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Clinical dermatology • Concise report

CED
Clinical and Experimental Dermatology

Persistent hypereosinophilia with Wells syndrome
J. Powell, M. Kaur, R. Muc, P. Colloby and A. Salim
Departments of Dermatology and Histopathology, Solihull Hospital, Heart of England NHS Foundation Trust, Birmingham, UK
doi:10.1111/j.1365-2230.2012.04370.x

Summary

Since Wells and Smith first described cases of eosinophilic cellulitis (Wells syndrome; WS) in 1979, it has been noted that some but not all patients with WS present with eosinophilia. In the face of idiopathic persistent eosinophilia patients will also then fall within the hypereosinophilic syndrome (HES), which represents a multifarious spectrum of disorders of varying severity, causes and outcomes. In this article we propose that patients who present within the HES spectrum with cutaneous findings of WS and with no extracutaneous disease be classified as having ‘persistent hypereosinophilia with Wells syndrome’ (PHEWS).

In 1979, Wells and Smith described cases of eosinophilic cellulitis (also known as Wells syndrome; WS). Since then, it has been noted that some patients with WS present with eosinophilia. In the face of idiopathic persistent eosinophilia, patients may also then fall within the description of hypereosinophilic syndrome (HES) which represents a multifarious spectrum of disorders of varying severity, causes and outcomes. We present the case of a patient with WS who also falls within the HES but with no extracutaneous manifestations and propose a new term and diagnostic criteria for this condition.

Report
A 64-year-old woman presented with a 6-year history of a pruritic skin eruption. Individual lesions persisted for several weeks before fading, leaving postinflammatory hyperpigmentation, but crops of new lesions continued to arise. The patient remained systemically well throughout. On physical examination, red papules, nodules and urticarial-like lesions were present on the patient’s trunk and limbs (Fig. 1a).

Correspondence: Dr James Powell, Department of Dermatology, Worcestershire Royal Hospital, Worcester WR5 1DD, UK E-mail: jbpowell@doctors.org.uk Conflict of interest: none declared. Accepted for publication 16 January 2012

On histological examination, the epidermis was normal in appearance. Perivascular and interstitial infiltrates were seen within the superficial dermis, containing numerous eosinophils and occasional flame figures (Fig. 1b). Laboratory investigations identified hypereosinophilia, which had been present throughout the illness, peaking at 4.12 · 109 eosinophils per litre (normal range 0–0.4 · 109 ⁄ L), and being persistently above 1.5 · 109 ⁄ L for 5 years. Full blood count, renal and liver function tests, autoimmune profile, and measurement of erythrocyte sedimentation rate, C-reactive protein, serum IgE and tryptase levels gave normal results. Tests for filarial, schistosomal and strongyloides serology were negative. No abnormalities were seen on chest radiographs. Cytogenetic and molecular studies did not identify any clonal haematological abnormality, including FIP1L1 ⁄ PDGFRA (family-interacting protein 1-like 1 ⁄ platelet-derived growth factor receptor-a) gene fusion. Three years previously, a short course of oral steroids had brought about a near-complete clinical remission and had markedly improved the eosinophil count, but a full relapse occurred shortly after the steroids were stopped. In this case, a clinicopathological diagnosis of WS could be made, however, we noted that the patient also falls within the HES spectrum. In their paper, Wells and Smith1 described the characteristic clinocopathological features of WS. Classically and in its most severe form, WS presents initially

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Ó The Author(s) CED Ó 2012 British Association of Dermatologists • Clinical and Experimental Dermatology, 38, 40–43

develop such complications. peripheral neuropathy. parasitic. For diagnostic purposes. and generalized central nervous system dysfunction such as upper motor neurone signs and encephalopathy.7 Such complications include cardiac failure and fibrosis. associated with signs and symptoms of hypereosinophilic disease. coated in granular eosinophilic material (haematoxylin and eosin. and choroidal abnormalities can all occur.1. Wells and Smith stated originally that WS is probably a hypersensitivity reaction induced by various triggers such as insect bites or drug reactions. Such multifarious clinical findings continue to be reported in patients diagnosed with WS. may result in severe complications and even death. despite chronic hypereosinophilia. firm and granulomatous.Persistent hypereosinophilia with Wells syndrome • J. which are often pruritic. the underlying aetiologies in some cases of HES have been identified.2 Such features include dermal oedema with infiltration of eosinophils and macrophages between connective-tissue bundles. (a) (b) Figure 1 (a) Multiple urticated plaques on the abdomen with excoriated areas. some patients with HES are asymptomatic or present with more ‘benign’ disease.7 However. Lesions then become infiltrated. with scattered ‘flame figures’ (clusters of eosinophils and macrophages around a central focus of collagen coated in granular eosinophilic material). and is unresponsive to antibiotics. Areas are red and oedematous. The commonest chromosomal mutation seen in M-HES is the deletion on chromosome 4q12. Powell et al. Since 1975. (b) flame figure showing clusters of eosinophils and macrophages around a central focus of collagen.3 HES4 and chronic lymphocytic leukaemia. leading to a protein with significant tyrosinekinase activity. during which lesions may resemble morphoea.6 In HES. and these patients may never. tissue eosinophilic infiltration and mediator release leads to variable end-organ damage. and no comment was made on how long any eosinophilia (if present) persisted. three criteria have been used to define HES: (i) blood eosinophilia over 1. annular and plaque-like lesions. patients with myeloproliferative (M)-HES can now be identified through molecular and genetic techniques. using flow cytometry. less severe. so long as secondary causes of eosinophilia. hepatic-vein obstruction. eosinophilic oesophagitis. 38. and (iii) signs and symptoms of organ damage. such as drug-induced. allergic and autoimmune causes. gastritis or colitis.5 It therefore seems that WS represents a cutaneous reaction pattern that can develop in any situation in which abnormal numbers of eosinophils are allowed to accumulate in the skin for any. causing the fusion of the FIP1L1 ⁄ PDGFRA (F ⁄ P) genes. Furthermore.8 For example. have been excluded. Hypereosinophilic syndrome is a term covering a wide range of heterogenous conditions.1 Wells and Smith then described other. there is no longer the insistence that the hypereosinophilia be ‘truly’ idiopathic. 40–43 41 . often unknown. meaning that the diagnosis will sometimes be made solely on characteristic cutaneous histological features. with an acute pseudocellulitis.1 Since their study. namely those with urticaria-like. but the affected skin does not have a raised temperature on palpation. hepatitis. Ó The Author(s) CED Ó 2012 British Association of Dermatologists • Clinical and Experimental Dermatology. (ii) no secondary cause for eosinophilia found. or if this recurred in the future. papular. reason. bullous. peripheral blood eosinophilia was not always present.5 · 109 ⁄ L for > 6 months or death within that time. WS has been reported to occur in systemic disorders associated with eosinophilia such as Churg–Strauss syndrome. resolving over several weeks. and may blister. with green-blue discoloration. which despite aggressive treatment. perhaps limited to the skin. Since it was first described. which may extend to affect the greater part of a limb. nodular. original magnification · 100).7.7 Pulmonary features (such as fibrosis and nonproductive cough). In the cases they presented. cutaneous presentations of WS. hypersplenism.

as with many issues around HES. We have therefore set out the case for distinguishing patients with WS from those with WS plus persistent idiopathic eosinophilia with no extracutaneous organ involvement. This will include referral for a haematological assessment. and therefore patients should not be regarded as having ‘solely’ WS.5 · 109 ⁄ L. dapsone. and regarded those affected as being at the ‘benign end’ of the HES spectrum (‘benign’ here indicating no extracutaneous complications resulting from eosinophilia).8. and (iii) no eosinophilia-mediated extracutaneous organ involvement. but since the identification of the F ⁄ P mutation. including transformation to leukaemia or lymphoma. which secrete eosinophilopoietic cytokines [interleukin (IL)-3 and ⁄ or IL-5] causing eosinophilia. eosinophilia. such questions will be answered in the future. (ii) L-HES (with demonstrable clonal or phenotypically aberrant lymphocyte population).Persistent hypereosinophilia with Wells syndrome • J. When carrying out investigations for any extracutaneous complications of persistent hypereosinophilia. and possibly bone-marrow biopsy with cytogenetic. especially if the eosinophilia is persistent. as it is not yet possible to predict what. tetracyclines and interferon-a2a have also been reported to be effective and useful as steroid-sparing agents in patients needing long-term treatment. with systemic corticosteroids used initially. as some patients with chronic eosinophilia can and will develop internal organ disease as detailed above. However. these patients are now treated successfully with imatinib mesylate. including episodic variants).5 · 109 ⁄ L). nodules.9 Identification of different subtypes of HES is important to allow treatment to be tailored and long-term outcomes predicted in individual cases within the HES spectrum.6 in 1975. to define ‘persistent hypereosinophilia’. (iii) familial eosinophilia (including an autosomal dominant form mapped to chromosome 5q31–33). 38. Such cases are a readily identifiable subgroup of patients within the HES spectrum.4 Wells and Smith1 recognized this overlap in 1979.12 Currently. Currently no classification system adequately identifies such patients. histochemical and immunophenotypic studies. In 2005.5 · 109 ⁄ L in the setting of another diagnosis. FIP1L1 ⁄ PDGFRA analysis.8. characterized by an aberrant population of T-cells of uncertain origin. if any. We hope that with the establishment of PHEWS as a distinct syndrome. and dose adjustments according to response.7. Furthermore. corticosteroids were initially the first-line treatment for all types of HES. azathioprine. lymphocytic (L)-HES has been identified. ‘Idiopathic’ here means that any causes of M-HES and secondary eosinophilia have been excluded. urticara-like lesions and angio-oedema have all been described. erythematous papules. those with WS and persistent idiopathic eosinophilia but no extracutaneous organ involvement do not fit happily into any single subtype of HES. although often present. as used in the HES diagnostic criteria established by Chusid et al. and pruritus.11 We have used the cutoff point of > 1. molecular. and for now remains as for WS. (ii) clinicopathological features of WS.7 Using current classification schemes. Topical corticosteroids alone may be sufficient.11 Diagnoses of WS occurring in such patients with HES continue to occur. including measurement of serum tryptase levels.9 Owing to this ongoing aetiological uncertainty in many cases of HES. time has shown that the term ‘benign’ is misleading. Antihistamines. an attempt has been made to classify patients within the spectrum based on their clinical and pathological features. in which eosinophilia has been described as a feature in a subset of those affected). treatments and outcomes in such cases can be defined. 42 Ó The Author(s) CED Ó 2012 British Association of Dermatologists • Clinical and Experimental Dermatology. griseofulvin. (v) overlap HES (eosinophilic disease restricted to one organ system with eosinophilia > 1. It is important to be able to identify and classify such patients on clinicopathological grounds. and include the case we describe above. using the following diagnostic criteria: (i) idiopathic persistent hypereosinophilia > 1. and thus we propose a new classification of persistent hypereosinophilia with Wells syndrome: ‘PHEWS’. with a low threshold of suspicion for cardiac and pulmonary involvement. six subtypes of HES were proposed:8 (i) M-HES (including F ⁄ P negative with myeloproliferative features. ciclosporin. F ⁄ P positive and chronic eosinophilic leukaemia with cytogenetic abnormalities). 40–43 . For example. Powell et al. (iv) unidentified HES (idiopathic with or without symptoms. Cutaneous involvement is present in 45–60% of patients with HES. Treatment in cases of confirmed PHEWS will largely be aimed at symptomatic relief. physicians can be guided by clinical findings and symptoms. patient outcome. so that the aetiology.10. is not needed to make a diagnosis of WS. treatment goals and disease progression are largely uncertain in PHEWS. Monitoring such patients with persistent hypereosinophilia on a long-term basis to some degree seems currently sensible.5 · 109 ⁄ L for > 6 months. and (vi) associated HES (eosinophilia > 1. damage such persistent hypereosinophilia may cause or whether a haematological malignancy will develop in the future.

Persistent hypereosinophilia with Wells syndrome • J. 27: 333–55. Patnaik MM. 114: 3736–41. 7 Sheikh J. 142: 1157–61. Tanaka T. 34: e643–6. Blood 2009. 126: 45–9. Beukers S. Kirtschig G. Learning points • Wells syndrome is a reactive process in which some patients present with eosinophilia and may therefore be within the HES spectrum. Vezzoli P. Eosinophilia: secondary. References 1 Wells GC. • Identifying such patients is important so longterm outcomes. Marzano AV. Dale DC. persistent hypereosinophilia (>1. 8 Klion AD. Br J Dermatol 1979. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. 4 Bogenrieder T. Ó The Author(s) CED Ó 2012 British Association of Dermatologists • Clinical and Experimental Dermatology. Clin Exp Dermatol 2009. Clin Exp Dermatol 2010. 40–43 43 . Hypereosinophilic syndrome in an atopic patient. Kato T. Snead D. Schiffner R et al. 34: e274–5. Wakabayashi M. 2 Caputo R. Vlachou C. 35: e3–4. Medicine (Baltimore) 1975. 38. 54: 1–27. Wells syndrome associated with Churg-Strauss syndrome. Thushara R. Eosinophilic cellulitis. 6 Chusid MJ. 3 Fujimoto N. Wells’ syndrome associated with hypereosinophilic syndrome. • Any eosinophilia present in the context of WS must be thoroughly investigated. • Patients can be diagnosed with ‘PHEWS’ if they have idiopathic. 100: 101–9. 5 Gambichler T. Pardanani A.5 · 109 ⁄ L) plus the clinicopathological features of WS with no evidence of any eosinophilmediated extracutaneous organ involvement. Wolff SM. Bochner BS et al. 12 Ladoyanni E. Rothenberg ME. 36: 46–8. Immunol Allergy Clin North Am 2007. Weller PF. Impetiginized Wells’ syndrome in a patient with chronic lymphocytic leukaemia. 10 Neve S. Rotterdam S et al. Br J Haematol 2006. A patient with Wells’ syndrome. J Allergy Clin Immunol 2010. 9 Simon HU. Smith NP. Powell et al. How I treat hypereosinophilic syndromes. Griese DP. especially if persistent. Clinical overview of hypereosinophilic syndromes. Clin Exp Dermatol 2009. West BC. Lunardon L. Clin Exp Dermatol 2010. clonal and idiopathic. Othlinghaus N. Arch Dermatol 2006. treatment goals and management strategies can be defined. Br J Dermatol 1997. Wells syndrome in adults and children. 133: 468–92. Refining the definition of hypereosinophilic syndrome. 137: 978–82. 11 Tefferi A.