitial infiltrate of lymphocytes, neutrophils, and eosinophils. The rapid resolution of the rash after drug discontinuation supports the diagnosis. (See "Exanthematous (maculopapular) drug eruption".)

•Drug reaction with eosinophilia and systemic symptoms (DRESS) – DRESS is a potentially life-threatening, systemic hypersensitivity reaction characterized by fever; malaise; lymphadenopathy; maculopapular, confluent skin eruption (picture 11A-B); variable organ involvement; and leukocytosis with eosinophilia and/or atypical lymphocytosis. The diagnosis is based upon the combination of clinical and laboratory findings and a history of exposure to drugs frequently associated to DRESS (table 1). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Hypereosinophilic syndromes:

•Episodic angioedema with eosinophilia − Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, elevated serum immunoglobulin M (IgM) levels, and marked eosinophilia that occur at three to four week intervals and resolve spontaneously [57,58]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

•Eosinophilic granulomatosis with polyangiitis (EGPA) − EGPA, formerly called Churg-Strauss syndrome, is a rare, systemic vasculitis characterized by chronic rhinosinusitis, asthma, and marked peripheral blood eosinophilia. Cutaneous manifestations of EGPA include palpable purpura, infiltrated nodules and papules, livedo reticularis, necrotizing livedo, and migratory erythema (picture 12). (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

•Eosinophilic fasciitis − Eosinophilic fasciitis, also called Shulman syndrome, is a rare disorder characterized in its early phase by symmetric limb or trunk erythema and edema that progresses to fibrosis, induration, and a peau d'orange appearance [59]. Peripheral eosinophilia is present in most patients. A deep skin biopsy down to the fascia and muscle surface shows edema of the subcutis and fascia with an infiltrate of lymphocytes, plasma cells, histiocytes, and eosinophils. (See "Eosinophilic fasciitis".)

●Inflammatory and allergic dermatoses – A number of inflammatory and allergic dermatoses may share histopathologic and clinical features with EC. These include atopic dermatitis, allergic contact dermatitis, urticarial dermatitis, prurigo nodularis, and granuloma annulare. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis" and "Clinical features and diagnosis of allergic contact dermatitis" and "Urticarial dermatitis" and "Prurigo nodularis" and "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

●Eosinophilic dermatosis of hematologic malignancy – Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare condition characterized by itchy and sometimes painful papules and plaques resembling exaggerated insect bite reactions that occurs in patients with chronic lymphocytic leukemia or, less frequently, B cell non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute monocytic leukemia, or large cell lymphoma [60-62]. EDHM lesions are predominately located on the limbs, but frequently occur on the trunk, and may be widespread. Histologically, there is a perivascular lymphohistiocytic and eosinophilic infiltrate in the papillary and mid-dermis that, in some cases, may extend to the reticular dermis and subcutaneous fat [62]. Overexpression of T helper type 2 (Th2) cell markers has been noted on immunohistochemistry [63].

●Mastocytoma – Cutaneous mastocytosis may present in children with reddish or skin-colored nodules or plaques that are in most cases solitary (picture 13A-B). If rubbed, these lesions develop an urticarial reaction (Darier sign) that is pathognomonic. There is usually an associated mild peripheral eosinophilia. A skin biopsy can confirm the diagnosis. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)

TREATMENT — There is no consensus regarding the optimal management of eosinophilic cellulitis (EC). No randomized controlled trials or large prospective studies of treatments in EC have been performed, and the available evidence is mainly derived from case reports and small case series [44,64].

Medium- to high-potency topical corticosteroids are the first-line therapy in patients with localized disease and especially in children [8,44]. Topical corticosteroids are applied twice daily until improvement.

Patients with generalized disease and those with localized disease that is not controlled with topical corticosteroids require a short course of systemic corticosteroids [44,51]. Prednisolone 0.5 to 1 mg/kg per day may be given for five to seven days and then tapered off over two to three weeks.

Alternative regimens that have been reported as effective include initial higher doses of oral corticosteroids (up to 2 mg/kg per day) [51], intravenous corticosteroids [47], and long courses of low-dose (5 mg every other day) oral corticosteroids [65]. If signs and symptoms recur upon discontinuation, alternative nonsteroidal therapies should be considered for long-term use.

Antihistamines may be an adjunctive therapy for control of pruritus but have no effect on the skin lesions [44,66]. Other therapies that have been used in recurrent or refractory cases include mepolizumab [67-69], omalizumab [70], dupilumab [71], cyclosporine [72], dapsone [73], azathioprine [54], griseofulvin [74], minocycline [75], colchicine [76], interferon alpha [77], and psoralen with ultraviolet A (PUVA) phototherapy [78].

PROGNOSIS — The overall prognosis of eosinophilic cellulitis (EC) is good. Lesions may spontaneously improve or improve with treatment of any underlying disorders [32]. However, recurrence is common in both adults and children, particularly among persons with multiple body areas involved and spreading of lesions beyond the area of initial involvement [8,44,54]. Multiple recurrences have been reported, with a mean number of four relapses in adults and three in children over many years [33].

FOLLOW-UP — Clinical follow-up is indicated for all patients with eosinophilic cellulitis (EC) to assess the response to treatment and disease recurrence. Surveillance for the development of hematologic malignancy is indicated particularly for patients with chronic comorbidities or presenting with systemic symptoms [60].

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Eosinophilic cellulitis (EC) is a rare inflammatory skin disorder characterized clinically by pruritic, erythematous plaques and/or vesicobullae resembling infectious cellulitis and histologically by the presence of edema, infiltration of eosinophils, and "flame figures" in the dermis. EC appears to be a reaction pattern to a variety of stimuli rather than a disease with a single etiology. Proposed trigger factors include infections, parasitic infestations, insect bites, vaccines, delayed type sensitizers, drugs, and malignancy. (See 'Pathogenesis' above.)

●Clinical presentation – EC presents with the sudden onset of single or multiple erythematous plaques most often located on the extremities (picture 1). Lesions resemble bacterial cellulitis, but are nontender and do not respond to antimicrobial therapy. In most cases, lesions resolve in two to eight weeks without scarring. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of EC should be suspected in patients with a clinical history of recurrent, pruritic, erythematous plaques resembling bacterial cellulitis that do not respond to antibiotic treatment. A skin biopsy showing characteristic histopathologic findings (eosinophilic dermal infiltrate, "flame figures," and a blood cell count demonstrating peripheral eosinophilia) supports the clinical diagnosis. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of EC is broad and includes infections and infestations, insect bites, drug reactions, bullous pemphigoid, hypereosinophilic syndromes with cutaneous manifestations, inflammatory and allergic dermatoses, and eosinophilic dermatosis associated with hematologic malignancy. (See 'Differential diagnosis' above.)

●Management – Medium- to high-potency topical corticosteroids are the first-line therapy for patients with localized disease and children with EC. Patients with extensive disease typically respond to a short course of oral corticosteroids. (See 'Treatment' above.)

●Prognosis – The overall prognosis of EC is favorable. However, patients may experience multiple relapses over months or years. (See 'Prognosis' above.)