Chapter 36. Eosinophils in Cutaneous Diseases

Eosinophils have myriad phlogistic activities that implicate them in disease.1–3 (See Chapter 31.) Peripheral blood eosinophilia and/or tissue infiltration by eosinophils occur in a variety of common and unusual diseases, including those of infectious, immunologic, and neoplastic etiologies. Organ-specific eosinophil disorders occur in the skin, lung, and gastrointestinal tract.4–6 Eosinophils are conspicuous in tissue sections stained with hematoxylin and eosin because of their intense avidity for eosin dye. Common dermatoses associated with eosinophils in lesional tissues include arthropod bites and drug eruptions. Parasitic infections, especially those due to ectoparasites and helminthes, typically have a marked host response with eosinophilia.7,8 Autoimmune blistering diseases, such as bullous pemphigoid and the various forms of pemphigus, often have prominent eosinophil infiltration, including histologic presentation as eosinophilic spongiosis.9,10 Infiltration of eosinophils in the subcutaneous tissues, so-called eosinophilic panniculitis, is not a specific diagnosis but rather is seen to a variable degree in diverse entities.11,12 Eosinophils may be found in Langerhans cell histiocytosis,13 cutaneous epithelial neoplasms,14 and lymphoproliferative disorders.15 Although eosinophils constitute one of the histologic features in numerous cutaneous diseases, eosinophil infiltration represents a criterion for histologic diagnosis in relatively few entities (Table 36-1). The absence, presence or number of eosinophils in skin biopsy specimens is often of limited value in reliably choosing among differential diagnoses with different and potentially important implications for clinical management, such as drug reaction versus acute graft-versus-host disease.16,17 Eosinophils play a role in certain categories of clinical reactions, particularly those characterized by edema.18 The degree of tissue eosinophil granule protein deposition in such diseases, that exhibit relatively few or no intact eosinophils, suggests that the pathogenic influence of eosinophils may be unrelated to their numbers in tissues. The degree of cutaneous eosinophil infiltration should be taken in the context of other clinical features, other histological features, and knowledge that its diagnostic power has limitations.19 However, eosinophils do have potent biological activities, particularly imparted by their distinctive granules, and eosinophils may play a pathogenic role in the absence of identifiable cells in tissues.

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History

 Prior to 1968, patients with marked blood eosinophilia, in the absence of helminthic infections or allergic disease, were diagnosed using various terms. In 1968, Hardy and Anderson coined the term “hypereosinophilic syndromes (HES)” to refer to eosinophil-associated diseases with common clinical features, including skin disease in more than 50% of patients.20 Chusid and colleagues proposed diagnostic criteria in 1975,21 and the clinical spectrum of HES was defined. Hypersensitivity was thought to play a pathogenic role in HES, and, in the 1990s, a subset of patients with HES was found to have clonal T cell proliferations, with increased production of Th2 cytokines including interleukin-5.22,23 Therefore, a lymphocytic subtype of HES was identified. Based on clinical observations that a subgroup of HES patients responded to treatments that were effective for chronic myelogenous leukemia (CML), namely, hydroxyurea, interferon, and, more recently, imatinib mesylate,24 a molecular explanation was uncovered that defined another HES subtype.25 Patients with this myeloproliferative HES subtype possessed a Fip1-like 1/platelet-derived growth factor receptor-α (FIP1L1-PDGFRA) fusion gene,26 whose protein product is a constitutively activated tyrosine kinase that is exquisitely sensitive to the inhibitory effects of imatinib. Other mutations have been described in myeloproliferative HES.27 Patients with eosinophil clonality also are regarded as having chronic eosinophilic leukemia. Some classification schemes consider idiopathic HES as a diagnosis of exclusion, reserved for patients with peripheral blood eosinophilia and organ involvement but without evidence of eosinophil clonality. There are patients with HES who have neither the lymphocytic nor the myeloproliferative form, and additional subtypes of HES have been partially classified.28,29 The classification of HES is evolving as new understanding of pathogenic mechanisms becomes available.30

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Epidemiology

The hypereosinophilic syndromes (HES) consist of a spectrum of disorders that occur worldwide and span all age groups. Over 90% of patients with myeloproliferative HES and the mutant gene are men, but lymphocytic HES shows equal gender distribution. The relative frequencies of these subtypes are unknown, although up to 25% of HES patients may have lymphocytic HES. Rare familial cases have been reported. A miniepidemic of eosinophilic esophagitis, a subtype of overlap HES with organ-restricted disease, emerged over the last decade with prevalence estimates as high as 1:2,500 among children and 1:4,000 among adults.31,32

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Etiology

Eosinophils are implicated as the cause of most end-organ damage in all HES subtypes.2,33 Clinical improvement usually parallels a decrease in eosinophil count. Patients with lymphocytic HES have abnormal T-cell clones with unusual surface phenotypes, including CD3+CD4−CD8− and CD3−CD4+. These T cells display activation markers, such as CD25, and secrete T helper 2 cytokines, including high levels of interleukin 5 (IL-5).23,34 An 800-kilobase deletion on chromosome band 4q12 that codes for a tyrosine kinase has been found in myeloproliferative HES.26 Patients with this FIP1L1-PDGFRA gene mutation form a distinct subset of HES, with cardiomyopathy and endomyocardial fibrosis, that responds to imatinib. Patients in this HES subset have elevated serum tryptase levels and increased atypical spindle-shaped mast cells in bone marrow.27,28,35 Although they do not have clinical manifestations of systemic mastocytosis or exhibit all its immunological markers, these patients satisfy criteria for mastocytosis.36 The FIP1L1-PDGFRA gene is detected in mast cells,37 eosinophils, neutrophils, and mononuclear cells. Many HES patients also have marked neutrophilia, likely due to the aberrant gene in the neutrophil lineage. Thus, alteration of several cell lines probably contributes to the pathogenesis of myeloproliferative HES.38,39 Multiple other chromosomal abnormalities have been identified in myeloproliferative HES, including translocations, partial and complete chromosomal deletions, and trisomies 8, 15, and 21. Myeloproliferative HES with documented mutations also is known as chronic eosinophilic leukemia. The World Health Organization has an updated 2008 classification scheme for myeloid disorders and eosinophilia.40,41 The etiology of the other HES variants is not well understood, although patients in several HES subtypes, including with episodic angioedema and eosinophilia [Gleich syndrome42; see section “Episodic Angioedema Associated with Eosinophilia (Gleich Syndrome)”] and the nodules, eosinophilia, rheumatism, dermatitis, and swelling (NERDS) syndrome,43 have developed T-cell clones.30

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Clinical Findings and Course

Patients satisfying HES diagnostic criteria (Table 36-2) present with signs and symptoms related to the organ systems infiltrated by eosinophils.44–46 HES often present with skin lesions47,48 that may be the only manifestations of HES.49–51 Pruritic erythematous macules, papules, plaques, wheals, or nodules are present in over 50% of patients.52 Lesions may involve the head, trunk, and extremities. Urticaria and angioedema occur in all HES subtypes and are characteristic of certain variant subtypes. Erythema annulare centrifugum,53–55 bullous pemphigoid,56 lymphomatoid papulosis,57 livedo reticularis, purpura and/or other signs of vasculitis,58–61 Wells syndrome (eosinophilic cellulitis),62,63 and multiple other mucocutaneous manifestations48 may be found in patients with HES (Table 36-3).

In myeloproliferative HES, the usual presenting complex includes fever, weight loss, fatigue, malaise, skin lesions, and hepatosplenomegaly.29,46,64,65 Mucosal ulcers of the oropharynx or anogenital region (Fig. 36-1) portend an aggressive clinical course; death is likely within 2 years of presentation if the disorder is untreated.64,66 Cardiac disease occurs frequently.67 Eosinophils adhere to endocardium and release granule proteins onto endothelial cells, thrombus formation follows, and, finally, subendocardial fibrosis with restrictive cardiomyopathy occurs. Mitral or tricuspid valvular insufficiency results from tethering of chordae tendineae.67 Cardiac abnormalities that are essentially identical to those of HES but are confined to the intramural regions can occur without appreciable peripheral blood eosinophilia.68,69 Splinter hemorrhages and/or nail fold infarcts may herald the onset of thromboembolic disease. The central and peripheral nervous system, lungs, and, rarely, kidneys may be affected.46 Patients with myeloproliferative HES frequently present with clinical features resembling those of chronic myelogenous leukemia and, depending on the classification, are regarded as having chronic eosinophilic leukemia. Although chromosomal abnormalities characterize this subtype and the disease may evolve into definite leukemia, the relatively mature nature of the eosinophils and lack of evidence for clonal expansion may preclude such classification.

Lymphocytic HES commonly is associated with severe pruritus, eczema, erythroderma, urticaria, and angioedema, as well as lymphadenopathy and, rarely, endomyocardial fibrosis.34 In contrast to myeloproliferative HES, lymphocytic HES generally follows a benign course, and T-cell clones can remain stable for years. Patients should be observed closely and regarded as having premalignant or malignant T-cell proliferation, because the disease may evolve into lymphoma.

Churg–Strauss syndrome (see Chapter 164) is a variant HES subtype. Other variant HES subtypes include Gleich syndrome42 [see section “Episodic Angioedema Associated with Eosinophilia (Gleich Syndrome)”], in which eosinophil counts fluctuate with extreme angioedema.

During the decade or more after diagnosis, HES may evolve into acute leukemia and, less commonly, has been associated with B-cell lymphomas. The overall 5-year survival rate for HES patients is 80%; congestive heart failure from the restrictive cardiomyopathy of eosinophilic endomyocardial disease is a major cause of death, followed by sepsis.

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Laboratory Tests

A key criterion for diagnosis is marked peripheral blood eosinophilia (see Table 36-2).44,70–72 Other causes of eosinophilia, including allergic and parasitic diseases, should be excluded. Tests to detect organ involvement, particularly measurement of liver enzyme levels, are important. Because eosinophilic endomyocardial disease can develop in any patient with prolonged peripheral blood eosinophilia, patients should undergo periodic echocardiography along with close observation for signs of thromboembolism. Increased serum levels of immunoglobulin E (IgE) are often present in lymphocytic HES, and levels of vitamin B12 and tryptase may be increased in myeloproliferative HES. The Chic2 fluorescent in situ hybridization assay detects the deletion that produces the FIP1L1-PDGFRA gene product and should be performed, because patients with this mutation respond to treatment with imatinib.35,37 Alternatively, the mutant gene can be detected by a polymerase chain reaction assay. Both tests are available commercially. In patients who lack the fusion gene, testing for other clonal cytogenetic abnormalities or abnormal clonal T-cell populations is warranted.27 Cytoflow of peripheral blood lymphocytes and immunophenotyping of tissue lymphocytes should be performed for the diagnosis of lymphocytic HES and repeated periodically to detect transformation from a variant HES type to lymphocytic HES or to T-cell lymphoma.34 An HES evaluation assessment scheme for patients with eosinophilia is presented in Table 36-4.

The cutaneous histopathological features of HES vary with the type of lesion. Skin biopsy specimens from urticarial lesions resemble idiopathic urticaria, with generally mild, nonspecific perivascular and interstitial infiltration of lymphocytes, eosinophils, and, occasionally, neutrophils. Immunostaining reveals extensive deposition of eosinophil granule proteins, in the absence of intact eosinophils, in episodic angioedema with eosinophilia,42 HES with mucosal ulcers,73 and in synovial tissues in NERDS.43 Other than in Churg–Strauss syndrome, vasculitis only rarely has been associated with HES.58–60

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Differential Diagnosis

(Box 36-1)

Clinically, parasitic infections and infestations may closely resemble HES.74 A history of travel to endemic areas or certain dietary exposure implicates helminthiasis. Along with eosinophilia, total serum IgE levels higher than 500 IU/mL commonly are found in helminthic infections. Examination of stool samples for ova and parasites and serologic testing for Strongyloides antibodies should be performed. In patients with isolated urticarial plaques with or without angioedema, the differential diagnosis includes common and persistent urticaria,75,76 but demonstration of multiorgan involvement supports HES. HES with episodic angioedema may resemble hereditary angioedema clinically, although patients with hereditary angioedema often have a family history of the disease rarely have the markedly elevated eosinophil counts that characterize HES, and may be distinguished by complement abnormalities. Pruritic eczematoid lesions of lymphocytic HES may resemble those of atopic dermatitis, contact dermatitis, drug reaction, fungal infection, and T-cell lymphoma. There are multiple diseases in the differential diagnosis of patients with orogenital ulcers,64 including those associated with thrombosis, such as Behçet syndrome, Crohn disease, ulcerative colitis, and Reiter syndrome. Others considerations are recurrent aphthous stomatitis, immunobullous diseases, erythema multiforme, lichen planus, herpes simplex infection, and syphilis.

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Treatment

The goal of treatment is to relieve symptoms and improve organ function while keeping peripheral blood eosinophils at 1,000 to 2,000/mm3 and minimizing treatment side effects (Fig. 36-2). Recent reviews have delineated evaluation and management of HES.29,70–72,77 Myeloproliferative HES is responsive to imatinib.78 In patients with the mutant gene FIP1L1-PDGFRA, administration of imatinib mesylate is indicated and usually induces hematologic remission, but endomyocardial disease may worsen during the first several days of treatment. Troponin levels should be monitored before and during imatinib therapy.79,80 To improve cardiac function, glucocorticoids should be given before and with initiation of imatinib therapy. Imatinib resistance can develop.81–83 In the absence of the gene mutation, after Strongyloides infection has been excluded,84 first-line therapy is prednisone. Approximately 70% of patients will respond, with peripheral eosinophil counts returning to normal. Patients for whom glucocorticoid monotherapy fails have a worse prognosis generally; in such cases or when long-term side effects become problematic, other treatments should be used. Effective treatment of HES in imatinib-responsive patients results in improvement of associated conditions including cardiac involvement with endocarditis85 and myelofibrosis86 and skin disease with bullous pemphigoid.56 Patients who have features of myeloproliferative HES but who lack FIP1L1-PDGFRA still may respond to imatinib.25 Interferon (IFN)-α has been beneficial in treating myeloid and lymphocytic HES.87,88 In one patient, loss of the FIP1L1-PDGFRA mutation after several years of IFN-α therapy was associated with complete remission.89 Extracorporeal photopheresis alone or in combination with IFN-α or other therapies represent additional therapeutic options. Other treatments for HES with reported benefit include hydroxyurea, dapsone, vincristine sulfate, cyclophosphamide, methotrexate, 6-thioguanine, 2-chlorodeoxyadenosine and cytarabine combination therapy, pulsed chlorambucil, etoposide, cyclosporine, intravenous immunoglobulin, and psoralen plus ultraviolet A (UVA) phototherapy.90 Refractory disease may respond to infliximab (antitumor necrosis factor-α)91 or alemtuzumab (anti-CD52),92–94 as well as to bone marrow and peripheral blood stem cell allogeneic transplantation.95,96 Two monoclonal antibodies against human IL-5 have been associated with clinical improvement and reductions in peripheral blood and dermal eosinophils, particularly in patients with lymphocytic HES.97–101 Treatments targeting IL-5 have provided new insights into understanding eosinophil-associated disease.33

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History

 G.C. Wells reported four patients who had recurrent edematous infiltrative plaques that resembled cellulitis at onset and morphea later,102 and identified the condition descriptively as “recurrent granulomatous dermatitis with eosinophilia.” Histologically, the lesions were characterized by diffuse dermal eosinophil and histiocyte infiltration and foci of amorphous and/or granular material associated with connective tissue fibers, which he named “flame figures.” In 1979, Wells and Smith described eight additional patients with the syndrome and introduced the term “eosinophilic cellulitis.” In that report, they also discussed nine patients with the histologic features of eosinophilic cellulitis who had a variety of other clinical diagnoses, including pemphigoid, eczema, and tinea.103 That same year, Spigel and Winkelmann104 proposed the eponym Wells’ syndrome for the disorder that Wells initially described in 1971 and later renamed “eosinophilic cellulitis.”102 This and subsequent reports of flame figures in lesions from patients with multiple other inflammatory conditions indicate that the flame figure per se, although characteristic in Wells’ syndrome, is not diagnostic of one clinical disorder.105

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Epidemiology

 Wells syndrome is primarily a disease of adults, but pediatric patients have been reported.102–104,106–115 Familial eosinophilic cellulitis has been described.116 The disease has no gender predilection.

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Etiology

 Whether Wells syndrome is a specific entity that is triggered by factors including underlying disease, infection, and drugs, or whether it is merely a reaction pattern may be difficult to discern from the reported cases and in practice.105 Association of eosinophilic cellulitis with a range of disorders (Table 36-5), including arthropod bites,103,111,117 insect stings,118 myeloproliferative diseases,117,119 ulcerative colitis,120 colon cancer,121 bronchogenic carcinoma,122 mastocytoma,123 reactions to vaccination,124–126 Churg–Strauss syndrome,110,127 hypereosinophilic syndromes,62,63 eosinophilic fasciitis,128 dermographism,129 onchocerciasis,106 molluscum contagiosum,130 herpes simplex infection,131 human immunodeficiency virus infection,132 immunobullous disease,103,133 and drug reactions134–136 suggests that it is a reactive or allergic hypersensitivity phenomenon, although the precise pathogenesis is unknown.137

 Deposition of toxic granule proteins in lesional tissues, revealed by immunofluorescence testing, provides evidence that eosinophil degranulation contributes to flame figure formation in Wells syndrome.113 Indeed, Wells and Smith postulated that infiltration of phagocytic histiocytes between collagen bundles may be a response to collagen damage induced by eosinophil cytotoxicity.103 The severity of Wells syndrome has been correlated with serum levels of IL-5128,138 and eosinophil cationic protein,138 and IL-5 is implicated in the development of hereditary eosinophilic cellulitis.116

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Clinical Findings and Course

Cutaneous edema was the common clinical thread in the first four cases reported by Wells.102 After prodromal burning or itching, lesions begin with erythema and edema (Fig. 36-3A), sometimes in the form of annular or arcuate plaques or nodules. Over a period of days, they evolve into large edematous plaques with violaceous borders. Bullae may develop.108,109,120,139 Individual lesions gradually change from bright red to brown–red and then to blue–gray or greenish gray, resembling morphea (Fig. 36-3B). Less common clinical presentations include papules, vesicles (Fig. 36-4), and hemorrhagic bullae. The cutaneous lesions may be single or multiple and may be located at any site, but typically involve the extremities and, less often, the trunk.137 The most frequent systemic complaint in patients with Wells syndrome is malaise; fever occurs in a minority of cases. Lesions resolve without scarring, usually within weeks to months, but multiple recurrences are common.

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Laboratory Tests and Histopathology

Peripheral blood eosinophilia is observed in approximately 50% of patients. Skin lesions histologically are characterized by diffuse dermal infiltration with eosinophils, histiocytes, and foci of amorphous and/or granular material associated with connective tissue fibers, which Wells termed flame figures.102 In the early stages, there also is dermal edema. Later, histiocytes palisade around flame figures. In addition to eight patients with the syndrome, the 1979 report of Wells and Smith includes nine patients with the typical histologic features of eosinophilic cellulitis but in association with a variety of clinical diagnoses, including pemphigoid, eczema, and tinea.103 This and subsequent reports of flame figures in lesions from patients with a wide spectrum of diseases (see Table 36-5 and referenced above) indicate that the flame figure is characteristic for, but not diagnostic of, Wells syndrome.105 When examined for eosinophil granule major basic protein by immunofluorescence, flame figures show bright extracellular staining (Fig. 36-5), indicating that extensive eosinophil degranulation has occurred.113

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Differential Diagnosis

(Box 36-2)

Urticaria, erysipelas, and acute cellulitis should be considered in the differential diagnosis of the early stages of Wells syndrome (see Fig. 36-3A). Later, plaques may resemble morphea (see Fig. 36-3B). The presence of blisters may suggest pemphigoid (see Fig. 36-4). Flame figures are the hallmark of Wells syndrome, but, because they have been identified in biopsy specimens from other dermatoses (Table 36-5), they are not alone sufficient for the diagnosis. However, a diagnosis of Wells syndrome in the absence of flame figures should be met with skepticism, even in the presence of dermal infiltration with eosinophils and histiocytes.105

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Treatment

Wells syndrome usually improves dramatically after administration of systemic glucocorticoids, and tapering of steroid dose over 1 month is well tolerated in most patients. Recurrences may be treated with additional courses of systemic glucocorticoids. For patients who fail to respond, or who experience relapse often enough to raise concerns about the long-term side effects of systemic glucocorticoid therapy, other options such as minocycline, dapsone, griseofulvin, and antihistamines may be beneficial. Cyclosporine and IFN-α also have been used with success. For treatment of mild disease, topical glucocorticoids may be sufficient.

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History

 Angiolymphoid hyperplasia with eosinophilia was described by Wells and Whimster in 1969,140 but such lesions have been reported by different authors under a variety of terms, including atypical pyogenic granuloma, inflammatory angiomatous nodule, papular angioplasia, inflammatory arteriovenous hemangioma, intravenous atypical vascular proliferation, histiocytoid hemangioma, and epithelioid hemangioma.141–143 Although initially thought to be part of the spectrum of lesions seen in Kimura disease, the above terms and evolution to a currently favored designation as epithelioid hemangioma underscore that angiolymphoid hyperplasia with eosinophilia fundamentally represents vascular proliferation with inflammation rather than an inflammatory process with exuberant vascularity.144

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Epidemiology

Angiolymphoid hyperplasia with eosinophilia (ALHE) occurs in both males and females, but there is a slight female predominance. Patients are generally in the third to fifth decade of life. In contrast to Kimura disease (KD), which develops mainly in patients from Asia, ALHE has no racial predilection.

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Etiology

The pathogenesis of ALHE is unknown, but it has been considered a vascular proliferation arising in response to or in association with underlying vascular malformation. There is a history of trauma in some cases. ALHE has been reported to occur in pregnancy, which implies that sex hormones may be a factor in its development.145 ALHE also has developed in patients with T-cell clonality, which suggests that it may be an early or low-grade T-cell lymphoma and further highlights a relationship between T-cells and eosinophils, particularly T-cells with the TH2 phenotype.146,147

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Clinical Findings and Course

ALHE shows a predilection for the head and neck area, including the ears,148 and is characterized by solitary, few, or multiple, sometimes grouped, erythematous, violaceous or brown papules, plaques, or nodules of the dermis and/or subcutaneous tissues (see Chapter 146). Lesions may be associated with pruritus or pain, or may pulsate. Although they are confined to the skin in most patients, mucosal involvement may occur.149 ALHE tends to be chronic and nonremitting over months to years.

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Laboratory Tests and Histopathology

Approximately 20% of patients have peripheral blood eosinophilia; IgE levels are unremarkable. There is no association with renal disease. The dominant histological feature is a well-defined area, in the dermis and/or subcutis, of prominent vascular proliferation with large epithelioid or histiocytoid endothelial cells that contain abundant eosinophilic cytoplasm, often with cytoplasmic vacuoles (see Chapter 147). There are variable numbers of eosinophils and lymphocytes,150 with an occasional finding of lymphoid nodules. In their report of 116 patients with ALHE, Olsen and Helwig found 53 cases in which “an arterial structure” appeared to be associated with venules or “was the area of endothelial proliferation,” which provided evidence that these lesions may represent a form of arteriovenous shunt.151 The stroma typically is myxoid, and fibrosis is minimal or absent. Mast cells may be a component of the histologic picture.

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Differential Diagnosis

(Box 36-3)

Lesions of ALHE generally are smaller, more superficial, and more numerous than those of KD, and often are symptomatic. Although lymphoid follicles may occur in ALHE, they represent the dominant characteristic of KD (Table 36-6), and although KD may exhibit some vascularity, it lacks the large epithelioid endothelial cells that are a key feature of ALHE (see Table 36-6). ALHE should be distinguished from a variety of benign and malignant vascular proliferations, including pyogenic granuloma, epithelioid hemangioendothelioma, and Kaposi sarcoma—all of which lack a noticeable eosinophil infiltrate.

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Treatment

Intervention is dictated in part by the number, location, size of lesions, and the patient's general health.152 Patients with solitary or a few small lesions may benefit from excision or Mohs surgery, 153 but there may be recurrence at the surgical site (see Fig. 36-6). A variety of other treatment modalities have been used with success, including systemic and intralesional glucocorticoid administration, INF-α therapy,154 cryotherapy,155 laser therapy,156 and topical application of tacrolimus.157

(Box 36-4)

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History

 Although initially described in 1937 by Kim and Szeto, in the Chinese literature, as “eosinophilic hyperplastic lymphogranuloma,” general recognition of this entity began after Kimura et al reported “on the unusual granulation combined with hyperplastic changes of lymphatic tissue” in 1948.158,159

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Epidemiology

 KD occurs predominantly in young adult Asian males. It also has been reported in non-Asians and in children.

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Etiology

 KD is an idiopathic disorder. The combination of peripheral blood eosinophilia, increased serum IgE levels, and histologic pattern of lymphoid nodules with germinal centers and numerous eosinophils suggests that KD represents an allergic hypersensitivity reaction, but reported finding of a T-cell clone in some patients suggests that it may be a manifestation of a T cell lymphoproliferative disorder. The pathogenic stimulus for the hypersensitivity response is unknown. Association with glomerulonephritis raises the possibility that KD has an autoimmune basis.

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Clinical Findings and Course

 Patients typically have one or a few asymptomatic, nontender, slowly enlarging subcutaneous nodules. Lesions characteristically involve the head and neck region but may be localized to the extremities, axilla, groin, or trunk. There often is associated regional lymphadenopathy and sometimes more widespread lymph node enlargement.160–162 The overlying skin appears normal. KD is typically chronic and recurrent.

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Laboratory Tests and Histopathology

 Peripheral blood eosinophil counts and serum IgE levels are elevated in most patients. Evaluation of renal function is indicated, because KD is associated with glomerulonephritis and nephrotic syndrome.163–165 Histologically, lesions are characterized by lymphoid aggregates, usually in the form of lymphoid follicles with germinal centers, numerous eosinophils (see eFig. 36-6.1), and fibrosis. Other features may include eosinophil abscesses and stromal vascularity, without the epithelioid or histiocytoid endothelial cells that are typical of ALHE.

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Differential Diagnosis

 Because lesions of KD are usually subcutaneous, with normal-appearing overlying skin, and are associated with lymphadenopathy, the possibility of lymphoma or metastatic carcinoma should be considered in the clinical differential diagnosis. Historically, there has been debate about whether ALHE and KD represent separate entities or are part of a single disease spectrum, a confusion that may be furthered by a report of KD and ALHE occurring in the same patient.166 Both ALHE and KD are characterized by persistent and recurrent lesions, primarily involving the head and neck areas. However, there are distinct clinical and histological differences between the two disorders (see Table 36-6), particularly the lymphoid follicles with germinal centers that dominate KD in contrast to the vascular proliferation with large epithelioid endothelial cells that characterizes ALHE.160 Lesional tissue and peripheral blood eosinophilia are more pronounced in KD.

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Treatment

Surgical excision is the treatment of choice when feasible in patients with a single or a limited number of nodules, but lesions may recur.167,168 Other therapeutic options include systemic glucocorticoids, cyclosporine, and radiation therapy.169,170 The presence of renal disease may influence or dictate the therapeutic regimen. The finding of platelet-derived growth factor-α and c-kit in tissues from KD patients suggests that imatinib or another tyrosine kinase inhibitor may be effective in the disease.171

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History

 In 1970, Ofuji et al described eosinophilic pustular folliculitis in three Japanese young men with recurrent pruritic papulopustules involving the face, trunk, and extremities.172 Then, in 1984, Lucky et al described five patients with eosinophilic pustules who were younger than 1 year of age.173 Subsequently, eosinophilic pustular folliculitis was reported in association with human immunodeficiency virus infection.174 It also has been observed in patients with other infectious diseases, as a drug reaction, in hematological disorders and following bone marrow transplantation. The supposition that “eosinophilic pustular folliculitis in infancy” is a distinct entity has been open to debate.175

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Epidemiology

 Predominantly a disease of males, eosinophilic pustular folliculitis (EPF) is now considered to encompass three clinical types:176: (1) Classical EPF is not racially restricted but typically occurs in Japanese adults in the third and fourth decades of life.177 (2) EPF of infancy presents during the first year of life,173,176 including the neonatal period. (3) EPF associated with human immunodeficiency virus (HIV) infection is now the most common type and may develop in the setting of antiretroviral therapy.174,178,179 The number of patients reported to have HIV-associated EPF far exceeds those in the other two categories. EPF associated with immunosuppression has been observed in HIV-negative patients who have hematologic or lymphoproliferative disease, including lymphoma, leukemia, polycythemia vera, and myelodysplastic syndrome.180–183 EPF following stem cell and bone marrow transplantation has been reported in increasing numbers of patients.184–187 EPF may develop with other infections, including parasitic,188,189 bacterial, and fungal.190–192 Drug-induced EPF also has been described.193,194 EPF has been observed in the nevoid basal cell carcinoma syndrome.195 EPF may worsen with pregnancy.196

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Etiology

 Although a variety of theories concerning the pathogenesis of EPF have been proposed, the etiology is unknown. Immune dysfunction and allergic hypersensitivity are considered to play a role. A case report demonstrated EPF in a patch test reaction.197 Fresh skin surface lipids from EPF patients are chemotactic for eosinophils,198 and eosinophil granule protein deposition is present in lesions.199 TH2 cytokines and eosinophil chemoattractants are present in HIV-associated EPF. Moreover, suppression of IL-5 mRNA expression accompanied therapeutic response to IFN-γ,200 and therapy with cyclosporine suppressed IL-4 and IL-13 mRNA expression,201 indicating an influence of TH2 activity in the disease.

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Clinical Findings and Course

Classical EPF presents as recurrent crops or clusters of follicular papules and pustules, which may form an annular pattern and usually resolve in 7 to 10 days. Lesions predominantly involve the face and trunk but also may affect the extremities, with involvement of the palms and soles in approximately 20% of patients.177 In EPF of infancy, lesions typically are located on the scalp but also may be found on the face and extremities. In some neonates who have pustular eruptions that clinically resemble EPF and typically have peripheral blood eosinophilia, the disorder may be classified more appropriately under the term eosinophilic pustulosis because the cutaneous infiltrates are not folliculocentric (see Chapter 107).202 In contrast, HIV-associated EPF tends to manifest as extremely pruritic discrete follicular papules, typically involving the head and neck and often the proximal extremities (see Fig. 198-3, Chapter 198). Rosenthal et al emphasized the urticarial quality of such lesions.178 EPF of infancy has a good prognosis, whereas classical and HIV-associated EPF are characterized by recurrences. Postinflammatory pigmentation may be seen as lesions resolve, but scarring does not occur.

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Laboratory Tests and Histopathology

Patients suspected of having EPF should be evaluated for underlying immune deficiency, particularly HIV infection. Peripheral blood eosinophilia is a component of all three types of EPF. Although patients with classical EPF usually have eosinophilia with leukocytosis, HIV-positive patients often exhibit eosinophilia with lymphopenia. Low CD4 cell counts and high IgE levels are typical of HIV-associated EPF.178 Histologically, the most striking feature is the infiltration of eosinophils into hair follicles and perifollicular areas (see eFig. 36-6.2), sometimes with follicular damage. The infiltrates also may contain lymphocytes and neutrophils, and may be perivascular as well as follicular.203 Follicular mucinosis (see Chapter 145) has been noted in association with EPF204; however, T-cell clonality is not observed in EPF-associated follicular mucinosis.205

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Differential Diagnosis

(Box 36-5)

Folliculitis secondary to bacterial or fungal infection must be kept in mind, particularly in immunosuppressed patients. Based on the distribution of lesions, seborrheic dermatitis should be considered, when there is head and neck involvement, and palmar–plantar pustular psoriasis may also be included in the differential diagnosis when there is hand and foot involvement. Acneiform eruptions may resemble EPF. Erythema toxicum neonatorum, acropustulosis, and acne neonatorum also should be considered in infants. Follicular mucinosis usually is clinically and histologically distinguishable from EPF.

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Treatment

Topical glucocorticoids and topical calcineurin inhibitors generally are the first approach to the treatment of all types of EPF. Topical tacrolimus is helpful for facial lesions.206 Nonsteroidal anti-inflammatory drugs, particularly indomethacin, also are recommended as first-line therapy; clinical improvement may be observed within 2 weeks and is associated with a decrease in peripheral blood eosinophil counts.207–209 A mechanism for this has been proposed based on the observation that indomethacin, not only inhibits cyclooxygenases and subsequent prostaglandin D2 synthesis, but also is associated with reduction in the prostaglandin D2 receptor (chemoattractant receptor homologous molecule expressed on TH2 cells, CRTH2) on eosinophils and lymphocytes.210 UV light therapy (UVB or psoralen and UVA) may be beneficial. Topical permethrin, systemic retinoids, systemic glucocorticoids, cyclosporine, itraconazole, metronidazole, cetirizine, minocycline, dapsone, and IFNs have been tried with success.207,208 Antiretroviral treatment that results in increased CD4 cell counts often is associated with improvement in HIV-associated EPF.

 Eosinophilic ulcer of the tongue, now referred to as eosinophilic ulcer of the oral mucosa, is a self-limited disease of the tongue, oral mucosa, or lips, manifested as a 1- to 2-cm ulcer with the histopathological pattern of massive eosinophil infiltration extending into underlying muscle.211–213 The infiltrate often contains lymphocytes, histiocytes, plasma cells, neutrophils, and mast cells. Eosinophilic ulcer of the oral mucosa has overlapping features of atypical histiocytic granuloma, mucosal angiolymphoid hyperplasia with eosinophilia and Kimura disease. The etiology is unknown but may be the result of reactive inflammation.214 The finding of large atypical CD30+ lymphocytes in eosinophilic ulcer of the oral mucosa suggests that it may be a lymphoproliferative disorder.215

There are a variety of diseases in which eosinophils may be present in cutaneous lesions, with or without associated peripheral blood eosinophilia, but either the histologic pattern is unremarkable or eosinophils are not critical for the histological diagnosis of the given entity (see Table 36-1). In many of these dermatoses, the eosinophil loses its morphologic integrity after disruption through cytolysis and is not identifiable histologically.216 However, toxic granule proteins and other phlogistic eosinophil products are deposited in skin, persist for extended periods of time, and cause tissue effects.73,217

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Edema

Prominent among the eosinophil-associated skin reactions are those manifesting edema, including urticarias.218–221 In addition to the presence of distinctive, toxic eosinophil cationic granule proteins in lesions, the ability of eosinophils to elaborate vasoactive mediators, induce histamine release from mast cells and basophils, and elicit a cutaneous wheal-and-flare reaction supports a role for the eosinophil as a primary participant in the edema associated with certain cutaneous diseases (see Chapter 31).2,18

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Episodic Angioedema Associated with Eosinophilia (Gleich Syndrome)

Episodic angioedema associated with eosinophilia is characterized by recurrent angioedema (with up to 30% increase in body weight), urticaria, fever, increased serum IgM levels, and leukocytosis as high as 100,000 cells/mm3 with up to 90% eosinophils; disease activity fluctuates with the peripheral eosinophil count.42,222 Skin biopsy specimens from this disorder42 and its localized variant, recurrent facial edema with eosinophilia,223 show few eosinophils, but immunofluorescence staining reveals extracellular deposition of eosinophil granule proteins around collagen bundles and blood vessels. The syndrome is associated with a number of immunologic abnormalities, including increased activated T cells224,225 and increased serum IL-5 levels.226,227 Capillary leak syndromes, due to administration of IL-2228 and granulocyte-macrophage colony-stimulating factor,229 also are associated with peripheral blood eosinophilia, increased serum IL-5 levels, and eosinophil degranulation.

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Chronic Dermatitis/Pruritus

Although infestations typically are associated with eosinophils, the histologic pattern is nondiagnostic unless a specific organism is identified in tissue sections.8,230 Infection with Onchocerca volvulus causes a pruritic dermatitis with lichenification, associated with slight cutaneous eosinophil infiltration but extensive deposition of eosinophil granule proteins throughout the dermis231; after treatment, extracellular deposition of eosinophil granule proteins is located around degenerating microfilaria.230,232 Although eosinophils are rarely a prominent histological feature of atopic dermatitis, extensive dermal deposition of eosinophil granule proteins is seen in lesions (Fig. 36-7) but not in normal-appearing skin.231,233 A link between keratinocytes and eosinophils in atopic dermatitis was reported through activity of a novel TH2 cytokine, IL-31.234 Prurigo nodularis235 and pachydermatous eosinophilic dermatitis236 exhibit a pattern of dermal extracellular eosinophil granule protein deposition similar to that seen in atopic dermatitis and onchocercal dermatitis. In both atopic dermatitis and prurigo nodularis, eosinophil granule products are deposited around cutaneous nerves,235,237 and there is evidence that eosinophils play a role in itch provocation.238–242 A particularly difficult clinical presentation is the patient with intractable itching and peripheral blood eosinophilia. Such patients may satisfy criteria for the hypereosinophilic syndromes, but their itch is refractory to most therapies. Understanding the eosinophil's role in the pathogenesis of this disorder may help with identifying effective therapies.

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Drug Reactions

Eosinophils are found in all types of drug reactions. There is evidence that, when eosinophils are part of the histologic pattern in leukocytoclastic vasculitis, the eruption is probably drug-induced243 (see Chapter 41). The drug reaction with eosinophilia and systemic symptoms syndrome, so-called DRESS and also known as drug hypersensitivity syndrome, is a serious multiorgan disorder. Many drugs induce DRESS, and a spectrum of skin lesions may present with DRESS. Eosinophils and other inflammatory cells infiltrate skin, lymph nodes, and organs, including the liver. Fulminant hepatitis is associated with a mortality rate of 10%, and transplanted livers may also be affected. Eosinophil infiltration with and without granulomas with hepatocyte necrosis and cholestasis are prominent in liver failure that occurs with DRESS.244–246

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Blisters

Autoimmune blistering diseases (see Chapters 54 and 56) often are associated with prominent infiltration of eosinophils, including presentation as eosinophilic spongiosis (Fig 36-8), and extracellular deposition of eosinophil granule proteins. IL-5 and eotaxin are present in pemphigoid blister fluid, and eosinophil-derived matrix metalloproteinase 9 that likely cleaves basement membrane zone.247,248,249

In addition to pemphigoid gestationis (which may exhibit eosinophilic spongiosis),250 other pruritic dermatoses of pregnancy (see Chapter 108) may demonstrate tissue eosinophilia.251–253

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Fibrosis

Eosinophils are found in association with fibrotic reactions, including those resulting from parasitic infections, pulmonary and hepatic drug sensitivity reactions, and HES.254 Eosinophils elaborate mediators (see Chapter 31) that degrade collagen and stimulate dermal fibroblast DNA synthesis and matrix production.255

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Eosinophilic Fasciitis

Eosinophilic fasciitis usually presents with pain, erythema, edema, and induration of the extremities, as well as peripheral blood eosinophilia and hypergammaglobulinemia.256 Contractures and rippling of the skin may develop (Fig. 36-9). There is infiltration of lymphocytes, plasma cells, mast cells, and eosinophils, as well as increased thickness of the fascia.

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Eosinophilia–Myalgia Syndrome

Eosinophilia–myalgia syndrome (EMS), historically related to ingestion of certain lots of l-tryptophan,257 is characterized by marked peripheral eosinophilia, disabling generalized myalgias, pneumonitis, myocarditis, neuropathy, encephalopathy, and fibrosis,258 a constellation of features that are similar to but distinguishable from eosinophilic fasciitis.259,260 Cutaneous abnormalities of EMS include edema, pruritus, a faint erythematous rash, hair loss, and peau d'orange or morphea-like skin lesions.261 Lungs, heart, and nervous system may be affected.262 There is a prominent inflammatory infiltrate in the perimysium and fascia, and striking evidence of eosinophil granule protein deposition in skin and around muscle bundles.257

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Toxic Oil Syndrome

Toxic oil syndrome (TOS), which resembles EMS, was linked to consumption of adulterated rapeseed oil distributed in the industrial belt around Madrid.263 Patients experienced acute respiratory symptoms followed by intense myalgias, thromboembolism, weight loss, and sicca syndrome, followed by a chronic phase characterized by eosinophilic fasciitis-like lesions, peripheral neuropathy, muscle atrophy, and pulmonary hypertension. The cutaneous manifestations of TOS were nonspecific pruritic, erythematous skin lesions that persisted up to 4 weeks, followed over the next 2 months by subcutaneous edema, mainly of the extremities, accompanied by myalgias, arthralgias, contractures, and peripheral blood eosinophilia. Over many years, patients developed indurated plaques of the pretibial areas, and, occasionally, the forearms and abdomen,263 with marked fibrosis extending into subcutaneous fat. Eosinophil infiltration and degranulation were especially prominent in the acute phase of TOS, and serum eosinophil granule protein levels were elevated during all phases.264 Potential pathogenic links between TOS and EMS and also eosinophilic fasciitis have been identified.265,266

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Vasculitis

In 1951, Churg and Strauss described the complex of systemic vasculitis, asthma, and eosinophilia as allergic granulomatosis.267 Cutaneous lesions develop in approximately two-thirds of cases and are variable consisting of nodules, urticaria, livedo reticularis, purpura, digital gangrene, and blisters. Histologically, the lesions are characterized by eosinophil infiltration, necrotizing vasculitis, and extravascular granulomas with prominent extracellular eosinophil granule protein deposition268–270 (see Chapter 164). Granuloma faciale is characterized clinically by brown–red infiltrative plaques of the face and represents a localized type of necrotizing vasculitis that contains infiltration of eosinophils as well as neutrophils, lymphocytes, and histiocytes (see Chapter 34). Eosinophilic vasculitis (EV) is associated with peripheral blood eosinophilia and is characterized by chronic, recurrent, widespread pruritic, erythematous, purpuric papules as well as angioedema of face and hands; skin biopsies show necrotizing small vessel vasculitis with prominent infiltration of eosinophils.271,272 EV may be idiopathic or associated with connective tissue disease,273 Raynaud phenomenon, or HES.58

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Malignancy

Eosinophils may be observed in a variety of cutaneous and extracutaneous neoplasms. Their presence in tumors appears to be independent of immune surveillance and likely is part of an early inflammatory reaction at the site of tumorigenesis.274 Various types of peripheral T-cell lymphomas are eosinophil-rich, including follicular mycosis fungoides and cutaneous anaplastic large cell lymphoma275–277; the prognostic significance of tissue eosinophilia in such lesions is not established. Underlying malignancy may prompt lesions associated with eosinophil infiltration, such as the exaggerated arthropod-bite reactions seen in patients with chronic lymphocytic leukemia.278

Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy (EPPER) is an uncommon idiopathic disorder that appears in patients undergoing radiation treatment for malignancy. Women are affected more often than men. Onset of the eruption is typically during radiation treatment, but delays up to 7 months are reported.279,280 Cutaneous findings are not localized to irradiated areas and may include local and generalized pruritus, erythematous papules, wheals, and vesicles and bullae. Eosinophils are prominent in affected skin, but not characteristically in the tumors.