Case Report and Review of Wells' Syndrome in Childhood Amy E

Bullous “Cellulitis” With Eosinophilia: Case Report and Review of Wells’ Syndrome in Childhood

Amy E. Gilliam, MD*; Anna L. Bruckner, MD‡; Rene´e M. Howard, MD*; Brian P. Lee, MD§; Susan Wu, MD§; and Ilona J. Frieden, MD*࿣

ABSTRACT. A 1-year-old girl presented with acute on- but later simplified the name to eosinophilic celluli- set of edematous erythematous plaques associated with tis.2 bullae on her extremities and accompanied by peripheral Wells’ syndrome is seen more commonly among eosinophilia. She was afebrile, and the skin lesions were adults but has been observed among children. Some pruritic but not tender. The patient was treated with hypothesize that this syndrome may represent a hy- intravenously administered antibiotics for presumed cel- persensitivity response to a circulating antigen.2 As- lulitis, without improvement. However, the lesions re- sponded rapidly to systemic steroid therapy. On the basis sociated precipitants include insect bites, medication of lesional morphologic features, peripheral eosino- reactions, recent immunization, myeloproliferative philia, and cutaneous histopathologic features, a diagno- disorders, malignancies, and infections. We describe sis of Wells’ syndrome was made. Wells’ syndrome is a case of a young child with no identifiable triggering extremely rare in childhood, with 27 pediatric cases re- factors, and we review the evidence for evaluation ported in the literature. Because it is seen so infre- and management of these pediatric cases. quently, there are no specific guidelines for evaluation and management of Wells’ syndrome among children. CASE REPORT The diagnosis should be considered for children with A previously healthy, 1-year-old girl presented with acute on- presumed cellulitis and eosinophilia who fail to respond set of edematous erythematous plaques, with associated bullae, on to antibiotics. Evaluation should include a directed his- her lower extremities and left arm (Fig 1). These lesions were tory, physical examination, complete blood count, and pruritic but not painful, and the patient was afebrile. Her parents stool testing for ova and parasites, to identify potential denied a history of insect bites, ingestion of medications, trauma, triggers. Treatment is with systemic steroid therapy un- or other intercurrent illness. The patient’s most recent immuniza- less disease is limited, in which case medium/high-po- tions had been received 3 months earlier. The patient did not have tency topical steroids may be indicated. If systemic fea- a history of asthma, and there was no family history of asthma or > atopic disease. tures are prominent or disease is chronic (lasting 6 The patient was admitted with presumed bacterial cellulitis months), then a referral to hematology/oncology should and was treated with intravenously administered oxacillin, with- be considered. Pediatrics 2005;116:e149–e155. URL: www. out improvement. Her laboratory studies were significant for an pediatrics.org/cgi/doi/10.1542/peds.2004-2273; cellulitis, elevated white blood cell count of 30 ϫ 109 cells per L, with eosinophilia, eosinophilic cellulitis, Wells’ syndrome. peripheral eosinophilia of 48%. After the patient failed to respond to systemically administered antibiotics, examination of vesicle fluid was performed and revealed numerous eosinophils. Subse- ABBREVIATIONS. CSS, Churg-Strauss syndrome; HES, hyper- quently, the diagnosis of probable Wells’ syndrome was made. eosinophilic syndrome; IL, interleukin. Oral steroid therapy was started at 2 mg/kg, and the patient’s cutaneous symptoms improved within 24 hours, leaving residual erythema and hyperpigmentation (Fig 2). Five days after the ini- ells’ syndrome, or eosinophilic cellulitis, is tiation of oral steroid therapy, a skin biopsy was performed from a rare, recurrent, inflammatory dermatosis Wof unknown pathogenesis. In 1971, Wells1 described 4 patients with an acute pruritic dermatitis clinically resembling bacterial cellulitis but with histopathologic findings characterized by dermal eosinophilia, phagocytic histiocytes, and the presence of flame figures. He initially called this syndrome recurrent granulomatous dermatitis with eosinophilia

From the Departments of *Dermatology and ࿣Pediatrics, University of Cal- ifornia, San Francisco, California; ‡Department of Dermatology, Stanford University School of Medicine, Stanford, California; and §Children’s Hos- pital and Research Center, Oakland, California. Accepted for publication Dec 29, 2004. doi:10.1542/peds.2004-2273 No conflict of interest declared. Address correspondence to Amy E. Gilliam, MD, Department of Dermatol- ogy, University of California, 1701 Divisadero St, 3rd Floor, San Francisco, CA 94115. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad- Fig 1. Acute onset of edematous erythematous plaques and bullae emy of Pediatrics. on the left arm of a 1-year-old girl.

www.pediatrics.org/cgi/doi/10.1542/peds.2004-2273Downloaded from www.aappublications.org/news by guestPEDIATRICS on September 29, Vol. 2021 116 No. 1 July 2005 e149 a persistently indurated area. Histopathologic assessment showed els.7–14 Fever, lymphadenopathy, arthralgias, and an interstitial infiltrate of histiocytes and waning flame figures, other systemic symptoms (such as pulmonary in- represented by collections of eosinophilic granules surrounded by a palisade of histiocytes (Fig 3). volvement) have been described for Wells’ syn- Oral steroid treatment was tapered over 3 weeks, and a topical drome, and these findings may be indicative of a triamcinolone preparation was applied to residual lesions twice more severe or progressive course.7 daily until the lesions resolved. At 1 year, the patient has not The differential diagnosis of Wells’ syndrome in- experienced recurrent disease. cludes bacterial cellulitis, Churg-Strauss syndrome DISCUSSION (CSS), eosinophilic fasciitis, and hypereosinophilic syndrome (HES) (Table 2). The skin lesions of Wells’ Wells’ syndrome is extremely rare in childhood, syndrome are distinguished from those of bacterial with only 27 pediatric cases reported (Table 1). It is cellulitis by the absence of tenderness and the pres- characterized by a combination of distinct clinical ence of pruritus, which is often the primary symp- and histopathologic findings. Classically, patients tom of Wells’ syndrome. Lack of warmth, failure to present with pruritic erythematous plaques, some- respond to antibiotic therapy, and characteristic his- times with associated bullae, that evolve rapidly over tologic findings are the other features that differen- 2 to 3 days. These resolve spontaneously over 2 to 8 tiate Wells’ syndrome from bacterial cellulitis. weeks, leaving residual skin atrophy and hyperpig- CSS should be considered for patients with persis- mentation, resembling morphea.2 There is usually no tent peripheral eosinophilia and skin lesions. Al- improvement with antimicrobial therapy; instead, a though more commonly seen among adults, CSS can rapid response to oral corticosteroid treatment is ob- present in childhood.15–17 This syndrome is charac- served, as in our case. It is not uncommon for pa- terized by asthma, peripheral eosinophilia, and vas- tients to have recurrent disease, with exacerbations culitis and is associated with autoantibodies to pe- and remissions occurring over several years. rinuclear antineutrophil cytoplasmic antibody, as The histopathologic findings are quite specific and well as cutaneous and systemic granulomas. Palpa- are characterized by flame figures, which are com- ble purpura, tender subcutaneous nodules, and cu- posed of eosinophil major basic protein deposited on taneous infarctions are more often the associated 3 - collagen bundles. With resolution, there is a granu skin findings in CSS, whereas patients present with lomatous phase of histiocytes palisading around the bullae and vesicular lesions in Wells’ syndrome. In flame figures. Vasculitis is absent, and direct immu- both conditions, flame figures can be identified his- nofluorescence findings are negative.4,5 topathologically, as can peripheral blood and tissue Associated laboratory findings include an elevated eosinophilia. However, the presence of vasculitis white blood cell count and peripheral eosinophilia, with extensive fibrinoid necrosis of collagen is more which is found in up to 50% of cases during the suggestive of CSS.2,9 5,6 - active phase of disease. The erythrocyte sedimen Eosinophilic fasciitis is another condition that can tation rate is elevated for some patients, and there resemble Wells’ syndrome. Also seen more fre- are several reports of associated elevated IgE lev- quently among adults but reported in children,18,19 it presents with acute onset of skin inflammation and resolves with hyperpigmentation and scleroderma- like skin changes. Unlike Wells’ syndrome, eosinophilic fasciitis is characterized by arthritis as a prominent symptom, and it follows a more chronic course, with individual lesions requiring months or years to resolve.12 It is distinguishable from Wells’ syndrome by the depth of inflammation, with eosinophilic in- vasion into deeper fascial tissues. Finally, idiopathic HES also should be considered when the diagnosis of Wells’ syndrome is being en- tertained. This condition is extremely rare in the pediatric age group but has been reported in childhood.20 HES is a lymphoproliferative disorder characterized by overproduction of eosinophils with a predilection to damage specific organs, especially the cardiovascular system. It is defined by sustained eosinophilia (Ͼ1.5 ϫ 109 cells per L, lasting for Ͼ6 months), with evidence of multiple-organ system involvement, in the absence of parasitic disease, aller- gic diatheses, or other conditions known to cause eosinophilia. The heart, lungs, central and peripheral nervous systems, kidneys, and gastrointestinal tract can be affected, and the cutaneous findings are similar to those of Wells’ syndrome, including erythem- Fig 2. Appearance of skin lesions after 5 days of oral steroid atous pruritic papules and nodules, urticaria, and 9,21–23 therapy, showing residual erythema, induration, and hyperpig- angioedema. Histopathologically, the skin le- mentation. sions of HES are nonspecific, and the flame figures

e150 WELLS’ SYNDROMEDownloaded IN CHILDHOOD from www.aappublications.org/news by guest on September 29, 2021 Fig 3. High-power view of a biopsy specimen from a resolving lesion, showing a waning flame figure, represented by collections of eosinophilic granules surrounded by a palisade of histiocytes. (Hematox- ylin-eosin; original magnification: ϫ100.)

and granulomatous infiltrate seen in Wells’ syn- tion.14,30,33,44 However, when no treatable underly- drome are absent.21 ing factor can be identified, systemic corticosteroid The pathogenesis of Wells’ syndrome is not well therapy is used frequently for both adults and chil- defined. One hypothesis is that it represents a hyper- dren. Most cases resolve after a single course of sensitivity mechanism triggered by factors such as systemic corticosteroid therapy; when recurrences infections, drugs, or internal disease. However, in occur, however, alternative treatments should be approximately one half of reported cases among chil- considered, to avoid the side effects of chronic sys- dren, there is no identifiable precipitating factor.24 temic steroid therapy.36 Topical steroid treatment Reported precipitants have included bites or stings has also been reported as successful therapy, both from ticks, bees, and spiders8,9,12,25–28 and infections alone2,29,39 and in combination with systemic steroid with mumps, molluscum contagiosum, varicella, and therapy.5 Specifically, topical steroid therapy alone herpes simplex virus.1,24,29,30 There are also several resolved skin lesions for 2 children, which suggests reports of Wells’ syndrome associated with bacterial, that topical steroid therapy may be a safe alternative parasitic, and fungal infections.2,9,14,31–33 Numerous to systemic corticosteroid therapy in the pediatric medications have been implicated as triggers for age group.29,39 Other therapies reported to be suc- Wells’ syndrome.1–3,5,9,34–38 Also, several cases of cessful include various antimicrobial agents,2,5,6,9,10,13,49 Wells’ syndrome occurred after vaccinations,39,40 colchicine,13 antimalarial drugs, cyclosporine,50 aza- and it was proposed that the preservative thimerosol thioprine,5 interferon-␣,51 psoralen with ultraviolet was the causative agent in those cases.39 Several A,52 and antihistamines.10,43,53 cases of Wells’ syndrome among adults have been The small numbers of cases and the fact that most associated with hematologic disorders,9,41 lympho- reports are anecdotal make it difficult to draw con- proliferative malignancies,1,34,42 and carcino- clusions regarding whether these therapies are truly ma.34,43–45 Zachary et al45 reported a case of Wells’ effective or these cases resolved spontaneously. syndrome in a 17-year-old girl with nasopharyngeal However, we think that first-line treatment for chil- carcinoma, which is the only pediatric case of Wells’ dren should be systemic corticosteroid therapy, with syndrome associated with malignancy reported in the addition of topical steroid treatment depending the literature. on the extent of disease. A dose of orally adminis- One of the key events in disease expression of tered prednisolone or prednisone of 2 mg/kg per Wells’ syndrome appears to be aberrant and inade- day for 5 to 7 days, with a taper over 2 to 3 weeks, is quate eosinophil skin homing. Increased interleukin appropriate. Topical steroid treatment may be used (IL)-5 levels have been observed in Wells’ syndrome, in combination. In cases in which there is limited and IL-5 not only mobilizes eosinophils from the body surface area involved (15–30%) and an absence bone marrow but also promotes homing of eosino- of systemic symptoms, it may be prudent to consider phils by altering expression of adhesion molecules. medium-potency topical steroid therapy alone, with In addition, increased levels of IL-5 appear to induce close follow-up monitoring. This would also be ap- expression of CD25, the ␣ chain of the IL-2 receptor, propriate for recurrent cases of Wells’ syndrome which enhances eosinophil degranulation and sub- identified early, when disease may be limited. sequent tissue destruction.46–48 Evaluation should be directed at ruling out other Treatment for Wells’ syndrome is sometimes un- conditions that mimic Wells’ syndrome, as well as necessary, because cases often resolve spontane- evaluating possible triggering factors. We recom- ously. If an infection or other treatable precipitating mend a complete history and review of systems, with factor can be identified, then there is often improve- specific attention to recent medications, vaccinations, ment with treatment of the underlying condi- insect bites, infections, or illnesses and associated

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TABLE 1. Summary of Reported Cases of Pediatric Wells’ Syndrome

EL’SNRM NCHILDHOOD IN SYNDROME WELLS’ Reference Age Gender Triggering Event(s) Associated Findings Treatment and Course of Disease Wells and Smith,2 1979 11 y M Mumps, penicillin Elevated WBC count (16 ϫ 109 cells per L), Prednisolone and sulfapyridine, fever recurrences over 3 y Wells and Smith,2 1979 12 y M Erysipelas, penicillin Elevated WBC count (26 ϫ 109 cells per L), Prednisolone, recurrences over eosinophilia (44%) 2–3 y Nielsen et al,25 1981 11 y M Unknown Elevated WBC count (42 ϫ 109 cells per L), Prednisone, 1 recurrence eosinophilia (13%), fever, ANA-positive, Downloaded from arthralgias, alopecia Saulsbury et al,12 1983 7 y M Possible insect bites Elevated WBC count (17 ϫ 109 cells per L), Ampicillin and antihistamines, eosinophilia (48%), fever, elevated IgE spontaneous resolution in 1 level, bone marrow eosinophilia, wk, with recurrences oculomotor nerve palsy Bonvalet et al,4 1983 2 y M Unknown Eosinophilia No treatment, spontaneous

www.aappublications.org/news resolution in 2 wk with recurrences Schorr et al,28 1984 3.5 y M Flea bite Fever No record of treatment, multiple recurrences Brehmer-Andersson et al,34 1986 14 y M Unknown None No treatment, spontaneous resolution in 1 wk, multiple recurrences over 8 y Wood, et al,26 1986 18 mo M Unknown None Wood et al,26 1986 10 y M Insect bites Eosinophilia Kamani and Lipsitz,7 1987 7 wk M Genetic (?), mother and brother Elevated WBC count (22 ϫ 109 cells per L), Systemic steroids, recurrences with Wells’ syndrome eosinophilia (16%), fever, elevated IgE responsive to steroids level, pericarditis, pulmonary infiltrates byguestonSeptember 29,2021 with eosinophilic exudates/effusions Kamani and Lipsitz,7 1987 3 wk M Genetic (?), mother and brother Elevated WBC count (29 ϫ 109 cells per L), Systemic steroids, recurrences with Wells’ syndrome eosinophilia (32%), fever, generalized responsive to steroids seizure, meningitis, pulmonary infiltrates with eosinophilic cerebrospinal fluid pleocytosis and pleural effusions Correia and Garcia e Silva,54 1988 12 y F Possibly diabetes mellitus Muscular weakness No record of treatment in English abstract Lindskov et al,11 1988 4 y F Unknown Elevated WBC count (13 ϫ 109 cells per L), Oral antibiotics, acyclovir, and eosinophilia (17%), fourfold increase in prednisone, gradual varicella titer resolution over 2 mo, recurrence treated with steroids Lindskov et al,11 1988 5 y F Unknown Elevated WBC count (47 ϫ 109 cells per L), Oral antibiotics and acyclovir, eosinophilia (55%), fever, ESR of 62 gradual resolution over 2 mo, mm/h, anemia, arthralgias, no recurrences lymphadenopathy, bone marrow eosinophilia, and fourfold increase in varicella titer Lindskov et al,11 1988 20 mo M Unknown Elevated WBC count (20 ϫ 109 cells per L), Oral and topical antibiotics, eosinophilia (13%), anemia, elevated IgE gradual resolution over 2 mo, level recurrences over 2 y Lindskov et al,11 1988 9 y M Unknown Elevated WBC (19 ϫ 109 cells per L), Topical antibiotics, spontaneous eosinophilia (13%), fever resolution over 2 wk with recurrences Reichel et al,29 1991 6 y M Varicella Eosinophilia (3%), varicella zoster virus titer Spontaneous improvement over of 1:32 1 mo, topical steroids cleared residua Paquet et al,13 1992 10 y M Unknown Eosinophilia (13.4%), elevated IgE level Systemic antibiotics and oral

Downloaded from steroids, no recurrences after 9 mo of follow-up monitoring Anderson et al,8 1995 4 y F Bee sting Elevated WBC (45 ϫ 109 cells per L), Systemic antibiotics and oral eosinophilia, elevated IgE and septicemia steroids, course complicated by systemic infection, improvement over 4 wk with recurrences www.aappublications.org/news Garty et al,55 1997 Ͻ1 mo F Possibly danazol, ingested by Elevated WBC count (15 ϫ 109 cells per L), Topical steroids, topical mother during pregnancy eosinophilia (25%), ESR of 30 mm/h, antibiotics, and antifungal mild hepatosplenomegaly, medications ineffective, lymphadenopathy spontaneous resolution over months but with recurrences Davis et al,57 1998 7 y M Unknown Eosinophilia of blood, tissue, and bone Systemic and topical steroids, marrow, familial case associated with frequent recurrences without

www.pediatrics.org/cgi/doi/10.1542/peds.2004-2273 short stature, mental retardation, resolution distinctive habitus Davis et al,46 1998 5 y F Unknown Eosinophilia of peripheral blood and bone No treatment, recurrences over marrow and elevated IgA, IgM, and IgG years

byguestonSeptember 29,2021 levels, familial case associated with short stature, mental retardation, and distinctive habitus Aroni et al,53 1999 12 y F Unknown Eosinophilia Cetirizine, resolved after 4 wk of treatment, recurrence after 18 mo Kuwahara et al,56 2001 Birth F Possibly penicillin or danazol None None, resolved by the 2-y ingested by mother during follow-up visit pregnancy Moossavi and Mehregan,5 2003 21 mo F Unknown None Prednisone and topical steroids, resolved without recurrence Koh et al,39 2003 3.5 y M Hepatitis B and DPT Slight peripheral eosinophilia Topical steroids (rapid vaccination improvement), recurrences treated with topical steroids Stavropoulos et al,24 2003 9 y F Molluscum contagiosum Eosinophilia (12%), ESR of 26 mm/h Oral prednisolone, no treated with cryosurgery recurrences Gilliam et al, 2005 1 y F Unknown Elevated WBC count (30 ϫ 109 cells per L), Oral prednisolone and topical eosinophilia (48%) steroids, no recurrences in 1 y of follow-up monitoring ANA indicates antinuclear antibody; WBC, white blood cell; ESR, erythrocyte sedimentation rate; DPT, diphtheria-pertussis-tetanus. e153 medical problems such as asthma. A thorough physical examination should be performed, with attention to the liver, spleen, and lymph nodes. Stool samples should be sent for ova and parasite testing, and a complete blood count with differential evaluation should be performed. If there is uncertainty regarding the diagnosis, then a skin biopsy should be performed to distinguish between Wells’ syndrome and

Standard Treatment* other conditions that mimic it. We do not recom- antibiotics cyclophosphamide, with addition of steroid-sparing agents for maintenance methotrexate chemotherapy mend a complete hematologic evaluation in all cases, Oral steroids Oral or intravenous Oral steroids with or without Oral steroids with or without Oral steroids with or without because it is rare to see cases of either HES or Wells’ syndrome triggered by hematologic or oncologic disorders in childhood. However, if a child presents with either systemic features, such as fevers, arthralgias, or other organ system involvement, or a chronic course, defined as Ͼ6 months of peripheral eosinophilia or recurrences of clinical disease, then a referral to hematology/oncology should be considered.

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Bullous ''Cellulitis'' With Eosinophilia: Case Report and Review of Wells' Syndrome in Childhood Amy E. Gilliam, Anna L. Bruckner, Renée M. Howard, Brian P. Lee, Susan Wu and Ilona J. Frieden Pediatrics 2005;116;e149 DOI: 10.1542/peds.2004-2273

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