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Symmetric Drug-Related Intertriginous and Flexural Exanthema
To the Editor:
Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a curious disorder that has undergone many clinical transformations since first being described by Andersen et al1 in 1984 using the term baboon syndrome. Initially described as a mercury hypersensitivity reaction resulting in an eruption resembling the red-bottomed baboon, this exanthema has expanded in definition with inciting agents, clinical features, and diagnostic criteria. Its prognosis, however, has remained stable and favorable throughout the decades. The condition is almost universally benign and self-limited.1-3 As new cases are reported in the literature and the paradigm of SDRIFE continues to shift, its prognosis also may warrant reconsideration and respect as a potentially destructive reaction.
[embed:render:related:node:231217]
A 39-year-old woman who was otherwise healthy presented to the emergency department after developing a rapidly evolving and blistering rash on the left flank. Hours later, the rash had progressed to a sharply demarcated, confluent, erythematous plaque with central ulceration and large flaccid bullae peripherally, encompassing 18% of total body surface area and extending from the gluteal cleft to the tip of the scapula along the left flank (Figure 1) with no vaginal or mucosal involvement. The patient recently had completed a 10-day course of amoxicillin–clavulanic acid 2 days prior for a cat bite on the right dorsal wrist. Additional history confirmed the absence of prodromal fever, fatigue, or chills. Inciting trauma, including chemical and thermal burns, was denied. Potential underlying psychosocial cofounders were explored and were unrevealing.
Laboratory test results, including complete blood cell count and metabolic panel as well as vital signs were unremarkable, except for slight leukocytosis at 14,000/µL (reference range 4500–11,000/µL). A punch biopsy was taken from the patient’s left upper back at the time of admission, which revealed a sparse, superficial, perivascular infiltrate of lymphocytes and rare neutrophils with largely absent epidermis and an occasional focal necrosis of adnexal epithelium (Figure 2). Immunofluorescence was negative for specific deposition of IgG, IgA, IgM, C3, or fibrinogen. Wound culture also returned negative, and the Naranjo adverse drug reaction probability scale score was calculated to be 4 out of 12, indicating possible adverse drug reaction.4
Given the extent and distribution of the rash as well as the full-thickness dermal involvement, the patient was transferred to the burn unit for subsequent care. At 8-month follow-up, she experienced severe, symptomatic, hypertrophic scarring and was awaiting intralesional triamcinolone acetonide injections. The patient subsequently was lost to follow up.
The clinical picture of SDRIFE has remained obscure over the last 30 years, likely owing to its rarity and unclear pathogenesis. Diagnostic criteria for SDRIFE were first proposed by Häusermann et al2 in 2004 and contained 5 elements: (1) occurrence after (re)exposure to systemic drugs, (2) sharply demarcated erythema of the gluteal region or V-shaped erythema of the inguinal area, (3) involvement of at least 1 other intertriginous location, (4) symmetry of affected areas, and (5) absence of systemic symptoms and signs. Based on these clinical criteria, our patients fulfilled 3 of 5 elements, with deductions for symmetry of affected areas and involvement of other intertriginous locations. Histopathologic findings in SDRIFE predominantly are nonspecific with superficial perivascular mononuclear infiltrates; however, prior reports have confirmed the potential for vacuolar changes and hydropic degeneration in the basal cell layer with subepidermal bullae formation.5,6 Similarly, although the presence of bullae are somewhat atypical in SDRIFE, it has been described.3 Taken together, we speculate that these findings may support a diagnosis of SDRIFE with atypical presentation, though an alternative diagnosis of bullous fixed drug eruption (FDE) cannot be ruled out.
Historically, SDRIFE has been associated with a benign course. The condition typically arises within a few hours to days following administration of the offending agent, most commonly amoxicillin or another β-lactam antibiotic.1 Most cases spontaneously resolve via desquamation within 1 to 2 weeks. We present an unusual case of amoxicillin-induced full-thickness epidermal necrosis resulting in symptomatic sequelae, which exhibits findings of SDRIFE, bullous FDE, or Stevens-Johnson syndrome/toxic epidermal necrolysis, suggesting the possibility for a common pathway underlying the pathogenesis of these conditions.
The diagnostic uncertainty that commonly accompanies these various toxic drug reactions may in part relate to their underlying immunopathogenesis. Although the exact mechanism by which SDRIFE results in its characteristic skin lesions has not been fully elucidated, prior work through patch testing, lymphocyte transformation assays, and immunohistochemical staining of biopsies suggests a type IV delayed hypersensitivity (DTH) reaction.7-10 Specifically, SDRIFE appears to share features of both DTH type IVa—involving CD4+ helper T cells (TH1), monocytes, and IFN-γ signaling—and DTH type IVc—involving cytotoxic CD4 and CD8 cells, granzyme B action, and FasL signaling.11,12 A similar inflammatory milieu has been implicated in numerous toxic drug eruptions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and FDE.11,13 This mechanistic overlap may explain the overlap seen clinically among such conditions.
[embed:render:related:node:231119]
In the undifferentiated patient, categorization of the clinical syndrome proves helpful in prognostication and therapeutic approach. The complexities and commonalities intrinsic to these syndromes, however, may simultaneously preclude certain cases from neatly following the predefined rules. These atypical presentations, while diagnostically challenging, can in turn offer a unique opportunity to reexamine the current state of disease understanding to better allow for appropriate classification.
Despite its rarity, SDRIFE should be considered in the differential of undiagnosed drug eruptions, particularly as new clinical presentations emerge. Careful documentation and timely declaration of future cases will prove invaluable for diagnostic and therapeutic advancements should this once-benign condition develop a more destructive potential.
- Andersen KE, Hjorth N, Menné T. The baboon syndrome: systemically-induced allergic contact dermatitis. Contact Dermatitis. 1984;10:97-100.
- Häusermann P, Harr TH, Bircher AJ. Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome? Contact Dermatitis. 2004;51:297-310.
- Tan SC, Tan JW. Symmetrical drug-related intertriginous and flexural exanthema. Curr Opin Allergy Clin Immunol. 2011;11:313-318.
- Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
- Wolf R, Orion E, Matz H. The baboon syndrome or intertriginous drug eruption: a report of eleven cases and a second look at its pathomechanism. Dermatol Online J. 2003;9:2.
- Elmariah SB, Cheung W, Wang N, et al. Systemic drug-related intertriginous and flexural exanthema (SDRIFE). Dermatol Online J. 2009;15:3.
- Hembold P, Hegemann B, Dickert C, et al. Symptomatic psychotropic and nonpigmenting fixed drug eruption due to cimetidine (so-called baboon syndrome). Dermatology. 1998;197:402-403.
- Barbaud A, Trechot P, Granel F, et al. A baboon syndrome induced by intravenous human immunoglobulins: a report of a case and immunological analysis. Dermatology. 1999;199:258-260.
- Miyahara A, Kawashima H, Okubo Y, et al. A new proposal for a clinical-oriented subclassification of baboon syndrome and review of baboon syndrome. Asian Pac J Allergy Immunol. 2011;29:150-160.
- Goossens C, Sass U, Song M. Baboon syndrome. Dermatology. 1997;194:421-422.
- Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139:123-129.
- Ozkaya E. Current understanding of baboon syndrome. Expert Rev Dermatol. 2009;4:163-175.
- Ozakaya E. Fixed drug eruption: state of the art. J Dtsch Dermatol Ges. 2008;6:181-188.
To the Editor:
Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a curious disorder that has undergone many clinical transformations since first being described by Andersen et al1 in 1984 using the term baboon syndrome. Initially described as a mercury hypersensitivity reaction resulting in an eruption resembling the red-bottomed baboon, this exanthema has expanded in definition with inciting agents, clinical features, and diagnostic criteria. Its prognosis, however, has remained stable and favorable throughout the decades. The condition is almost universally benign and self-limited.1-3 As new cases are reported in the literature and the paradigm of SDRIFE continues to shift, its prognosis also may warrant reconsideration and respect as a potentially destructive reaction.
[embed:render:related:node:231217]
A 39-year-old woman who was otherwise healthy presented to the emergency department after developing a rapidly evolving and blistering rash on the left flank. Hours later, the rash had progressed to a sharply demarcated, confluent, erythematous plaque with central ulceration and large flaccid bullae peripherally, encompassing 18% of total body surface area and extending from the gluteal cleft to the tip of the scapula along the left flank (Figure 1) with no vaginal or mucosal involvement. The patient recently had completed a 10-day course of amoxicillin–clavulanic acid 2 days prior for a cat bite on the right dorsal wrist. Additional history confirmed the absence of prodromal fever, fatigue, or chills. Inciting trauma, including chemical and thermal burns, was denied. Potential underlying psychosocial cofounders were explored and were unrevealing.
Laboratory test results, including complete blood cell count and metabolic panel as well as vital signs were unremarkable, except for slight leukocytosis at 14,000/µL (reference range 4500–11,000/µL). A punch biopsy was taken from the patient’s left upper back at the time of admission, which revealed a sparse, superficial, perivascular infiltrate of lymphocytes and rare neutrophils with largely absent epidermis and an occasional focal necrosis of adnexal epithelium (Figure 2). Immunofluorescence was negative for specific deposition of IgG, IgA, IgM, C3, or fibrinogen. Wound culture also returned negative, and the Naranjo adverse drug reaction probability scale score was calculated to be 4 out of 12, indicating possible adverse drug reaction.4
Given the extent and distribution of the rash as well as the full-thickness dermal involvement, the patient was transferred to the burn unit for subsequent care. At 8-month follow-up, she experienced severe, symptomatic, hypertrophic scarring and was awaiting intralesional triamcinolone acetonide injections. The patient subsequently was lost to follow up.
The clinical picture of SDRIFE has remained obscure over the last 30 years, likely owing to its rarity and unclear pathogenesis. Diagnostic criteria for SDRIFE were first proposed by Häusermann et al2 in 2004 and contained 5 elements: (1) occurrence after (re)exposure to systemic drugs, (2) sharply demarcated erythema of the gluteal region or V-shaped erythema of the inguinal area, (3) involvement of at least 1 other intertriginous location, (4) symmetry of affected areas, and (5) absence of systemic symptoms and signs. Based on these clinical criteria, our patients fulfilled 3 of 5 elements, with deductions for symmetry of affected areas and involvement of other intertriginous locations. Histopathologic findings in SDRIFE predominantly are nonspecific with superficial perivascular mononuclear infiltrates; however, prior reports have confirmed the potential for vacuolar changes and hydropic degeneration in the basal cell layer with subepidermal bullae formation.5,6 Similarly, although the presence of bullae are somewhat atypical in SDRIFE, it has been described.3 Taken together, we speculate that these findings may support a diagnosis of SDRIFE with atypical presentation, though an alternative diagnosis of bullous fixed drug eruption (FDE) cannot be ruled out.
Historically, SDRIFE has been associated with a benign course. The condition typically arises within a few hours to days following administration of the offending agent, most commonly amoxicillin or another β-lactam antibiotic.1 Most cases spontaneously resolve via desquamation within 1 to 2 weeks. We present an unusual case of amoxicillin-induced full-thickness epidermal necrosis resulting in symptomatic sequelae, which exhibits findings of SDRIFE, bullous FDE, or Stevens-Johnson syndrome/toxic epidermal necrolysis, suggesting the possibility for a common pathway underlying the pathogenesis of these conditions.
The diagnostic uncertainty that commonly accompanies these various toxic drug reactions may in part relate to their underlying immunopathogenesis. Although the exact mechanism by which SDRIFE results in its characteristic skin lesions has not been fully elucidated, prior work through patch testing, lymphocyte transformation assays, and immunohistochemical staining of biopsies suggests a type IV delayed hypersensitivity (DTH) reaction.7-10 Specifically, SDRIFE appears to share features of both DTH type IVa—involving CD4+ helper T cells (TH1), monocytes, and IFN-γ signaling—and DTH type IVc—involving cytotoxic CD4 and CD8 cells, granzyme B action, and FasL signaling.11,12 A similar inflammatory milieu has been implicated in numerous toxic drug eruptions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and FDE.11,13 This mechanistic overlap may explain the overlap seen clinically among such conditions.
[embed:render:related:node:231119]
In the undifferentiated patient, categorization of the clinical syndrome proves helpful in prognostication and therapeutic approach. The complexities and commonalities intrinsic to these syndromes, however, may simultaneously preclude certain cases from neatly following the predefined rules. These atypical presentations, while diagnostically challenging, can in turn offer a unique opportunity to reexamine the current state of disease understanding to better allow for appropriate classification.
Despite its rarity, SDRIFE should be considered in the differential of undiagnosed drug eruptions, particularly as new clinical presentations emerge. Careful documentation and timely declaration of future cases will prove invaluable for diagnostic and therapeutic advancements should this once-benign condition develop a more destructive potential.
To the Editor:
Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a curious disorder that has undergone many clinical transformations since first being described by Andersen et al1 in 1984 using the term baboon syndrome. Initially described as a mercury hypersensitivity reaction resulting in an eruption resembling the red-bottomed baboon, this exanthema has expanded in definition with inciting agents, clinical features, and diagnostic criteria. Its prognosis, however, has remained stable and favorable throughout the decades. The condition is almost universally benign and self-limited.1-3 As new cases are reported in the literature and the paradigm of SDRIFE continues to shift, its prognosis also may warrant reconsideration and respect as a potentially destructive reaction.
[embed:render:related:node:231217]
A 39-year-old woman who was otherwise healthy presented to the emergency department after developing a rapidly evolving and blistering rash on the left flank. Hours later, the rash had progressed to a sharply demarcated, confluent, erythematous plaque with central ulceration and large flaccid bullae peripherally, encompassing 18% of total body surface area and extending from the gluteal cleft to the tip of the scapula along the left flank (Figure 1) with no vaginal or mucosal involvement. The patient recently had completed a 10-day course of amoxicillin–clavulanic acid 2 days prior for a cat bite on the right dorsal wrist. Additional history confirmed the absence of prodromal fever, fatigue, or chills. Inciting trauma, including chemical and thermal burns, was denied. Potential underlying psychosocial cofounders were explored and were unrevealing.
Laboratory test results, including complete blood cell count and metabolic panel as well as vital signs were unremarkable, except for slight leukocytosis at 14,000/µL (reference range 4500–11,000/µL). A punch biopsy was taken from the patient’s left upper back at the time of admission, which revealed a sparse, superficial, perivascular infiltrate of lymphocytes and rare neutrophils with largely absent epidermis and an occasional focal necrosis of adnexal epithelium (Figure 2). Immunofluorescence was negative for specific deposition of IgG, IgA, IgM, C3, or fibrinogen. Wound culture also returned negative, and the Naranjo adverse drug reaction probability scale score was calculated to be 4 out of 12, indicating possible adverse drug reaction.4
Given the extent and distribution of the rash as well as the full-thickness dermal involvement, the patient was transferred to the burn unit for subsequent care. At 8-month follow-up, she experienced severe, symptomatic, hypertrophic scarring and was awaiting intralesional triamcinolone acetonide injections. The patient subsequently was lost to follow up.
The clinical picture of SDRIFE has remained obscure over the last 30 years, likely owing to its rarity and unclear pathogenesis. Diagnostic criteria for SDRIFE were first proposed by Häusermann et al2 in 2004 and contained 5 elements: (1) occurrence after (re)exposure to systemic drugs, (2) sharply demarcated erythema of the gluteal region or V-shaped erythema of the inguinal area, (3) involvement of at least 1 other intertriginous location, (4) symmetry of affected areas, and (5) absence of systemic symptoms and signs. Based on these clinical criteria, our patients fulfilled 3 of 5 elements, with deductions for symmetry of affected areas and involvement of other intertriginous locations. Histopathologic findings in SDRIFE predominantly are nonspecific with superficial perivascular mononuclear infiltrates; however, prior reports have confirmed the potential for vacuolar changes and hydropic degeneration in the basal cell layer with subepidermal bullae formation.5,6 Similarly, although the presence of bullae are somewhat atypical in SDRIFE, it has been described.3 Taken together, we speculate that these findings may support a diagnosis of SDRIFE with atypical presentation, though an alternative diagnosis of bullous fixed drug eruption (FDE) cannot be ruled out.
Historically, SDRIFE has been associated with a benign course. The condition typically arises within a few hours to days following administration of the offending agent, most commonly amoxicillin or another β-lactam antibiotic.1 Most cases spontaneously resolve via desquamation within 1 to 2 weeks. We present an unusual case of amoxicillin-induced full-thickness epidermal necrosis resulting in symptomatic sequelae, which exhibits findings of SDRIFE, bullous FDE, or Stevens-Johnson syndrome/toxic epidermal necrolysis, suggesting the possibility for a common pathway underlying the pathogenesis of these conditions.
The diagnostic uncertainty that commonly accompanies these various toxic drug reactions may in part relate to their underlying immunopathogenesis. Although the exact mechanism by which SDRIFE results in its characteristic skin lesions has not been fully elucidated, prior work through patch testing, lymphocyte transformation assays, and immunohistochemical staining of biopsies suggests a type IV delayed hypersensitivity (DTH) reaction.7-10 Specifically, SDRIFE appears to share features of both DTH type IVa—involving CD4+ helper T cells (TH1), monocytes, and IFN-γ signaling—and DTH type IVc—involving cytotoxic CD4 and CD8 cells, granzyme B action, and FasL signaling.11,12 A similar inflammatory milieu has been implicated in numerous toxic drug eruptions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and FDE.11,13 This mechanistic overlap may explain the overlap seen clinically among such conditions.
[embed:render:related:node:231119]
In the undifferentiated patient, categorization of the clinical syndrome proves helpful in prognostication and therapeutic approach. The complexities and commonalities intrinsic to these syndromes, however, may simultaneously preclude certain cases from neatly following the predefined rules. These atypical presentations, while diagnostically challenging, can in turn offer a unique opportunity to reexamine the current state of disease understanding to better allow for appropriate classification.
Despite its rarity, SDRIFE should be considered in the differential of undiagnosed drug eruptions, particularly as new clinical presentations emerge. Careful documentation and timely declaration of future cases will prove invaluable for diagnostic and therapeutic advancements should this once-benign condition develop a more destructive potential.
- Andersen KE, Hjorth N, Menné T. The baboon syndrome: systemically-induced allergic contact dermatitis. Contact Dermatitis. 1984;10:97-100.
- Häusermann P, Harr TH, Bircher AJ. Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome? Contact Dermatitis. 2004;51:297-310.
- Tan SC, Tan JW. Symmetrical drug-related intertriginous and flexural exanthema. Curr Opin Allergy Clin Immunol. 2011;11:313-318.
- Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
- Wolf R, Orion E, Matz H. The baboon syndrome or intertriginous drug eruption: a report of eleven cases and a second look at its pathomechanism. Dermatol Online J. 2003;9:2.
- Elmariah SB, Cheung W, Wang N, et al. Systemic drug-related intertriginous and flexural exanthema (SDRIFE). Dermatol Online J. 2009;15:3.
- Hembold P, Hegemann B, Dickert C, et al. Symptomatic psychotropic and nonpigmenting fixed drug eruption due to cimetidine (so-called baboon syndrome). Dermatology. 1998;197:402-403.
- Barbaud A, Trechot P, Granel F, et al. A baboon syndrome induced by intravenous human immunoglobulins: a report of a case and immunological analysis. Dermatology. 1999;199:258-260.
- Miyahara A, Kawashima H, Okubo Y, et al. A new proposal for a clinical-oriented subclassification of baboon syndrome and review of baboon syndrome. Asian Pac J Allergy Immunol. 2011;29:150-160.
- Goossens C, Sass U, Song M. Baboon syndrome. Dermatology. 1997;194:421-422.
- Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139:123-129.
- Ozkaya E. Current understanding of baboon syndrome. Expert Rev Dermatol. 2009;4:163-175.
- Ozakaya E. Fixed drug eruption: state of the art. J Dtsch Dermatol Ges. 2008;6:181-188.
- Andersen KE, Hjorth N, Menné T. The baboon syndrome: systemically-induced allergic contact dermatitis. Contact Dermatitis. 1984;10:97-100.
- Häusermann P, Harr TH, Bircher AJ. Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome? Contact Dermatitis. 2004;51:297-310.
- Tan SC, Tan JW. Symmetrical drug-related intertriginous and flexural exanthema. Curr Opin Allergy Clin Immunol. 2011;11:313-318.
- Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-245.
- Wolf R, Orion E, Matz H. The baboon syndrome or intertriginous drug eruption: a report of eleven cases and a second look at its pathomechanism. Dermatol Online J. 2003;9:2.
- Elmariah SB, Cheung W, Wang N, et al. Systemic drug-related intertriginous and flexural exanthema (SDRIFE). Dermatol Online J. 2009;15:3.
- Hembold P, Hegemann B, Dickert C, et al. Symptomatic psychotropic and nonpigmenting fixed drug eruption due to cimetidine (so-called baboon syndrome). Dermatology. 1998;197:402-403.
- Barbaud A, Trechot P, Granel F, et al. A baboon syndrome induced by intravenous human immunoglobulins: a report of a case and immunological analysis. Dermatology. 1999;199:258-260.
- Miyahara A, Kawashima H, Okubo Y, et al. A new proposal for a clinical-oriented subclassification of baboon syndrome and review of baboon syndrome. Asian Pac J Allergy Immunol. 2011;29:150-160.
- Goossens C, Sass U, Song M. Baboon syndrome. Dermatology. 1997;194:421-422.
- Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139:123-129.
- Ozkaya E. Current understanding of baboon syndrome. Expert Rev Dermatol. 2009;4:163-175.
- Ozakaya E. Fixed drug eruption: state of the art. J Dtsch Dermatol Ges. 2008;6:181-188.
Practice Points
- Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) appears in the absence of systemic signs and symptoms such as fever, which may help differentiate it from infectious causes.
- β-Lactam antibiotics, particularly amoxicillin, are common offenders in the pathogenesis of SDRIFE, but new drug relationships frequently are being described.
- Symmetric drug-related intertriginous and flexural exanthema commonly follows a benign course but warrants respect, as it may have devastating potential.
Red-Brown Plaque on the Leg
The Diagnosis: Wells Syndrome
A punch biopsy taken from the perimeter of the lesion demonstrated mild spongiosis overlying a dense nodular to diffuse infiltrate of lymphocytes, neutrophils, and numerous eosinophils, some involving underlying fat lobules (Figure, A and B). In some areas, eosinophilic degeneration of collagen bundles surrounded by a rim of histiocytes, "flame features," were observed (Figure C). The clinical and histological features were consistent with Wells syndrome (WS), also known as eosinophilic cellulitis. Given the localized mild nature of the disease, the patient was started on a midpotency topical corticosteroid.
Wells syndrome is a rare inflammatory condition characterized by clinical polymorphism, suggestive histologic findings, and a recurrent course.1,2 This condition is especially rare in children.3,4 Caputo et al1 described 7 variants in their case series of 19 patients: classic plaque-type variant (the most common clinical presentation in children); annular granuloma-like (the most common clinical presentation in adults); urticarialike; bullous; papulonodular; papulovesicular; and fixed drug eruption-like. Wells syndrome is thought to result from excess production of IL-5 in response to a hypersensitivity reaction to an exogenous or endogenous circulating antigen.3,4 Increased levels of IL-5 enhance eosinophil accumulation in the skin, degranulation, and subsequent tissue destruction.3,4 Reported triggers include insect bites, viral and bacterial infections, drug eruptions, recent vaccination, and paraphenylenediamine in henna tattoos.3-7 Additionally, WS has been reported in the setting of gastrointestinal pathologies, such as celiac disease and ulcerative colitis, and with asthma exacerbations.8,9 However, in half of pediatric cases, no trigger can be identified.7
Clinically, WS presents with pruritic, mildly tender plaques.7 Lesions may be localized or diffuse and range from mild annular or circinate plaques with infiltrated borders to cellulitic-appearing lesions that are occasionally associated with bullae.5,6 Patients often report prodromal symptoms of burning and pruritus.5,6 Lesions rapidly progress over 2 to 3 days, pass through a blue grayish discoloration phase, and gradually resolve over 2 to 8 weeks.5,6,10 Although patients generally heal without scarring, WS lesions have been described to resolve with atrophy and hyperpigmentation resembling morphea.5-7 Additionally, patients typically experience a relapsing remitting course over months to years with eventual spontaneous resolution.1,5 Patients also may experience systemic symptoms including fever, lymphadenopathy, and arthralgia, though they do not develop more widespread systemic manifestations.2,3,7
Diagnosis of WS is based on clinicopathologic correlation. Histopathology of WS lesions demonstrates 3 phases. The acute phase demonstrates edema of the superficial and mid dermis with a dense dermal eosinophilic infiltrate.1,6,10 The subacute granulomatous phase demonstrates flame figures in the dermis.1,2,6,7,10 Flame figures consist of palisading groups of eosinophils and histiocytes around a core of degenerating basophilic collagen bundles associated with major basic protein.1,2,6,7,10 Finally, in the resolution phase, eosinophils gradually disappear while histiocytes and giant cells persist, forming microgranulomas.1,2,10 Notably, no vasculitis is observed and direct immunofluorescence is negative.3,7 Although flame figures are suggestive of WS, they are not pathognomonic and are observed in other conditions including Churg-Strauss syndrome, parasitic and fungal infections, herpes gestationis, bullous pemphigoid, and follicular mucinosis.2,5
Wells syndrome is a self-resolving and benign condition.1,10 Physicians are recommended to gather a complete history including review of medications and vaccinations; a history of insect bites, infections, and asthma; laboratory workup consisting of a complete blood cell count with differential and stool samples for ova and parasites; and a skin biopsy if the diagnosis is unclear.7 Identification and treatment of underlying causes often results in resolution.6 Systemic corticosteroids frequently are used in both adult and pediatric patients, though practitioners should consider alternative treatments when recurrences occur to avoid steroid side effects.3,6 Midpotency topical corticosteroids present a safe alternative to systemic corticosteroids in the pediatric population, especially in cases of localized WS without systemic symptoms.3 Other medications reported in the literature include cyclosporine, dapsone, antimalarial medications, and azathioprine.6 Despite appropriate therapy, patients and physicians should anticipate recurrence over months to years.1,6
- Caputo R, Marzano AV, Vezzoli P, et al. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142:1157-1161.
- Smith SM, Kiracofe EA, Clark LN, et al. Idiopathic hypereosinophilic syndrome with cutaneous manifestations and flame figures: a spectrum of eosinophilic dermatoses whose features overlap with Wells' syndrome. Am J Dermatopathol. 2015;37:910-914.
- Gilliam AE, Bruckner AL, Howard RM, et al. Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood. Pediatrics. 2005;116:E149-E155.
- Nacaroglu HT, Celegen M, Karkıner CS, et al. Eosinophilic cellulitis (Wells' syndrome) caused by a temporary henna tattoo. Postepy Dermatol Alergol. 2014;31:322-324.
- Heelan K, Ryan JF, Shear NH, et al. Wells syndrome (eosinophilic cellulitis): proposed diagnostic criteria and a literature review of the drug-induced variant. J Dermatol Case Rep. 2013;7:113-120.
- Sinno H, Lacroix JP, Lee J, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): a case series and literature review. Can J Plast Surg. 2012;20:91-97.
- Cherng E, McClung AA, Rosenthal HM, et al. Wells' syndrome associated with parvovirus in a 5-year-old boy. Pediatr Dermatol. 2012;29:762-764.
- Eren M, Açikalin M. A case report of Wells' syndrome in a celiac patient. Turk J Gastroenterol. 2010;21:172-174.
- Cruz MJ, Mota A, Baudrier T, et al. Recurrent Wells' syndrome associated with allergic asthma exacerbation. Cutan Ocul Toxicol. 2012;31:154-156.
- Van der Straaten S, Wojciechowski M, Salgado R, et al. Eosinophilic cellulitis or Wells' syndrome in a 6-year-old child. Eur J Pediatr. 2006;165:197-198.
The Diagnosis: Wells Syndrome
A punch biopsy taken from the perimeter of the lesion demonstrated mild spongiosis overlying a dense nodular to diffuse infiltrate of lymphocytes, neutrophils, and numerous eosinophils, some involving underlying fat lobules (Figure, A and B). In some areas, eosinophilic degeneration of collagen bundles surrounded by a rim of histiocytes, "flame features," were observed (Figure C). The clinical and histological features were consistent with Wells syndrome (WS), also known as eosinophilic cellulitis. Given the localized mild nature of the disease, the patient was started on a midpotency topical corticosteroid.
Wells syndrome is a rare inflammatory condition characterized by clinical polymorphism, suggestive histologic findings, and a recurrent course.1,2 This condition is especially rare in children.3,4 Caputo et al1 described 7 variants in their case series of 19 patients: classic plaque-type variant (the most common clinical presentation in children); annular granuloma-like (the most common clinical presentation in adults); urticarialike; bullous; papulonodular; papulovesicular; and fixed drug eruption-like. Wells syndrome is thought to result from excess production of IL-5 in response to a hypersensitivity reaction to an exogenous or endogenous circulating antigen.3,4 Increased levels of IL-5 enhance eosinophil accumulation in the skin, degranulation, and subsequent tissue destruction.3,4 Reported triggers include insect bites, viral and bacterial infections, drug eruptions, recent vaccination, and paraphenylenediamine in henna tattoos.3-7 Additionally, WS has been reported in the setting of gastrointestinal pathologies, such as celiac disease and ulcerative colitis, and with asthma exacerbations.8,9 However, in half of pediatric cases, no trigger can be identified.7
Clinically, WS presents with pruritic, mildly tender plaques.7 Lesions may be localized or diffuse and range from mild annular or circinate plaques with infiltrated borders to cellulitic-appearing lesions that are occasionally associated with bullae.5,6 Patients often report prodromal symptoms of burning and pruritus.5,6 Lesions rapidly progress over 2 to 3 days, pass through a blue grayish discoloration phase, and gradually resolve over 2 to 8 weeks.5,6,10 Although patients generally heal without scarring, WS lesions have been described to resolve with atrophy and hyperpigmentation resembling morphea.5-7 Additionally, patients typically experience a relapsing remitting course over months to years with eventual spontaneous resolution.1,5 Patients also may experience systemic symptoms including fever, lymphadenopathy, and arthralgia, though they do not develop more widespread systemic manifestations.2,3,7
Diagnosis of WS is based on clinicopathologic correlation. Histopathology of WS lesions demonstrates 3 phases. The acute phase demonstrates edema of the superficial and mid dermis with a dense dermal eosinophilic infiltrate.1,6,10 The subacute granulomatous phase demonstrates flame figures in the dermis.1,2,6,7,10 Flame figures consist of palisading groups of eosinophils and histiocytes around a core of degenerating basophilic collagen bundles associated with major basic protein.1,2,6,7,10 Finally, in the resolution phase, eosinophils gradually disappear while histiocytes and giant cells persist, forming microgranulomas.1,2,10 Notably, no vasculitis is observed and direct immunofluorescence is negative.3,7 Although flame figures are suggestive of WS, they are not pathognomonic and are observed in other conditions including Churg-Strauss syndrome, parasitic and fungal infections, herpes gestationis, bullous pemphigoid, and follicular mucinosis.2,5
Wells syndrome is a self-resolving and benign condition.1,10 Physicians are recommended to gather a complete history including review of medications and vaccinations; a history of insect bites, infections, and asthma; laboratory workup consisting of a complete blood cell count with differential and stool samples for ova and parasites; and a skin biopsy if the diagnosis is unclear.7 Identification and treatment of underlying causes often results in resolution.6 Systemic corticosteroids frequently are used in both adult and pediatric patients, though practitioners should consider alternative treatments when recurrences occur to avoid steroid side effects.3,6 Midpotency topical corticosteroids present a safe alternative to systemic corticosteroids in the pediatric population, especially in cases of localized WS without systemic symptoms.3 Other medications reported in the literature include cyclosporine, dapsone, antimalarial medications, and azathioprine.6 Despite appropriate therapy, patients and physicians should anticipate recurrence over months to years.1,6
The Diagnosis: Wells Syndrome
A punch biopsy taken from the perimeter of the lesion demonstrated mild spongiosis overlying a dense nodular to diffuse infiltrate of lymphocytes, neutrophils, and numerous eosinophils, some involving underlying fat lobules (Figure, A and B). In some areas, eosinophilic degeneration of collagen bundles surrounded by a rim of histiocytes, "flame features," were observed (Figure C). The clinical and histological features were consistent with Wells syndrome (WS), also known as eosinophilic cellulitis. Given the localized mild nature of the disease, the patient was started on a midpotency topical corticosteroid.
Wells syndrome is a rare inflammatory condition characterized by clinical polymorphism, suggestive histologic findings, and a recurrent course.1,2 This condition is especially rare in children.3,4 Caputo et al1 described 7 variants in their case series of 19 patients: classic plaque-type variant (the most common clinical presentation in children); annular granuloma-like (the most common clinical presentation in adults); urticarialike; bullous; papulonodular; papulovesicular; and fixed drug eruption-like. Wells syndrome is thought to result from excess production of IL-5 in response to a hypersensitivity reaction to an exogenous or endogenous circulating antigen.3,4 Increased levels of IL-5 enhance eosinophil accumulation in the skin, degranulation, and subsequent tissue destruction.3,4 Reported triggers include insect bites, viral and bacterial infections, drug eruptions, recent vaccination, and paraphenylenediamine in henna tattoos.3-7 Additionally, WS has been reported in the setting of gastrointestinal pathologies, such as celiac disease and ulcerative colitis, and with asthma exacerbations.8,9 However, in half of pediatric cases, no trigger can be identified.7
Clinically, WS presents with pruritic, mildly tender plaques.7 Lesions may be localized or diffuse and range from mild annular or circinate plaques with infiltrated borders to cellulitic-appearing lesions that are occasionally associated with bullae.5,6 Patients often report prodromal symptoms of burning and pruritus.5,6 Lesions rapidly progress over 2 to 3 days, pass through a blue grayish discoloration phase, and gradually resolve over 2 to 8 weeks.5,6,10 Although patients generally heal without scarring, WS lesions have been described to resolve with atrophy and hyperpigmentation resembling morphea.5-7 Additionally, patients typically experience a relapsing remitting course over months to years with eventual spontaneous resolution.1,5 Patients also may experience systemic symptoms including fever, lymphadenopathy, and arthralgia, though they do not develop more widespread systemic manifestations.2,3,7
Diagnosis of WS is based on clinicopathologic correlation. Histopathology of WS lesions demonstrates 3 phases. The acute phase demonstrates edema of the superficial and mid dermis with a dense dermal eosinophilic infiltrate.1,6,10 The subacute granulomatous phase demonstrates flame figures in the dermis.1,2,6,7,10 Flame figures consist of palisading groups of eosinophils and histiocytes around a core of degenerating basophilic collagen bundles associated with major basic protein.1,2,6,7,10 Finally, in the resolution phase, eosinophils gradually disappear while histiocytes and giant cells persist, forming microgranulomas.1,2,10 Notably, no vasculitis is observed and direct immunofluorescence is negative.3,7 Although flame figures are suggestive of WS, they are not pathognomonic and are observed in other conditions including Churg-Strauss syndrome, parasitic and fungal infections, herpes gestationis, bullous pemphigoid, and follicular mucinosis.2,5
Wells syndrome is a self-resolving and benign condition.1,10 Physicians are recommended to gather a complete history including review of medications and vaccinations; a history of insect bites, infections, and asthma; laboratory workup consisting of a complete blood cell count with differential and stool samples for ova and parasites; and a skin biopsy if the diagnosis is unclear.7 Identification and treatment of underlying causes often results in resolution.6 Systemic corticosteroids frequently are used in both adult and pediatric patients, though practitioners should consider alternative treatments when recurrences occur to avoid steroid side effects.3,6 Midpotency topical corticosteroids present a safe alternative to systemic corticosteroids in the pediatric population, especially in cases of localized WS without systemic symptoms.3 Other medications reported in the literature include cyclosporine, dapsone, antimalarial medications, and azathioprine.6 Despite appropriate therapy, patients and physicians should anticipate recurrence over months to years.1,6
- Caputo R, Marzano AV, Vezzoli P, et al. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142:1157-1161.
- Smith SM, Kiracofe EA, Clark LN, et al. Idiopathic hypereosinophilic syndrome with cutaneous manifestations and flame figures: a spectrum of eosinophilic dermatoses whose features overlap with Wells' syndrome. Am J Dermatopathol. 2015;37:910-914.
- Gilliam AE, Bruckner AL, Howard RM, et al. Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood. Pediatrics. 2005;116:E149-E155.
- Nacaroglu HT, Celegen M, Karkıner CS, et al. Eosinophilic cellulitis (Wells' syndrome) caused by a temporary henna tattoo. Postepy Dermatol Alergol. 2014;31:322-324.
- Heelan K, Ryan JF, Shear NH, et al. Wells syndrome (eosinophilic cellulitis): proposed diagnostic criteria and a literature review of the drug-induced variant. J Dermatol Case Rep. 2013;7:113-120.
- Sinno H, Lacroix JP, Lee J, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): a case series and literature review. Can J Plast Surg. 2012;20:91-97.
- Cherng E, McClung AA, Rosenthal HM, et al. Wells' syndrome associated with parvovirus in a 5-year-old boy. Pediatr Dermatol. 2012;29:762-764.
- Eren M, Açikalin M. A case report of Wells' syndrome in a celiac patient. Turk J Gastroenterol. 2010;21:172-174.
- Cruz MJ, Mota A, Baudrier T, et al. Recurrent Wells' syndrome associated with allergic asthma exacerbation. Cutan Ocul Toxicol. 2012;31:154-156.
- Van der Straaten S, Wojciechowski M, Salgado R, et al. Eosinophilic cellulitis or Wells' syndrome in a 6-year-old child. Eur J Pediatr. 2006;165:197-198.
- Caputo R, Marzano AV, Vezzoli P, et al. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142:1157-1161.
- Smith SM, Kiracofe EA, Clark LN, et al. Idiopathic hypereosinophilic syndrome with cutaneous manifestations and flame figures: a spectrum of eosinophilic dermatoses whose features overlap with Wells' syndrome. Am J Dermatopathol. 2015;37:910-914.
- Gilliam AE, Bruckner AL, Howard RM, et al. Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood. Pediatrics. 2005;116:E149-E155.
- Nacaroglu HT, Celegen M, Karkıner CS, et al. Eosinophilic cellulitis (Wells' syndrome) caused by a temporary henna tattoo. Postepy Dermatol Alergol. 2014;31:322-324.
- Heelan K, Ryan JF, Shear NH, et al. Wells syndrome (eosinophilic cellulitis): proposed diagnostic criteria and a literature review of the drug-induced variant. J Dermatol Case Rep. 2013;7:113-120.
- Sinno H, Lacroix JP, Lee J, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): a case series and literature review. Can J Plast Surg. 2012;20:91-97.
- Cherng E, McClung AA, Rosenthal HM, et al. Wells' syndrome associated with parvovirus in a 5-year-old boy. Pediatr Dermatol. 2012;29:762-764.
- Eren M, Açikalin M. A case report of Wells' syndrome in a celiac patient. Turk J Gastroenterol. 2010;21:172-174.
- Cruz MJ, Mota A, Baudrier T, et al. Recurrent Wells' syndrome associated with allergic asthma exacerbation. Cutan Ocul Toxicol. 2012;31:154-156.
- Van der Straaten S, Wojciechowski M, Salgado R, et al. Eosinophilic cellulitis or Wells' syndrome in a 6-year-old child. Eur J Pediatr. 2006;165:197-198.
A healthy 7-year-old boy presented with an enlarging hyperpigmented plaque on the anterior aspect of the lower left leg of 2 months' duration. His mother reported onset following a mosquito bite. Clotrimazole was used without improvement. His mother denied recent travel, similar lesions in close contacts, fever, asthma, and arthralgia. Physical examination revealed a 5.2 ×3-cm nonscaly, red-brown, ovoid, thin plaque with a slightly raised border.
