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Eosinophilic Disorder/Wells Syndrome is characterized clinically by an acute dermatitis resembling cellulitis and histopathologically by dermal eosinophilic infiltration.
Wells syndrome is a rare eosinophilic disorder that primarily affects the skin. Affected people typically develop a skin rash that is often preceded by itching or burning skin. The rash consists of raised, red, swollen areas that may be warm to the touch.
Wells syndrome is a rare, idiopathic dermatosis with recurrent, erythematous, urticarial plaques that become more indurated and subsequently heal with mild pigmentation. The course of the disease is mild despite occasional constitutional symptoms. Although Wells syndrome is usually sporadic, familial,[rx] neonatal,[rx] and childhood[rx] cases have been reported. There is wide polymorphism in the clinical and histological presentation of the disease, depending upon the nature and location of the infiltrate.[rx] Blood eosinophilia may or may not be found
The pathogenesis of Wells syndrome is obscure. Many triggering factors have been reported including insect bites, viral infections (parvovirus B19, herpes simplex virus, varicella-zoster virus, mumps virus), parasitic infections[rx] (Ascaris, Toxocara canis, Giardia), bacterial or fungal infections, drugs (antibiotics, non-steroidal anti-inflammatory drugs, thiazide diuretics, anti-TNF, biomedicines) and vaccines. Association of Wells syndrome with other diseases has also been described such as hematologic malignancies (chronic myeloid leukemia,[rx] chronic lymphocytic leukemia, polycythemia vera, non-Hodgkin lymphoma), malignant tumors, ulcerative colitis,[rx] eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome),[rx] hypereosinophilic syndrome[rx]). Wells syndrome may be prior, revealing, or concomitant to these diseases. The fortuitous nature of some of these situations cannot be ruled out, but one must remain vigilant in case of prolonged evolution beyond 6 months, persistent eosinophilia and/or systemic manifestations associated with Wells syndrome.[rx]
The most interesting associations from a pathogenic point of view are certainly those belonging to the spectrum of eosinophilic diseases,[rx] such as Shulman syndrome, Churg-Strauss syndrome, and hypereosinophilic syndrome. Wells syndrome could be the first clinical manifestation of these diseases.[rx][rx][rx]
The physiopathogenic links between the triggering factors and the associations mentioned above are not clearly established. Inappropriate activation of a Th2-like T lymphocyte clone, synthesizing IL-5, and other eosinophil-stimulating cytokines in response to various, often unidentified, antigenic stimuli is the commonly accepted assumption.
Causes of Eosinophilic Disorder
The pathogenesis of Wells syndrome is unknown. It may be explained as an inappropriate eosinophilic reaction to a wide variety of stimuli due to an abnormal function of eosinophil regulatory systems. Many triggering factors have been proposed: insect bites, drugs, allergic contact dermatitis, an underlying myeloproliferative disorder, and infections (e.g., dermatophytes, viruses, Toxocara canis).
Symptoms of Eosinophilic Disorder
- Plaque type
- Annular granuloma-like
- Fixed drug eruption-like.
Diagnosis of Eosinophilic Disorder
The histological images vary according to the progressive stage of the lesions. Initially, significant edema and a dermal infiltrate of eosinophils are seen. Some of the eosinophils are degranulated. The sub-acute stage is characterized by images called “flame-figures,” located in the mid to deep dermis. The flame-figures are composed of a central part consisting of collagen fibers and eosinophilic granules, surrounded by a histiocytic and eosinophilic infiltrate.[rx] Subsequently, eosinophils tend to disappear and are replaced by phagocytic granulomas, consisting of histiocytes and sometimes giant cells, around the flame figures. The absence of vasculitis is an important negative sign.
The flame-figures are not specific to Wells syndrome and can be observed in many other skin conditions in which degranulation of eosinophils occurs including prurigo, eczema, arthropod bite, scabies, bullous pemphigoid, pemphigus vegetans, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).
The study in electron microscopy shows many eosinophils in degranulation, expressing signs of membrane cytolysis. Intact or fragmented free granules are seen in the dermis around the collagen fibers, thus forming the flame figures.[rx]
The diversity of clinical aspects of Wells syndrome is probably explained by the level of eosinophilic infiltrate, which may be dermic (superficial or deep), hypodermic thus giving an image of eosinophilic panniculitis,[rx] or even subcutaneous.[rx]
History and Physical
Wells described the first patient in 1971 as “recurrent granulomatous dermatitis with eosinophilia.” He later renamed the disease “eosinophilic cellulitis.”[rx] In 1979, Spiegel and Winkelmann proposed the eponym “Wells syndrome.”
Wells syndrome has a sudden onset. In the classic form, symptomatology is marked by large well limited inflammatory erythematous and edematous patches that are often covered with vesicles or bullae. The lesions are located preferentially on the trunk and the extremities. The eruption is preceded by sensations of itching or burning. General signs are rare. A low fever can be associated with the cutaneous symptoms. The evolution in the following days is marked by an extension of the patches, which take an annular configuration, with the center healing while the border becomes purple. Inflammatory signs regress within approximately 10 days while the plaques become indurated. Restitutio ad integrum usually occurs in 4 to 6 weeks. Recurrence is the rule, with variable locations. The period between recurrences varies from a few months to several years; however, the prognosis remains good with long-term recovery.
Biologically, the main element is peripheral blood eosinophilia which is found in about 50% of cases during the acute phase.
- Diagnosis is by complete blood count (CBC) – However, in some cases, a more accurate absolute eosinophil count may be needed.[rx][rx]
- Specific test – for causative conditions are performed, often including chest x-ray, urinalysis, liver and kidney function tests, and serologic tests for parasitic and connective tissue diseases.
- The stool – is often examined for traces of parasites (i.e. eggs, larvae, etc.) though a negative test does not rule out parasitic infection; for example, trichinosis requires a muscle biopsy.[rx]
- Elevated serum B12 or low white blood cell – alkaline phosphatase, or leukocytic abnormalities in a peripheral smear indicates a disorder of myeloproliferation.[rx] In cases of idiopathic eosinophilia, the patient is followed for complications. A brief trial of corticosteroids can be diagnostic for allergic causes, as the eosinophilia should resolve with suppression of the immune over-response.[rx]
- Marrow aspiration and biopsy – Neoplastic disorders are diagnosed through the usual methods, such as bone marrow aspiration and biopsy for the leukemias, MRI/CT to look for solid tumors, and tests for serum LDH and other tumor markers.[rx]
- The evaluation for primary eosinophilia – should begin with screening peripheral blood for FIP1L1- PDGFRA gene fusion. Diagnostic testing should start with a peripheral smear. Cytogenetic testing and FISH analysis can be performed on peripheral blood as well.[rx][rx]
- Concurrent cytophilic or cytopenias – if present, can help for diagnosis. In that case, bone marrow biopsy, along with karyotype and genetic screen of chromosomes, may be required.[rx][rx]
- B12 level and tryptase level – along with cytogenetic/immunophenotypic testing and marrow findings, help diagnose chronic mastocytosis, acute/chronic myeloid leukemia, myelodysplastic syndrome, MDS/MPN overlap. When skin rashes are present, skin biopsy helps to diagnose cutaneous disorders like pemphigoid, eczema, mycosis fungoides, Sezary syndrome. Imaging of the chest helps diagnose aspergillosis, Loeffler syndrome, Churg Strauss syndrome. An ultrasound abdomen helps to evaluate for splenomegaly. Stool testing helps to assess for parasitic infections.
Treatment of Eosinophilic Disorder
The treatment of Wells syndrome is not codified. Apart from the etiological treatment of a triggering or associated disease, corticosteroids and dapsone are the two main treatments for Wells syndrome.
- Corticosteroids – It is the reference treatment for all reactional dermatoses whether neutrophilic or eosinophilic. General corticotherapy reduces the duration and importance of relapses in 10% of cases.[rx] Initial doses range from 0.5 to 1 mg/kg/day, with rapid tapering. During the decrease of the treatment, it is not uncommon to observe a relapse of the lesions, which can lead, in certain cases, to a real corticosteroid dependence. Local corticosteroids represent an interesting alternative to general corticosteroids, especially in superficial forms, with inconsistent results of the order of 50%.[rx] However, it should not be used in deep hypodermic or extended forms.
- Dapsone – Dapsone is an interesting therapeutic alternative to corticosteroids, with doses ranging from 50 to 200 mg daily. It would reduce the duration of relapses. The optimal duration of treatment is not clearly defined but can be several months in the absence of adverse effects requiring discontinuation of treatment. It can be used alone or in combination with other treatments, including corticosteroids. It can also serve as a relay for general corticosteroids, especially in cases of corticosteroid dependence.
- Antihistamines – Antihistamines, especially hydroxyzine if pruritus, is important and maybe tried as a first intention, because of their excellent tolerance even if their effectiveness does not seem to exceed 25% of the cases.[rx] They sometimes allow the practitioner to avoid the use of general steroid treatment. The dosage varies from 50 to 100 mg/day. Hydroxyzine can be combined with other antihistamines.
- Phototherapy – narrow band ultraviolet (UV) B preferred to broadband UVB, as well as psoralen plus UVA (PUVA), is often used as an adjuvant to the above therapeutic modalities.
In most cases, general corticosteroids (10 to 80 mg daily) allow rapid healing. Tapering the dose over one month is generally well tolerated. Continued low-dose therapy with corticosteroids allows preventing recurrences. Dapsone may be prescribed as first-line treatment in low inflammatory forms. It also seems to give good results in case of corticosteroids resistance [rx]. IFN-alpha and IFN-beta could represent interesting alternatives.[rx][rx] For mild cases, topical corticosteroids may be sufficient. Finally, the treatment of an associated disease, when it is found, is essential. It must be prescribed as a first-line treatment and can cure Wells syndrome.[rx]
In aggressive forms of the disease, second-line cytotoxic agents and stem cell transplants have proven some benefit. Antibody use against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), and CD52 (alemtuzumab), as well as other targets on eosinophils, continues to be an active area of investigation.[rx][rx] Timely intervention is vital to reduce morbidity and mortality.
Treatment is directed toward the underlying cause.[rx] However, in primary eosinophilia, or if the eosinophil count must be lowered, corticosteroids such as prednisone may be used. However, immune suppression, the mechanism of action of corticosteroids, can be fatal in patients with parasitosis.[rx]