Eosinophil-Related Disease and the Skin

Clinical Management Review

Eosinophil-Related Disease and the Skin Kristin M. Leiferman, MDa, and Margot S. Peters, MDb

Salt Lake City, Utah; and Rochester, Minn

Eosinophils are bone marrow-derived cells that infiltrate skin and mucous membrane in a broad spectrum of primary and reactive inflammatory diseases and malignancies. The eosinophil has potent proinflammatory activities, particularly, through the effects of its toxic granule proteins. In addition, eosinophils have prothrombotic and profibrotic activities. Eosinophil participation in the pathogenesis of certain diseases without identifiable intact eosinophil infiltration may not be recognized because eosinophil degranulation is poorly visualized on hematoxylin-and-eosinestained histopathology sections. Eosinophil-related pathophysiology can involve virtually every component of skin. Commonly recognized dermatoses associated with eosinophils are arthropod bite and sting reactions and drug eruptions, “bugs and drugs.” Skin involvement is common in eosinophil-related systemic diseases including the hypereosinophilic syndromes. Eosinophil-related pathophysiology may play a key role in numerous disorders that, therefore, may benefit from therapies targeted to reduce or eliminate eosinophils.
2018 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2018;6:1462-82) Key words: Eosinophil; Eosinophil granule proteins; Eosinophilrelated cutaneous disease; Eosinophil-related dermatoses; Eosinophilic cellulitis; Eosinophilic spongiosis; Skin disease

BACKGROUND Historical notes Paul Ehrlich was a histology prodigy who lived during a time when the field of chemistry was blossoming in Europe. Ehrlich extended his understanding of the chemistry of dyes used for staining organic fabrics to develop techniques for staining cells and tissues, recognizing that he could distinguish cells by their variable tinctorial properties. In 1879, he designated the “eosinophil” as the cell that demonstrated intense staining of its cytoplasmic granules with the acidic dye, eosin. Ehrlich also a

Department of Dermatology, University of Utah, Salt Lake City, Utah Department of Dermatology and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication April 20, 2018; revised manuscript received and accepted for publication June 4, 2018. Available online June 12, 2018. Corresponding author: Kristin M. Leiferman, MD, Department of Dermatology, University of Utah, 4A330 School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132-2409. E-mail: [email protected]. 2213-2198
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described how to recognize the neutrophil, basophil, mast cell, and lymphocyte, and how to quantitate cells in blood. He further identified increased eosinophils in urticaria, with medication exposure, and in “pemphigus” (probably the disease we now know as pemphigoid, which was not clinically distinguished from pemphigus until more than half a century later). He documented various other disorders associated with peripheral blood eosinophilia including asthma, helminthiasis, and malignant tumors. He prophetically surmised that the bone marrow was the site of eosinophil development, and that “the phenomenon of eosinophilia is dependent on the circulation of a substance which has a chemotactic action on eosinophils, and which serves to release preformed eosinophils from the bone marrow into the blood.”1

Homeostasis and roles in immunity Eosinophils are formed in the bone marrow and circulate as mature cells in blood. Other than gastrointestinal tract distal to the esophagus and lymphoid tissues (including spleen, thymus, and lymph nodes), eosinophils are not normally found in human organs and tissues, including skin.2 Eosinophil infiltration, however, characterizes a number of pathological states, especially parasitic infections and allergic reactivity. Cytokines, including IL-5 and eotaxins (eotaxin-1 or C-C motif ligand 11 [CCL11], eotaxin-2 or CCL24, and eotaxin-3 or CCL26), are known to mediate eosinophil development and participation in inflammation. However, why eosinophils are found normally in certain uninflamed tissues and what the mechanism for basal eosinophil regulation is, including circadian cycling of peripheral blood eosinophils, have remained unexplained until recently with the identification of innate lymphoid cells (ILCs). Long-lived type 2 ILCs, also known as ILC2s, now designated as part of the “TH2 franchise,”3 are resident in peripheral tissues and regulate tissue eosinophil accumulation and basal eosinophilopoiesis through homeostatic and stimulated cytokine expression.4-6 ILC2s secrete IL-5 constitutively and are induced to coexpress IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. Studies regarding interactions of skin ILCs with other cell types reveal that dermal ILCs interact selectively and strongly with mast cells.6,7 An emerging understanding of ILC2s with accompanying eosinophil activities in atopic dermatitis5 and allergic respiratory disease8 helps explain associated tissue remodeling and fibrosis.9 Interactions of eosinophils with nerves may partly explain pruritus, vide infra,10,11 and other neurophysiological aberrations in eosinophilinfiltrated tissues. Epithelial and endothelial expression, considered structural cell factors as compared with immunologic cell (lymphocyte) factors, and interactions also likely influence eosinophils in homeostasis.12,13 Eosinophilic spongiosis is a common presentation in areolar inflammation of female breast compared with other skin,14 potentially related to differential innate immunologic expression.

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Abbreviations used ALHE- Angiolymphoid hyperplasia with eosinophilia CCL- C-C motif ligand CCR3- C-C chemokine receptor type 3 DRESS- Drug reaction with eosinophilia and systemic symptoms ECP- Eosinophil cationic protein EDN- Eosinophil-derived neurotoxin EGPA- Eosinophilic granulomatosis with polyangiitis (ChurgStrauss syndrome) eMBP1- Eosinophil major basic protein 1 EMS- Eosinophilia myalgia syndrome EPO- Eosinophil peroxidase GM-CSF- Granulocyte-macrophage colony-stimulating factor H&E- Hematoxylin and eosin HES- Hypereosinophilic syndromes IgG4-RD- IgG4-related disease ILC- Innate lymphoid cell ILC2- Type 2 ILC MMP-9- Matrix metalloproteinase-9 PAF- Platelet activating factor RANTES- Regulated on activation, normal T cell expressed and secreted TLR- Toll-like receptor TOS- Toxic oil syndrome

Eosinophils demonstrate other roles in immune responses. As a granulocyte, the eosinophil is capable of phagocytosing and killing bacteria and other small microbes in vitro, although eosinophils cannot effectively defend against bacterial infections when neutrophil function is deficient. Nevertheless, eosinophils may have a role in innate immunity against bacteria using a unique DNA trap mechanism, which may be an important response, particularly in mucosal epithelium. Eosinophils rapidly release mitochondrial DNA when exposed to bacteria, complement component C5a, or C-C chemokine receptor type 3 (CCR3) ligands.15 The traps contain granule proteins, eosinophil cationic protein (ECP), and eosinophil major basic protein 1 (eMBP1). In the extracellular space, the granule proteins and mitochondrial DNA form structures that bind and kill bacteria both in vitro and in vivo. Eosinophils, unlike neutrophils, do not undergo cell death during this process. Interestingly, eosinophil extracellular traps are found in a number of inflammatory skin diseases, particularly Wells syndrome, vide infra, and in cutaneous infections.16 Through major histocompatibility complex class II expression and IL-1a production, eosinophils may function as antigen presenting cells for various viral, parasitic, and microbial antigens, including staphylococcal superantigens, and allergens.17 Activation of eosinophils via toll-like receptor 7 (TLR7) and TLR9 affects several eosinophil functions; the overall response is influenced by a TH2-like cytokine milieu.18 Isolated eosinophil granules, often observed in biopsy specimens from skin lesions, express extracellular domains for IFN-g receptor and CCR3 and, on stimulation, respond independently as organelles by releasing ECP.19 The functional diversity of eosinophils in both innate and acquired immunity has abundant ramifications in homeostasis and disease pathogenesis.

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PATHOPHYSIOLOGY Activities and effects of eosinophils The pathology in eosinophil-related cutaneous disorders, including inflammatory and neoplastic dermatoses, is impacted by eosinophil activity in tissues and blood. Eosinophils express a myriad of cell surface receptors and elaborate numerous biologically active factors that guide their roles in homeostasis and disease. Directly and indirectly, eosinophils influence and are influenced by other cells. Eosinophils elaborate potent toxins that kill cells and damage tissues. Many publications review these activities and the studies on which they are based.20-28 Eosinophils circulate transiently in blood (8-18 hours) and are constantly replenished to maintain a stable pool. Eosinophil infiltration in tissues is determined by a unique combination of factors relevant to adhesion, migration, and homing. Blood vessels are regulated by cytokines, chemokines, and other biologically active factors to express ligands with which eosinophils interact, and proinflammatory peptides and cytokines, including IL-1, commonly induce cell surface receptor expression on both eosinophils and endothelial cells that prompts eosinophils to tissue sites. Epithelial-derived cytokines, particularly IL-33, may influence inflammatory mechanisms by activating ILC2s, inducing the development of TH2 cells and activating other cells with high receptor levels, including mast cells, basophils, and eosinophils.13 IL-33 also may be a product of structural cells such as endothelial cells and fibroblasts as well as dendritic cell, mast cells, and monocytes.13 Eosinophils are recruited to and activated in tissues by cytokines from the TH2 subset of T cells, which produces IL-4, IL-5, IL-10, and IL-13, as well as by cytokines that also are produced by TH1 cells, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3. Members of the C-C chemokine gene superfamily are chemotactic for eosinophils and include the eotaxin family, eotaxins 1, 2, and 3 (CCL11, CCL24, CCL26), and regulated on activation, normal T cell expressed and secreted (RANTES) (CCL5), which signal primarily through CCR3. Eotaxins 1, 2, and 3 are chemotactic specifically for eosinophils, while RANTES also is chemotactic for monocytes, T lymphocytes, natural killer cells, and basophils (but not neutrophils). In addition to chemotactic properties, the eotaxins and RANTES induce production of reactive oxygen species by eosinophils, indicating that they have both chemotactic and functional activation effects. As eosinophil chemoattractants, eotaxins are stronger than RANTES, and eotaxins 1 and 2 also have greater ability to induce reactive oxygen species by eosinophils than do eotaxin 3 and RANTES. Eotaxins 1, 2, and 3 and RANTES are produced by dermal fibroblasts, and RANTES also is produced by keratinocytes, well positioning these mediators for participation in cutaneous inflammation. After movement across vessels, eosinophils are present in the extracellular matrix, where cell surface integrins recognize as receptors substances that exert effects on eosinophil activity, such as fibrous proteins (in particular, fibronectin, laminin, and collagen) and glycosaminoglycans (especially hyaluronic acid and chondroitin sulfate). Integrin expression, specifically CD11b/ CD18 (MAC-1), is critical for eosinophil effector functions, including degranulation. Mast cellederived cytokines contribute to eosinophil activation and vice versa with bidirectional interactions.29 Human natural killer cells, which respond to some of the same chemokines as eosinophils, also produce IL-5.

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TABLE I. Diseases/disorders with eosinophil-related etiopathogenesis Strong/direct

Allergic reactions Atopic diseases Drug reactions Ectoparasitic infestations: scabies, pediculosis, pthiriasis, cimicosis Helminth infections Hypereosinophilic syndromes

Immunobullous diseases: particularly, pemphigoid Myiasis

Weaker/indirect

Adrenal insufficiency (Addison disease) Atheroembolic disorders/cholesterol embolization Autoimmune lymphoproliferative syndrome Chronic graft-versus-host disease Chronic inflammatory disorders, including inflammatory bowel disease Fibrotic reactions Fungal infections: allergic bronchopulmonary aspergillosis, coccidioidomycosis, paracoccidioidomycosis, basidiobolomycosis, histoplasmosis, cryptococcosis Human immunodeficiency virus and human T-cell lymphotropic virus I and II IgG4-related diseases Immunodeficiency syndromes: hyperimmunoglobulin E syndromes, Omenn syndrome, IPEX, ZAP-70 deficiency Irradiation Langerhans cell histiocytosis Leukemias: acute myelogenous, B cell, acute lymphoblastic/lymphocytic Lymphomas: Hodgkins, T cell, B cell Mastocytosis Sarcoidosis Solid tumors/malignancy (development or progression)

IPEX, Immunodysregulation polyendocrinopathy enteropathy X-linked; ZAP-70, zeta chain-associated protein kinase of 70 kD.

Eosinophils themselves elaborate important inflammatory and regulatory cytokines, including IL-1a, TGF-a and TGF-b1, GM-CSF, IL-3, IL-5, IL-6, IL-8, IL-31, TNF-a, and macrophage inflammatory protein-1a. As a result, eosinophil activation occurs in an autocrine manner. In cytotoxicity assays, eosinophils are maximally activated by GM-CSF, followed by IL-3, IL-33 and IL-5, TNF-a, and IL-4, in order of potency.30 Eosinophils express a number of other biologically active cell surface molecules, including complement receptors, toll-like receptors, Fc receptors, gangliosides, various structural glycoproteins, and various lineage-restricted myeloid antigens. On activation, eosinophils release granule contents into their extracellular surroundings via 3 mechanisms: cytolytic degranulation, piecemeal degranulation, and regulated secretion.31 Cytolytic degranulation is characterized by cytoplasmic membrane rupture, chromatolysis of nuclei with loss of morphological integrity by electron microscopy, and eosinophil identity by histopathology with hematoxylin and eosin staining, and extensive deposition of eosinophil granules and granule products within tissue—a process that occurs in many skin and extracutaneous diseases. Eosinophil granule proteins are among the products of eosinophils with damaging potential in tissues. Furthermore, the granule proteins are “footprints” of eosinophil activity when eosinophils lose characteristic morphology through cytolysis in tissues.32 Once deposited, granule proteins may persist in tissues—eosinophils peroxidase (EPO) for 1 week, ECP for 2 weeks, eosinophil-derived neurotoxin (EDN) for 2.5 weeks, and eMBP1 for up to 6 weeks.33 Awareness of the biological actions of these eosinophil granule proteins provides insight into their effects in human disease. eMBP1, the constituent of specific eosinophil granule crystalline cores, directly damages helminths, mammalian cells and

tissues, exemplified by its ability to cause exfoliation of bronchial epithelial cells. eMBP1, but none of the other eosinophil granule proteins, stimulates histamine release from human basophils. Furthermore, eMBP1 stimulates neutrophils, inducing release of superoxide and lysozyme, and is a potent platelet agonist. eMBP1 also is toxic to tumor cells. ECP or RNase3 and EDN or RNase2 are members of the RNase family. ECP is a potent toxin for parasites through a different mechanism than eMBP1 and is more effective at killing certain helminths than eMBP1. As the name implies, EDN has neurotoxic activities and also has activity against RNA viruses. EPO (also known as EPX, its encoding gene and to distinguish it from erythropoietin, commonly abbreviated EPO) kills numerous microorganisms in the presence of hydrogen peroxide, generated by eosinophils and other phagocytes, and halide. This combination of products also initiates mast cell secretion. EPO and eMBP1 are potent platelet agonists that lead to the release of 5-hydroxytryptamine (serotonin) and promote clotting. Binding of EPO to microbes, including Staphylococcus aureus, greatly potentiates their killing by phagocytes. EPO-coated tumor cells are spontaneously lysed by activated macrophages. Each of these granule proteins can induce direct tissue damage to microbes and to host cells, including myocytes, endothelium, neurons, epithelium, and smooth muscle. The specific activities listed likely have analogous pathophysiological effects in various tissues in different disease settings. All 4 granule proteins, EPO, ECP, EDN, and eMBP1, contribute to the edema observed in skin diseases, due to their vasodilatory effects in concert with eMBP1-induced release of histamine by mast cells and basophils.34 Eosinophil granule proteins injected into skin produce lesions, including dose-dependent wheal-and-flare reactions by eMBP1 and ulcerations by ECP and EDN.34,35 Moreover,

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wound healing is delayed in the presence of eosinophils and eosinophil granule proteins.36,37 Eosinophils are a source of matrix metalloproteinase-9 (MMP-9), which is important for their migration through basement membranes. Eosinophil-derived MMP-9 is found in basal cell and squamous cell carcinomas38,39 and in lesions of bullous pemphigoid where eosinophil infiltration and degranulation are prominent.40-42 MMP-9 cleaves type XVII collagen (BP 180), a transmembrane molecule of the epidermal hemidesmosome, likely contributing to or directly causing basement membrane zone separation in bullous pemphigoid and other eosinophil-related blistering diseases. The application of eMBP1, ECP, or EPO to airway epithelium in primates produces ciliostasis, desquamation, and hyperreactivity of respiratory smooth muscle mimicking the pathology of asthma.43,44 Damage to endothelium in eosinophilic endomyocardial disease likely is the initiating factor in the cardiomyopathy that develops in the hypereosinophilic syndromes.45 As noted, eosinophil granule proteins have procoagulant activities, and thromboses are a feature of the hypereosinophilic syndromes, in which case reports of hepatic vein obstruction (Budd-Chiari syndrome) have been described, and in which cutaneous signs may importantly herald their development. Thromboses may develop from multiple effects in various settings: direct endothelial damage, via the ability of eMBP1 and ECP to neutralize heparin, platelet agonist activity of eMBP1 and EPO, and/or by platelet activating factor (PAF), which is released by eosinophils, causing platelet aggregation. Eosinophils elaborate mediators that degrade collagen and stimulate dermal fibroblast DNA synthesis and matrix production supporting a role in tissue remodeling and fibrotic reactions.

Etiopathologic associations As reviewed in the above sections, eosinophils are recruited to and activated in tissues by cytokine activity from the TH2 subset of T cells and from the type 2 subset of innate lymphoid cells (ILC2s), which produce IL-4, IL-5, IL-10, and IL-13.46 Therefore, eosinophils in skin disease etiologically are associated with other disorders displaying this immunologic profile (Table I), plus pathogenic contributions from mast cells, basophils, and IgE.47,48 Dermatologic disorders commonly associated with eosinophil infiltration include arthropod bite and sting reactions, drug eruptions (“bugs and drugs”), parasitic infestations (eg, ectoparasites and helminths), and Wells syndrome (eosinophilic cellulitis). In addition, blistering diseases, notably bullous pemphigoid, have eosinophil infiltrates in skin lesions. The histopathologic features of urticaria, urticarial dermatitis, and cutaneous vasculitis, especially eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), often include eosinophils. Mild-to-moderate eosinophil infiltration is one of the key morphological features of the recently described IgG4-related disease (IgG4-RD) spectrum in which fibrosis is a major development.49 Eosinophils are found in association with tissue remodeling and other aspects of fibrosis in various conditions,50 including asthma and atopic dermatitis as well as parasitic infections, pulmonary and hepatic drug sensitivity reactions, and the hypereosinophilic syndromes.51 TH2 eosinophil-related diseases with skin manifestations range from diseases associated with atopy, particularly atopic dermatitis and asthma, to mastocytosis, parasite infestation, and

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autoimmune immunobullous disease. Furthermore, immunologic lines separating TH2- and TH1-associated diseases are not distinct as evidenced by chronic contact dermatitis, a manifestation of classical TH1, T-cell-mediated, delayed-type hypersensitivity, which characteristically shows eosinophil (and basophil) infiltration. Increasingly recognized is a pathogenic association of eosinophil activity in autoimmune disease in which multiple effector functions have been identified.52 Multiple primary immunodeficiencies with immunodysregulation from various etiologies have associated peripheral blood and tissue eosinophilia; commonly occurring skin manifestations, especially in children, are eczema and urticaria in addition to bacterial, fungal, and viral cutaneous infections.53 A common link is the tissue response to the effects of eosinophil activities. Notably, many skin diseases with eosinophil infiltration and degranulation have itch as a prominent symptom with a likely pathogenic relationship.

Eosinophils and itch There is considerable evidence that eosinophils play an important role in the pruritus that accompanies many cutaneous diseases. Sarcoptes scabiei (whose name is derived from the Latin word “to scratch”), an ectoparasite infestation of skin, is an example of a relationship between eosinophils and itch. Eosinophil products, including eMBP1, PAF, and IL-2, directly induce itching. Eosinophils and/or their products are found in lesional skin of numerous other pruritic disorders, notably atopic dermatitis, bullous pemphigoid, and prurigo nodularis, known to exhibit aberrant neurophysiological responses in addition to itch.54 Bullous pemphigoid characteristically is a blistering dermatosis accompanied by peripheral blood and tissue eosinophilia (intact eosinophils and degranulation products),41 but also may present as pruritus or an eczematous eruption without blisters.55 Mast cells and eosinophils, often found together in skin lesions, including those noted above,56-59 may stimulate each other, indicating that they can act in concert to trigger and perpetuate pruritus. Both eosinophils and mast cells have effects on nerve fibers implicated in the sensation of itch. Activated mast cells exhibit effects on 2 types of C-fibers linked to itch and inflammation, through histamine-independent and -dependent stimulatory mechanisms.60 The relationship between eosinophils and nerves is broadly known, but the influence of eosinophils on itchpromoting nerve activation is not as well understood. Eosinophils synthesize neurotrophins, including nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3. Eosinophils are prominent in several mouse models of pruritus; eosinophils localize to the skin near increased nerves, and eosinophils cause branching of sensory neurons in cultures together. Eosinophil granule proteins, particularly eMBP1, block neuronal M2 muscarinic receptors,61 likely playing a role in airway hypersensitivity in asthmatic patients and possibly lowering the itch threshold.62 Eosinophils and mast cells, therefore, likely interact synergistically to enhance nerve activation, individually through direct effects on nerves and effects on each other.63 A recently described novel TH2 cytokine, IL-31, is strongly associated with itch in various studies. Notably, an IL-31 receptor complex is present on dorsal root ganglion neurons,64 indicating that IL-31 can directly activate sensory nerve fibers. Overexpression of murine IL-31 is associated with severe

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FIGURE 1. Atopic dermatitis (A) skin biopsy section stained for eosinophil granule major basic protein 1 shows extensive extracellular dermal granule protein deposition with staining of only 3 intact eosinophils, arrows, (original magnification
400) and (B) H&E counterstain of (A) shows perivascular lymphocytic infiltration and chronic inflammatory changes including thickening of the basement membrane zone with fibrosis under rete pegs and 3 identifiable eosinophils, arrows corresponding to those in (A), (original magnification
400). eMBP1, Eosinophil granule major basic protein 1; H&E, hematoxylin and eosin. From Leiferman KM, Ackerman SJ, Sampson HA, Haugen HS, Venencie PY, Gleich GJ. Dermal deposition of eosinophil-granule major basic protein in atopic dermatitis. Comparison with onchocerciasis. N Engl J Med 1985;313:282-5.82 Copyright ª 1985 Massachusetts Medical Society. Reprinted with permission.

pruritus.65,66 In spontaneously developing atopic dermatitis-like skin lesions in Nc/Nga mice, mRNA levels of IL-31 correlate with the number of scratch bouts,67,68 and intraperitoneally administered monoclonal IL-31 antibodies ameliorate scratching behavior.69 Systemic and local administration of IL-31 induces scratching behavior, not only in rodents but also in dogs and cynomolgus monkeys.68 In humans, IL-31 levels are increased in serum of patients with chronic urticaria, bullous pemphigoid, and atopic dermatitis and correlate with disease severity in patients with atopic dermatitis.70,71 IL-31 induces elongation and branching of small-diameter neurons in nerve explant models,72 which may play a role in the increased nerve density observed in atopic dermatitis-affected skin. Moreover, anti-IL-31 therapy significantly improves pruritus in patients with moderate-tosevere atopic dermatitis.73 IL-31 expression is increased in lesions of prurigo nodularis and atopic dermatitis.70,74 Furthermore, the treatment of skin with staphylococcal exotoxins rapidly induces IL-31 expression in atopic individuals,75-77 and the antimicrobial peptides human b-defensin and cathelicidin have been shown to induce IL-31 expression in human mast cells.78 IL-31 is produced not only by TH2 cells and mast cells but also by eosinophils.79 Receptors for IL-31 are present on neurons, as noted, and also on keratinocytes/epithelial cells and eosinophils themselves.80 Therefore, eosinophils are a source of IL-31 and release it in an autocrine manner.79 The observations

that IL-31 release by eosinophils is higher in patients with atopic dermatitis and that TH2 cytokines further increase the IL-31 release in eosinophils suggest an important regulatory pathway for inflammatory skin diseases including atopic dermatitis in which eosinophils and eosinophil granule proteins are found around cutaneous nerves.74 In addition, studies have shown that IL-31 affects eosinophils functionally with induction of chemotaxis, mobilization of calcium, release of CCL26 (eotaxin-3), and generation of reactive oxygen species.79 IL-31, a TH2 cytokine, serves as a direct link between immunologic expression involving eosinophils and a neurophysiological effect manifesting as itch.

EOSINOPHIL-RELATED SKIN DISEASE Classification and range Eosinophil-related cutaneous disease is characterized by skin and/or mucosal infiltration of few to many eosinophils and/or evidence of eosinophil degranulation, with and without increased eosinophils in peripheral blood. This definition encompasses a wide range of inflammatory dermatoses and malignancies that may develop at any age in life. In these diseases, eosinophil granule protein deposition may be unrecognized on examination with standard histopathologic staining, particularly in tissue specimens that lack identifiable intact eosinophils. In particular,

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TABLE II. Cutaneous manifestations demonstrating extracellular eosinophil granule protein deposition and patterns of eosinophil involvement Clinical presentations Eczematous dermatoses Atopic dermatitis32,82,84 (Figure 1) Onchocercal dermatitis82,85 Prurigo nodularis59 Pachydermatous eosinophilic dermatitis86 Edema34 Chronic urticaria87 Solar urticaria88 Delayed pressure urticaria89,90 IgE-mediated late phase reaction91 Episodic angioedema with eosinophilia (Gleich syndrome)92-94 (Figure 2) Facial edema with eosinophilia95 Nodules, eosinophilia, rheumatism, dermatitis, swelling syndrome96 (Figure 3) GM-CSF reaction97 IL-2 capillary leak syndrome98 Eosinophilic cellulitis (Wells syndrome)99-101 (Figure 4) Blistering Pemphigoid (herpes) gestationis102,103 Bullous pemphigoid41 Bullous morphea104 Eosinophilic granulomatosis with polyangiitis blisters105 (Figure 5) Incontinentia pigmenti106 Sclerosis or Fibrosis Eosinophilic fasciitis107 Eosinophilia myalgia syndrome107,108 Toxic oil syndrome109 Vasculitis110 Recurrent cutaneous eosinophilic vasculitis111 Eosinophilic vasculitis in connective tissue disease112 Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)105,113 (Figure 5) Patterns of eosinophil involvement based on eosinophil granule protein tissue staining Eosinophil infiltration of few to many intact cells Intact eosinophils with extracellular eosinophil granule protein deposition proportionate to the numbers of infiltrating eosinophils Intact eosinophils with extensive extracellular eosinophil granule protein deposition disproportionately greater than the numbers of infiltrating eosinophils Extensive extracellular eosinophil granule protein deposition with few or no infiltrating eosinophils (in this pattern, eosinophil involvement may not be recognized on histopathologic examination) (Figure 1) Each pattern may be found either with or without peripheral blood eosinophilia/ hypereosinophilia.

atopic dermatitis is characterized by increased serum IgE levels and variable peripheral blood eosinophilia, and affected skin usually contains few or no eosinophils.81 However, eosinophil granule proteins are extensively deposited in atopic dermatitis as revealed by immunofluorescence with specific antibodies to granule proteins (Figure 1), and eosinophil disruption has been documented by electron microscopy.32,82 These findings provide evidence for eosinophil involvement in the absence of discernible infiltrating intact cells. Skin manifestations in which eosinophil

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granule protein deposition has been demonstrated include edema, eczema, blisters, vasculitis, and fibrosis (Table II); in many of the lesions, extracellular eosinophil granule protein deposition is disproportionately greater than the number of intact cells, indicating that the infiltrating cells have degranulated and lost morphological integrity. The degree of tissue eosinophilia, therefore, does not necessarily reflect the influence of eosinophils in the disease pathophysiology. Eosinophils are found in histopathologic reaction patterns throughout the depth of the skin (Table E1, available in this article’s Online Repository at www.jaci-inpractice.org), from epidermis (eosinophilic spongiosis) into muscle (eosinophilic myositis). Diseases often show overlapping patterns or evolving patterns involving more than 1 compartment, which does not necessarily indicate additional diagnoses.114 Eosinophil-related cutaneous diseases can be categorized into 3 groups based on histopathology: (1) eosinophils are a key feature in histopathologic diagnosis, (2) eosinophils are commonly observed but not required for diagnosis, and (3) eosinophils are of limited or uncertain diagnostic value (Table III).115 In some of the disorders, extracellular deposition of eosinophil granule proteins has been documented, presumably indicating eosinophil activation with tissue effects from the granule proteins (Table II); in others, however, the presence and extent of eosinophil granule protein deposition and, thus, eosinophil involvement may not be known because staining for eosinophil granule proteins is not commonly performed. Differential diagnoses to be considered with eosinophil-related dermatoses include many common skin afflictions (Table E2, available in this article’s Online Repository at www.jaci-inpractice.org) and clinical clues can direct consideration of an eosinophil-related disease (Table E3, available in this article’s Online Repository at www.jaci-inpractice.org); additional information regarding eosinophil-related cutaneous diseases can be found in multiple sources, including text books,115-117 reviews,118-121 and referenced publications.

Eosinophilic spongiosis. Eosinophilic spongiosis is a descriptive term for a pattern of eosinophil infiltration observed in certain common and uncommon eosinophil-related dermatoses, including atopic dermatitis and allergic contact dermatitis, immunobullous diseases such as pemphigoid and pemphigus, incontinentia pigmenti, papuloerythroderma of Ofugi, Wells syndrome, and certain cutaneous manifestations of the hypereosinophilic syndromes. Eosinophilic spongiosis is characterized by edema between epidermal keratinocytes, giving a sponge-like appearance, with variable eosinophil infiltration (Figure 6); the underlying dermal abnormalities may provide more specific clues to the diagnosis. This common inflammatory pattern may correlate with humoral or T-cell immune-mediated reactions. Eosinophilic pustulosis, rather than spongiosis, characterizes other eosinophil-related dermatologic diseases including erythema toxicum neonatorum, a common cutaneous eruption in newborns. Eosinophilic cellulitis (Wells syndrome). Wells syndrome is among the edematous eosinophil-related dermatoses. Recurrent episodes of prodromal itching or burning are followed by the development of markedly edematous plaques and nodules (Figure 4), which may have an annular or arcuate configuration and violaceous borders, most frequently involving the extremities, but may affect the trunk. Patients often are misdiagnosed as having erysipelas or acute bacterial cellulitis. Less

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FIGURE 2. Episodic angioedema with eosinophilia (Gleich syndrome) in a 2-year-old girl showing (A) marked facial edema during an episode compared with (B) normal appearance between episodes. Reproduced with permission from Katzen DR, Leiferman KM, Weller PF, Leung DY. Hypereosinophilia and recurrent angioneurotic edema in a 2 1/2-year-old girl. Am J Dis Child 1986;140:62-4.94 Copyright ª 1986 American Medical Association. All rights reserved.

FIGURE 3. Nodules, eosinophilia, rheumatism, dermatitis, and swelling with subcutaneous nodules over the anterior surface of the ankle with similar nodules on legs and hands; nodules are painless, not pruritic, and nonpulsatile. Reprinted with permission from Butterfield JH, Leiferman KM, Gleich GJ. Nodules, eosinophilia, rheumatism, dermatitis and swelling (NERDS): a novel eosinophilic disorder. Clin Exp Allergy 1993;23:571-80.96 Copyright ª 1993 John Wiley and Sons.

common clinical presentations include papules, vesicles, and bullae. The bright red, initial edematous lesions fade to a pinkbrown or slate-gray color, sometimes followed by induration that may resemble morphea. The lesions typically resolve over 4 to 8 weeks. Precipitating events, including arthropod bites, have been described in a minority of patients. The most common systemic complaint is malaise, with fever in less than 25%. Peripheral blood eosinophilia is common, and activated eosinophils likely play a major role in Wells syndrome.99,122 The histopathologic pattern consists of dermal infiltration with eosinophils; histiocytes and eosinophils surround foci of amorphous/granular material termed “flame figures.” Flame figures demonstrate prominent localization of eosinophil granule proteins by immunostaining, indicating that eosinophil degranulation and deposition of granule proteins contribute to their formation.99 Similar mechanisms may be involved in the Splendore-Hoeppli phenomenon.123 Flame figures have been observed in skin biopsies of various disorders (Table IV)115; therefore, the flame figure is a characteristic histopathologic feature, but not diagnostic, of Wells syndrome.100 A distinction between eosinophilic cellulitis as a specific entity and as a secondary reaction pattern can be difficult; Wells syndrome is a diagnosis of exclusion after other flame figure-associated dermatoses have been considered.124 Eosinophilic cellulitis usually shows dramatic improvement with systemic glucocorticoid therapy.125 For patients who fail to respond satisfactorily or who flare often enough to raise concerns about the long-term side effects of systemic glucocorticoids, other therapeutic options include minocycline, colchicine, antimalarials, dapsone, griseofulvin, IFN-a, cyclosporine, and antihistamines. With a potential role for IL-5 in the disease,122 therapy with the recently approved anti-IL-5 monoclonal antibodies may be effective. For mild cases, potent topical glucocorticoids may be sufficient.

Drug reactions, DRESS. Drug reactions span a range of cutaneous presentations (Table E4, available in this article’s Online Repository at www.jaci-inpractice.org). Eosinophils are

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FIGURE 4. Flame figure (A) by H&E and (B) by immunostaining for eosinophil granule major basic protein 1 (eMBP1) showing degenerating collagen fibers on which extensive extracellular eMBP1 is deposited as characteristically found in (C) Wells syndrome and (D) bullous eosinophilic cellulitis lesions and in multiple other inflammatory conditions (Table IV). eMBP1, Eosinophil granule major basic protein 1; H&E, hematoxylin and eosin. A, B, D Reprinted with permisssion from Davis MD, Brown AC, Blackston RD, Gaughf C, Peterson EA, Gleich GJ, et al. Familial eosinophilic cellulitis, dysmorphic habitus, and mental retardation. J Am Acad Dermatol 1998;38:919-28.101 C, Reprinted with permission from Leiferman KM, Peters MS. Eosinophils in cutaneous diseases. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick’s Dermatology in General Medicine. 8th ed. San Francisco: McGraw-Hill Medical; 2012.115

observed in many types but are absent in biopsy specimens from up to half of the patients with drug reactions. Therefore, eosinophils are unreliable histopathologic markers of drug reaction etiology. Drugs also may exacerbate existing diseases and/or unmask incipient disease. Drug-induced pemphigoid is increasingly recognized, including in diabetic patients treated with dipeptidyl peptidase-4 inhibitors (gliptins),126,127 and shows the same clinical and histopathologic features as its idiopathic (spontaneous) counterpart, with eosinophilic spongiosis, and/or eosinophil-rich subepidermal blisters, or a nonspecific urticarialike perivascular infiltrate that includes eosinophils in the urticarial disease phase. The drug-induced hypersensitivity syndrome, also known as the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a severe life-threatening drug reaction characterized by, often, widespread cutaneous involvement of various eruptions, accompanied by fever, lymphadenopathy, hematologic, and liver abnormalities; renal, pulmonary, and cardiac involvement also have been reported. DRESS syndrome

has been attributed to a synergistic interaction of lymphocyte activation, drug metabolic enzyme defects with accumulation of drug metabolites, eosinophil activity, and viral infection reactivation (human herpesvirus-6, cytomegalovirus, Epstein-Barr virus) in individuals with genetic susceptibility conferred by certain human leukocyte antigen class I alleles.128 Autoantibody formation and autoimmune diseases, attributed to depletion of regulatory T cells on recovery from DRESS syndrome, may occur up to 4 years after resolution, including type I diabetes mellitus, autoimmune thyroid disease, sclerodermoid graftversus-host disease, systemic lupus erythematosus, and bullous pemphigoid.129

IgG4-RD. IgG4-RD initially was described as a pancreatic disorder with increased serum IgG4 levels and numerous IgG4positive plasma cells in tissue; subsequently, IgG4-RD was reported to involve 1 or more of multiple organs, and many previously described disorders of specific organs are now considered to be variants in the spectrum of IgG4-RD

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TABLE III. Eosinophils in histopathologic diagnoses

TABLE III. (Continued)

Eosinophils are a key feature in diagnosis Annular erythema of infancy Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy Eosinophilic pustular folliculitis Classical (Ofugi disease) Infantile/neonatal Human immunodeficiency virus associated Eosinophilic annular erythema Eosinophilic cellulitis (Wells syndrome) (Figure 4) Eosinophilic dermatosis of hematologic malignancy Erythema toxicum neonatorum Eosinophilic ulcer of oral mucosa Hypereosinophilic dermatitis of Nir-Westfried Hypereosinophilic syndromes IgG4-related cutaneous diseases Angiolymphoid hyperplasia with eosinophilia Granuloma faciale Kimura disease Juvenile temporal arteritis Pachydermatous eosinophilic dermatitis Diseases commonly associated with tissue eosinophils Arthropod bite and sting reactions Autoimmune blistering diseases Pemphigoid Pemphigus Epidermolysis bullosa acquisita Dermatoses of pregnancy Pemphigoid gestationis Polymorphic eruption of pregnancy, pruritic urticarial papules and plaques of pregnancy Drug reactions DRESS (drug reaction with eosinophilia and systemic symptoms) also known as drug-induced hypersensitivity syndrome Interstitial granulomatous drug reaction Cutaneous involvement (Table E4, available in this article’s Online Repository at www.jaci-inpractice.org) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) Hereditary syndromes Incontinentia pigmenti Hyper IgE syndromes and other immunodeficiency syndromes (Table II) Autoimmune lymphoproliferative syndrome Histiocytic diseases Langerhans cell histiocytosis Juvenile xanthogranuloma Itchy, red bump disease (papular dermatitis) Oid-oid disease (exudative discoid and lichenoid chronic dermatosis of Sulzberger and Garbe) Papuloerythroderma of Ofugi Parasitic diseases/infestations Cysticercosis, dirofilariasis, fascioliasis, gnathostomiasis, larva migrans, loiasis, myiasis, onchocerciasis, paragonimiasis, schistosomiasis, strongyloidiasis, tungiasis Scabies, pediculosis, pthiriasis, cimicosis Swimmer’s itch (cercarial dermatitis) and seabather’s itch

Pruritic papular eruption of human immunodeficiency virus disease Sclerosis or fibrosis Eosinophilic fasciitis Eosinophilia myalgia and toxic oil syndromes Drugs including statins Iron infusion Lymphoma and leukemia Graft versus host disease after stem cell or bone marrow transplantation Urticaria and angioedema Vasculitis Eosinophils of limited or unreliable value in histopathologic diagnosis Granuloma annulare Interstitial granulomatous dermatitis Lymphoproliferative disorders (except HES variants) Mycosis fungoides Anaplastic large cell lymphoma (except neutrophil-rich and eosinophil-rich variants) Lymphomatoid papulosis Mastocytosis Neoplasms Keratoacanthoma-type squamous cell carcinoma Invasive squamous cell carcinoma

(continued)

HES, Hypereosinophilic syndromes.

(Table V),49 including certain eosinophil-related disorders of skin or mucosa, such as granuloma faciale, angiolymphoid hyperplasia with eosinophilia, Kimura disease, and eosinophilic angiocentric fibrosis of the upper respiratory tract and orbit. A classification of IgG4-related skin disease has been put forth that separates patients who have a primary, mass-forming lesion with infiltration of many plasma cells, and secondary cutaneous lesions resulting from IgG4-mediated inflammation.130 IgG4-RD is clinically characterized by swelling or mass lesion(s), increased serum IgG4 levels, peripheral blood eosinophilia, and increased serum IgE. The pathogenesis is thought to derive from cross-talk between innate and acquired immunity.131 Criteria for the diagnosis of IgG4-RD are principally histopathologic and include dense lymphoplasmacytic infiltrates, storiform fibrosis, mild-tomoderate, sometimes strong, eosinophil infiltration, and obliterative phlebitis. IgG4-producing plasma cells are found in many inflammatory disorders, but a ratio of IgG4/IgG-positive cells greater than 40% or absolute number of IgG4-positive cells per high-power field greater than 10 supports the diagnosis.132,133 Disorders now considered to be in the IgG4-RD spectrum have in common a strong association with eosinophils and fibrosis.51

Granuloma faciale. Granuloma faciale is characterized by one or few red-brown infiltrative papules, nodules, or plaques usually on the face and/or ears, occurring predominantly in middle-aged Caucasian men but also in African American and Asian men as well as women. Involvement of trunk or extremities is uncommon.134,135 Individual lesions of granuloma faciale are chronic and only occasionally resolve spontaneously. Not associated with systemic disease, granuloma faciale previously was classified, along with erythema elevatum diutinum, to be a chronic cutaneous vasculitis. However, now

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FIGURE 5. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) skin lesions in 2 patients at presentation: patient 1 (A, B, C) and patient 2 (D, E, F): hemorrhagic bullae and palpable purpura on the ankle and foot (A) and hemorrhagic infarcted lesions on the hand and fingers (B) of patient 1 with vasculitis on H&E-stained histopathology of a biopsy specimen (C); and indurated, annular lesions on upper-left posterior shoulder (D) and lower back (E) of patient 2 with intense eosinophil infiltration and flame figure (arrows) in dermis on H&E-stained histopathology of a biopsy specimen (F). H&E, Hematoxylin and eosin. A-C, Reprinted with permission from Leiferman KM, Gleich GJ, Peters MS. Dermatologic manifestations of the hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007;27:415-41.83

it is considered in the spectrum of IgG4-RD, based on clinical and immunohistopathologic features,136 although not all studies support that categorization.137 The histopathologic pattern consists of brisk perivascular, more than interstitial, dermal infiltrates of neutrophils with leukocytoclasia (neutrophil disruption), lymphocytes, predominantly IgG4positive plasma cells, and many eosinophils, with sparing of the papillary dermis (Grenz zone). Examination of direct immunofluorescence staining demonstrates granular deposition of IgG, IgA, IgM, and/or C3 in blood vessel walls, a finding that implicates immune complexes in the pathophysiology. Older lesions show fewer neutrophils and more eosinophils and plasma cells as well as fibrosis. Although the complete pathogenesis remains unknown, IFN-g and increased local IL-

5 production are implicated as important mediators.138 An increased ratio of IgG4/IgG-bearing circulating plasma cells and/or relative increases of IgG4-positive plasma cells in skin lesions are observed. Because of the location on the face, treatment often is desired, with intralesional steroid injection a common first choice. Unfortunately, in many patients, granuloma faciale is relatively resistant to therapy. There are many anecdotal therapies described including oral dapsone (50-150 mg daily), oral clofazimine (300 mg daily), ultraviolet light, and topical calcineurin inhibitors (pimecrolimus, tacrolimus). Surgical excision, cryosurgery, dermabrasion, electrosurgery, and CO2 or pulsed dye laser therapy have been advocated, but each carries a significant risk of scarring given the depth of inflammation. Recurrences after excision have

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FIGURE 6. Photomicrograph of H&Eestained section of a skin biopsy specimen from a patient with bullous pemphigoid showing eosinophilic spongiosis and upper dermal eosinophil infiltration and granules. TABLE IV. Flame figures in skin biopsy specimens                        

Angiolymphoid hyperplasia with eosinophilia Arthropod bite and sting reaction Dermographism Drug reaction Eczema Eosinophilic cellulitis (Wells syndrome) (Figure 4) Eosinophilic fasciitis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (Figure 5) Eosinophilic pustular folliculitis Fungal disease including dermatophyte infection (Splendore Hoeppli phenomenon may be same/similar) Herpes simplex infection Human immunodeficiency virus infection Hypereosinophilic syndromes Immunobullous diseases (pemphigoid, pemphigoid gestationis, pemphigus vegetans) Incontinentia pigmenti Kimura disease Malignancies, solid organ (bronchogenic carcinoma, colonic adenocarcinoma) Mastocytoma Molluscum contagiosum Myeloproliferative disorders involving skin Parasite infestation (ascariasis, gnathostomiasis, onchocerciasis, toxocariasis) Urticaria Vaccination site reactions Varicella

been reported. With recognition of granuloma faciale as an IgG4-RD and with eosinophil-targeted monoclonal antibodies available, agents such as rituximab, mepolizumab, reslizumab, or benralizumab may be considered, although the risk-benefit ratio will need to be addressed for this chronic, typically localized cutaneous disease.

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Angiolymphoid hyperplasia with eosinophilia. Angiolymphoid hyperplasia with eosinophilia (ALHE) is characterized by solitary, few, or multiple, sometimes grouped, erythematous, violaceous or brown papules, plaques, or nodules of the dermis and/or subcutis, with predilection for head and neck, including occasional mucosal involvement.139,140 Lesions may be associated with pruritus or pain, or may pulsate, reflecting their vascular nature. ALHE tends to be chronic and nonremitting over months to years. ALHE has no racial predilection, and the disease typically occurs in the third to fifth decade of life, affecting males and females with slight female predominance. ALHE is considered a vascular proliferation of unknown etiology, possibly arising in response to or in association with underlying vascular malformation.141 There is a history of trauma in some patients. ALHE has been reported to occur in pregnancy, implying that sex hormones may be a factor in pathogenesis.142 ALHE has also developed in patients with T-cell clonality, highlighting a potential relationship between TH2 cells and eosinophils.143,144 Approximately 20% of patients have peripheral blood eosinophilia; IgE levels are unremarkable. There is no association with renal disease. The dominant histopathologic feature is a relatively well-defined vascular proliferation with large epithelioid or histiocytoid endothelial cells mainly in the dermis, but also may be located in the subcutis, accompanied by a variable infiltrate of eosinophils and lymphocytes with occasional lymphoid nodules.145 Mast cells may be a component of the histopathology. Therapy is dictated in part by the number, location, and size of lesions.146 Patients with solitary or a few small lesions may benefit from surgical excision, but efficacy is limited by recurrences.147 A variety of other beneficial treatment modalities have been described, mainly in case reports, including systemic and intralesional glucocorticoids, thalidomide,148 IFN-a therapy,149 cryotherapy,150 laser therapy,151 intralesional radiofrequency ablation,152 and topical application of tacrolimus.153,154 As with granuloma faciale, therapy directed toward IgG4 or eosinophils may be considered. Kimura disease. Kimura disease was once thought to be a variant in a group with ALHE. However, distinctive clinicopathological features distinguish the disorders.145,155 Kimura disease presents as large subcutaneous masses on the head and neck, mainly in Asian males, with predominantly lymphocytic infiltration, often forming nodules with germinal centers, and with a tendency for deeper (mostly subcutaneous) involvement.156 Lesions may recur after treatment.157 Associated renal disease is found in this disorder.158,159 Kimura disease has been considered an IgG4-RD,160 and patients with Kimura disease often have peripheral blood eosinophilia and also increased serum IgE. Associated necrotizing eosinophilic vasculitis presenting with recurrent peripheral arterial occlusive disease developed in a patient with Kimura disease, highlighting the possibility of clinically relevant pathology, including tissue damage, in this eosinophil-related disease.161 Skin manifestations of the hypereosinophilic syndromes Dermatologic involvement is the most frequent presenting clinical manifestation of the hypereosinophilic syndromes (HES).162 Skin and/or mucous membrane lesions occur in more than half of all patients with HES, particularly pruritic

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FIGURE 7. Mucocutaneous lesions in hypereosinophilic syndrome, primary (neoplastic) variant: (A) lower face of the patient, with prominent crusting overlying scattered erosions in perioral distribution, on cheeks, and with eyelid swelling; (B) hemorrhagic crusting of erosions on glans penis, with lesions on fingers also present; (C) hemorrhagic follicular crusts, with ulcers and plaques on arms (similar lesions on legs); (D) toenails showing subungual hyperkeratosis and onycholysis with periungual erythema. Reprinted with permission from Leiferman KM, Gleich GJ. Hypereosinophilic syndrome: case presentation and update. J Allergy Clin Immunol 2004;113:50-8.45

erythematous macules, papules, plaques or nodules involving trunk and extremities, or urticaria and angioedema, blisters, and mucosal ulcerations.83 Other cutaneous manifestations include erythema annulare centrifugum, retiform purpura, livedo reticularis, and superficial thrombophlebitis (Table VI).83 HES variants are classified into one of 2 types: neoplastic/primary and reactive/secondary.47,163-167 Mucosal ulcers of oropharynx or anogenital region are associated with neoplastic (primary) HES and portend a fatal prognosis unless treated,168 but are responsive to imatinib. Neoplastic (primary) HES may present with fever, weight loss, fatigue, malaise, in addition to increased serum vitamin B12 and tryptase levels and various skin lesions (Figure 7).162,169 Cardiac involvement with thrombus formation, progressive subendocardial fibrosis, and restrictive cardiomyopathy are common. Mitral or tricuspid valve insufficiency results from tethering of chorda tendineae. Cutaneous involvement with splinter hemorrhages and/or nailfold infarcts can provide the initial clues to thromboembolic disease and constitute a medical emergency because of the strong potential for serious sequelae.

Hepatosplenomegaly is another common feature in neoplastic (primary) HES. The central and peripheral nervous systems also may be affected, in addition to lungs and rarely kidneys.162 Reactive (secondary) HES, associated with multiple underlying conditions, commonly manifests with severe pruritus, dermatitis, erythroderma and/or urticaria, and angioedema, in addition to lymphadenopathy. A lymphocytic subtype of reactive HES is caused by clonal proliferation of T cells with increased production of TH2 cytokines, particularly IL-5.170,171 Patients with reactive (secondary) HES usually do not develop endomyocardial fibrosis. However, intramural cardiac damage has been observed in patients in the absence of appreciable blood eosinophilia, and eosinophilic endomyocardial abnormalities can develop in any patient with eosinophil-related disease. The histopathology of cutaneous lesions of HES is nonspecific and varies depending on the type of lesion. For example, urticarial lesions in HES demonstrate modest infiltration of lymphocytes, eosinophils, and occasional neutrophils, in a perivascular more than interstitial distribution, as in common urticaria. Biopsy specimens from papules or plaques exhibit

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TABLE V. IgG4-related disease Characteristic findings Clinical: swelling or masses in 1 or more organ(s)/tissue(s) Blood: increased serum IgG4 level, increased serum IgE level, eosinophilia, or hypereosinophilia Histopathology of affected organ(s)/tissue(s): Dense infiltrates of lymphocytes and plasma cells Fibrosis (typically in storiform pattern) IgG4+ to IgG+ plasma cells >40%; >10 IgG4+ plasma cells/highpower field (wide range, site dependent) Eosinophil infiltration Obliterative phlebitis Affected organs/tissues and/or manifestations—emerging spectrum Aorta (aortitis, periaortitis) Kidney (tubulointerstitial nephritis, membranous glomerulonephritis, renal pyelitis) Lacrimal glands (dacryoadenitis, bilateral) Lung, pleura Orbit (pseudotumor, proptosis, orbital myositis) Pancreas (autoimmune pancreatitis) Periarteritis Retroperitoneal fibrosis (previously considered idiopathic) Salivary glands (often bilateral submandibular, sialadenitis, parotitis) Sclerosing cholangitis Sinonasal eosinophilic angiocentric fibrosis Thyroid (Riedels thyroiditis, fibrous variant of Hashimotos thyroiditis) Skin Angiolymphoid hyperplasia with eosinophilia Granuloma faciale Kimura disease Pseudolymphoma Others Association with vasculitides Association with rheumatologic disorders Rosai-Dorfman disease Lymphoplasmacytic gastritis Sclerosing mastitis, pseudotumor of breast Mediastinitis Hypophysitis Mesenteritis Pachymeningitis Pericarditis Perineural disease Paratesticular pseudotumor Epididymo-orchitis Prostatitis

spongiosis in addition to dermal infiltrates that usually contain at least a few intact eosinophils. Flame figures are occasionally found. Thrombosis of dermal blood vessels has been observed in biopsy specimens from retiform purpura and necrotic skin lesions of patients with HES. When studied with stains for specific eosinophil granule proteins, biopsy specimens of mucosal ulcers in HES show extensive deposition of eosinophil granule proteins in the absence of morphologically identifiable intact eosinophils.35 The principal means of eosinophil degranulation is via cytolysis, and

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eosinophils disrupt within tissues during or soon after infiltration; the footprint of eosinophil participation is its granule protein deposition, which remains in the tissue while the cell itself is not morphologically identifiable, although parts of the eosinophil may be recognizable by electron microscopy. Clinical manifestations, including in skin, result from the spectrum of proinflammatory, prothrombotic, and profibrotic effects of activated eosinophils in tissues and/or from eosinophil-derived factors circulating in blood. Clinical features may include fibrosis involving heart, lung, digestive tract, and genitourinary tract, in addition to skin, thrombosis with or without thromboembolic sequelae, and peripheral and/or central neuropathy with chronic or recurrent neurological deficit.

Eosinophilic granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, can clinically resemble HES and is considered by some authors to be within the HES spectrum. Similar mechanisms involving eosinophils likely are functioning in the 2 disorders and may explain neurological and other common clinical features. Peripheral blood and tissue eosinophilia is the hallmark of the disease.172 Cutaneous lesions develop in more than two-thirds of patients with EGPA, including palpable purpura, cutaneous and/or subcutaneous nodules, erythematous papules and macules, vesicles and bullae, cutaneous infarction, livedo reticularis, urticaria, ulceration, and facial edema.173,174 Skin lesions may be the presenting sign of EGPA (Figure 5).175 Vasculitic lesions more often demonstrate small-vessel than medium-vessel vasculitis. The papulonodules lesions typically are tender and histopathologically are extravascular palisading granulomas with necrosis and eosinophils. Although various skin lesions are not specific to EPGA, such findings in context with the extracutaneous features of EPGA can lead to an early diagnosis, treatment, and, thus, prevention of irreversible tissue damage. Notably, skin biopsy specimens show marked cellular and extracellular staining of eosinophil granule proteins, and IL-5 and eosinophil granule proteins are found in blister fluid, implicating eosinophils in the pathophysiology.105 Patients with EGPA have asthma and other organ involvement along with dysregulation of humoral immunity including prominent IgG4 and IgE responses.176,177 The allergic features (allergic rhinitis, asthma, and positive skin tests) suggest heightened TH2 immunity.178 Abnormal eosinophil function is likely due to a combination of increased eosinophil recruitment by TH2 cytokines and decreased eosinophil apoptosis.179 EGPA is a disease in which eosinophil-targeted therapy is beneficial,180 and administration of anti-IL-5, mepolizumab, is approved for treatment. Fibrosis and eosinophils Eosinophils interact with matrix components and elaborate mediators that degrade collagen and stimulate dermal fibroblast DNA synthesis and matrix production.50 Eosinophils, therefore, likely play a role in cutaneous and extracutaneous tissue remodeling, including in asthma and atopic dermatitis,181 and in inflammatory conditions characterized by prominent clinical and histopathologic fibrosis, particularly parasitic infections, pulmonary and hepatic drug sensitivity reactions, scleroderma-like cutaneous syndromes,182,183 HES, and IgG4-RD, including retroperitoneal fibrosis, sclerosing mediastinitis, sclerosing cholangitis, and

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TABLE VI. Mucocutaneous manifestations in hypereosinophilic syndromes83 Angioedema Bulla(e) Dermographism Digital gangrene Eczema Eosinophilic cellulitis (flame figures of Wells syndrome) Erosions Erythema Erythema annulare centrifugum Erythroderma Excoriation(s) Livedo reticularis Lymphomatoid papulosis Macules Mucosal ulcer(s) (oral and genital) (Figure 7) Nail fold infarction(s) Necrosis Nodules Papules Patches Pruritus Purpura Raynaud’s phenomenon Splinter hemorrhage(s) Ulcer(s) Urticaria Vasculitis

pulmonary fibrosis.51,184 Eosinophils may not be histopathologically conspicuous but patients may have peripheral blood eosinophilia.

Eosinophilic fasciitis. Eosinophilic fasciitis usually presents with pain, erythema, edema, and induration of the extremities with limitation of motion, as well as peripheral blood eosinophilia and hypergammaglobulinemia.185,186 Contractures and rippling of the skin may develop. Histopathological examination demonstrates sclerotic increase in thickness of subcutaneous fat septa and fascia, with lymphoplasmacytic inflammation within and adjacent to sclerotic zones, and a variable number (often few) eosinophils. Distinction from morphea profunda is based on clinical rather than histopathologic features, including clinical morphology, distribution of lesions, and the absence of peripheral eosinophilia in morphea.187 Eosinophilia-myalgia syndrome. Eosinophilia-myalgia syndrome (EMS),107,188,189 historically related to ingestion of certain lots of L-tryptophan, is characterized by marked peripheral eosinophilia, disabling generalized myalgias, pneumonitis, myocarditis, neuropathy, encephalopathy, and fibrosis, a constellation of features that are similar to but distinguishable from eosinophilic fasciitis.190-192 There is evidence that TGF-b1 may play an important role in the development of the connective tissue alterations present in EMS-associated diffuse fasciitis.193,194

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Cutaneous abnormalities in EMS include edema, pruritus, a faint erythematous rash, hair loss, and peau d’orange skin lesions. Lungs, heart, and nervous system may be affected.195 There is a prominent inflammatory infiltrate in the perimysium and fascia and evidence of extracellular eosinophil granule protein deposition in skin and around muscle bundles.107

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.196 Patients experienced acute respiratory symptoms followed by intense myalgias, thromboembolism, weight loss, and sicca syndrome, followed by a chronic phase characterized by eosinophilic fasciitislike lesions, peripheral neuropathy, muscle atrophy, and pulmonary hypertension. Cutaneous manifestations of TOS were nonspecific pruritic erythematous 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 pretibial leg skin and, occasionally forearms and abdomen, with marked fibrosis of dermis and subcutis. Eosinophil infiltration and degranulation were especially prominent in the acute phase of TOS, and serum eosinophil granule protein concentrations were increased during all phases.109 Potential pathogenic links between TOS, EMS, and eosinophilic fasciitis have been identified.197,198 EVALUATION AND TREATMENT CONSIDERATIONS Published literature48,199-201 and the report by Khoury and Bochner202 in this issue detail evaluation and management of eosinophil-related disease. Clinical manifestations result from specific organ involvement of activated eosinophils in tissues and/ or from eosinophil-derived factors circulating in blood. From the dermatological perspective, a few points deserve emphasis. Medical history should include appraisal for atopic diathesis and documentation of skin symptoms (pruritus, burning, and pain) as well as systemic signs (fevers, night sweats, and unintentional weight loss). Travel, living, or working in endemic areas of parasitic diseases, particularly, but also fungal infections should be considered, recognizing that “exotic exposures are only a plane ride away.” Querying for other exposures should include potential contact allergens at work or home (eg, occupational related, hobbies, skin, hair, and nail care) and ingested allergens (drugs, foods, dietary supplements, and health foods). Other close human and animal exposures to infection (human immunodeficiency virus, herpesvirus, and syphilis) or infestation (ectoparasites and myiasis) (Figure 8) should be considered.203 Physical examination should include complete skin and mucosal assessment, noting lesion morphology and distribution, as well as evaluation for lymphadenopathy. Particular attention should be paid to the nails for splinter hemorrhages and/or nail fold infarcts that constitute a medical emergency as indicators of thromboembolic phenomena. Notably, eosinophilic endomyocardial disease can develop in any patient with eosinophil-related disease and should be monitored. Laboratory evaluation often should include skin biopsy or biopsies (Figure 9) and serum testing for immunobullous disease along with monitoring peripheral blood eosinophil levels. If there is any possible exposure to a parasite, even remotely, particularly strongyloides, parasite serologies should be performed before

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FIGURE 8. Myiasis with indurated, erythematous pruritic plaques (arrows) on (A) backs of legs and (B) lateral trunk, recurrent lasting 4-7 days, associated with protracted multisystem disease and eosinophilia caused by (C) Hypoderma lineatum. Reprinted with permission from Leiferman KM. Eosinophil-associated diseases with dermatologic manifestations. In: Callen JP, Jorizzo JL, editors. Dermatological Signs of Systemic Disease. Philadelphia, PA: Elsevier; 2017:69-76.117

starting immunosuppressive therapy. Because glucocorticoids continue to be a first-line therapy for eosinophil-related diseases, it is important to consider that a severe life-threatening hyperinfection syndrome, associated with sepsis and meningitis from enteric flora (probably related to worm migration across the intestinal mucosa), may develop when a patient with latent Strongyloides stercoralis infection has received even a short course of glucocorticoids or another immunosuppressant, such as methotrexate or a tumor-necrosis-factor inhibitor.204-207 Therapy for eosinophil-related diseases often starts with a course of glucocorticoids, but also should be directed at specific disease management that may be inducing eosinophil-related inflammation, including avoidance of allergens, contactants and ingestants, and, particularly, treatment of infection. Hydroxyurea and IFN-a have been used for years in the treatment of HES and various other eosinophil-related diseases. Relatively recently, imatinib mesylate and other kinases inhibitors have been found to be effective in primary (neoplastic) HES.167,208,209 Rituximab has been helpful in IgG4-related disease, which often is associated with both tissue eosinophils and peripheral blood eosinophilia.210 With recognition that IL-5 is a key factor for multiple aspects of eosinophil activity including proliferation, maturation, and activation, therapies directed at IL-5 have emerged and shown efficacy.211,212 Mepolizumab and reslizumab, monoclonal antibodies to IL-5, and benralizumab, a monoclonal antibody to the IL-5 receptor-a, are approved asthma treatments; their potential benefits for eosinophil-related skin disease have not been reported, either as primary or adjunctive therapy. Mepolizumab also is approved for treating eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome),180 which has treatment-responsive cutaneous manifestations. Benralizumab induces antibody-dependent cell-mediated cytotoxicity of eosinophils and basophils, effectively “knocking out” the cells; collateral effects on skin diseases that are found in asthma-treated patients should soon be recognized. Other therapies are in development, including agents that target

different surface receptors or mediators associated with eosinophilic inflammation, or agents that interfere with eosinophil activity.213-220 The main therapeutic goals are relief of symptoms and keeping the peripheral eosinophil count under 1-2
109/L blood, while minimizing adverse effects of single- or multiple-agent therapy.

SUMMARY AND CONCLUSIONS Eosinophils, found in many and various disorders and reaction patterns in cutaneous and systemic diseases and in homeostasis, are recruited to and activated in tissues by the TH2 subset of T cells in acquired immunity and the ILC2 subset of innate lymphocytes in innate immunity. IL-5 is a key cytokine in both. When activated, eosinophils are proinflammatory, prothrombotic, and profibrotic. Activated eosinophils and their products affect the function of and mediate damage to cells, tissues, and organs. However, much remains to be understood as to how and why eosinophils are involved in diseases, affecting certain organs and tissues, with the skin well represented across many eosinophil-related diseases. In addition, it is unclear why different patterns of eosinophil involvement are found even in the same disease process, or how the relationship between peripheral blood eosinophilia and tissue eosinophilia is established. Tissue eosinophilia and levels of peripheral blood eosinophils are defined in Figure 10. Although gradations of peripheral blood eosinophils are designated, degrees and patterns of tissue eosinophilia are not specified, in part, because markers of eosinophil degranulation in tissues are not widely available and documented. Various patterns of eosinophil involvement in tissues are recognized (Table II), and each pattern may be found either with or without peripheral blood eosinophilia/hypereosinophilia. For now, we conclude that eosinophils are observed in biopsy specimens and peripheral blood from patients with various dermatologic abnormalities including specific eosinophil-related cutaneous diseases, and clinicopathological correlation is needed to arrive at the correct diagnosis. Eosinophils commonly

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Test performed on sections from skin/mucosal specimen* Histopathology Brightfield microscopic examination of formalin-fixed, paraffin-embedded, H&E-stained tissue sections

Direct immunofluorescence (DIF)† Testing for immunoglobulins, complement, and fibrinogen performed on sections from tissue placed in Michel or Zeus transport medium or from snapfrozen tissue Note: DIF cannot be performed on formalin-fixed tissue Eosinophil-specific immunostain Cellular and extracellular eosinophil granule protein localization on sections from tissue placed in Michel or Zeus transport medium, formalin-fixed or snap-frozen tissue

Biopsy site by lesion type

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Additional considerations

New pink-erythematous macular or papular lesion OR Border of erythematous or edematous lesion

More than one biopsy may be indicated if clinical morphology is varied

OR Blister edge, or entire blister if small (less than 4-mm punch) In a patient with Border of a new erythematous or generalized pruritus but no edematous skin lesion primary skin lesions, DIF may be obtained from OR normal-appearing flexural Perilesional tissue immediately skin of upper arm or thigh adjacent to a blister or from the trunk For mucosa, non-lesional tissue from region of active disease (if biopsy too close to lesion, the epithelium is likely to detach) New pink-slightly erythematous lesion/affected area

OR Perilesional tissue immediately adjacent to a blister

Skin or mucosal biopsy from a blister or erosion, must be mostly “intact” (epithelium attached to underlying dermis/stroma)

Complete blood count, with differential white blood cell count, to assess peripheral blood eosinophil level

*Biopsy size   

A 4-mm or 5-mm punch biopsy is preferred if the specimen is submitted for a single test A 6-mm or larger diameter punch biopsy is preferred when a single specimen will be split into 2 parts: 1/2 for histopathology and 1/2 for direct immunofluorescence  Note that the preferred site for the two tests may differ If using a single specimen for 2 tests, carefully bisect the tissue to minimize epithelial separation

†Serum testing by indirect immunofluorescence and/or ELISA for antibodies associated with immunobullous diseases may provide additional diagnostic information FIGURE 9. Eosinophil-related cutaneous disease; biopsy specifications for testing and site selection.

disrupt and lose their morphological integrity as they deposit toxic granule proteins and other inflammatory mediators in tissues, prominently in urticarial, eczematous, and pruritic skin lesions. Therefore, the presence or absence of intact eosinophils in tissue specimens may not accurately reflect their pathogenic role in disease. Peripheral blood eosinophilia is an abnormality in many diseases that may provide a clue to diagnosis, but it is not a diagnostic marker except when levels of peripheral blood eosinophils are in the “hypereosinophilic” range as in the hypereosinophilic syndromes. Notably, however, in patients with persistent peripheral blood eosinophilia from any cause, tissue infiltration and eosinophil-derived effector molecules may cause clinically relevant pathology, including irreversible organ damage. The recognition of cutaneous eosinophil involvement has importance for understanding pathophysiology and roles for eosinophil-directed therapy. The eosinophil may or may not be the principal pathogenic factor in a disease, but, based on its

effects on tissues and cells, can play a role in mediating damage directly and/or in potentiating and causing collateral inflammatory consequences. Depending on the pathological mechanisms in eosinophil-mediated cutaneous disease, eosinophil-targeted therapy may control the disease primarily or critically block the inflammatory cascade/network. What happens if eosinophil-targeted therapy results in complete removal of eosinophils—that is, are eosinophils necessary for human health? Leaders in eosinophil research have opined that the absence of eosinophils is not associated with any characteristic abnormality,221 that eosinophils are likely a vestige of prehygienic times when parasitic disease was nearly universal, and, now, are showing escalating emergence in such diseases as atopic dermatitis, asthma, and eosinophilic esophagitis, and, possibly, bullous pemphigoid, as part of the “allergy epidemic.”222 Nevertheless, it is possible that eosinophils are put to good use in certain conditions such as tumor containment.223,224

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(1) Peripheral Blood Eosinophils

Counts x 109/L blood

Hypereosinophilia

>1.5 recorded on at least 2 determinations with a minimum time interval of 4 weeks (unless immediate designation is required to initiate therapy because of eosinophil-related organ dysfunction)

Eosinophilia

0.5-1.5

Normal

0.05-0.5 (1-6% of white blood cell count range)

(2) Tissue hypereosinophilia The percentage of eosinophils exceeds 20% of all nucleated bone marrow cells, and / or Pathologist is of the opinion that tissue eosinophil infiltration is extensive (massive) compared with the normal physiological range, compared with other inflammatory cells or both, and / or A specific eosinophil granule protein stain (e.g. eosinophil granule major basic protein 1, eMBP1, or eosinophil-derived neurotoxin, EDN) demonstrates extensive extracellular deposition indicative of local eosinophil activation and degranulation even in the absence of local eosinophil infiltration

Normal

No eosinophils or extracellular eosinophil granule protein deposition except as known in specific organs and tissues (bone marrow, spleen, thymus, lymph nodes, gastrointestinal tract distal to esophagus); occasional intravascular eosinophils may be observed by histopathology, particularly with increased peripheral blood eosinophils

FIGURE 10. Definition and gradations of peripheral blood eosinophilia and tissue hypereosinophilia in eosinophil-related diseases. World Health Organization classifies peripheral blood eosinophilia as 1 of 3 levels: mild, absolute eosinophil count (AEC) from the upper limit of normal to 1,500/mL; moderate, AEC 1,500e5,000/mL; and severe, AEC >5,000/mL.167 Modified with permission from Valent P, Klion AD, Horny HP, Roufosse F, Gotlib J, Weller PF, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol 2012;130:607-12.e9.47 REFERENCES 1. Kay AB. Paul Ehrlich and the early history of granulocytes. Microbiol Spectr 2016;4: MCHD-0032-2016. https://doi.org/10.1128/microbiolspec.MCHD0032-2016. 2. Kato M, Kephart GM, Talley NJ, Wagner JM, Sarr MG, Bonno M, et al. Eosinophil infiltration and degranulation in normal human tissue. Anat Rec 1998;252:418-25. 3. Mjosberg J, Spits H. Type 2 innate lymphoid cells-new members of the “type 2 franchise” that mediate allergic airway inflammation. Eur J Immunol 2012;42: 1093-6. 4. Nussbaum JC, van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A, Molofsky AB, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 2013;502:245-8. 5. Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med 2013;210:2939-50. 6. Roediger B, Kyle R, Yip KH, Sumaria N, Guy TV, Kim BS, et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 2013;14:564-73. 7. Spits H. Group 2 innate lymphoid cells show up in the skin. Immunol Cell Biol 2013;91:390-2. 8. Walker JA, Barlow JL, McKenzie AN. Innate lymphoid cells—how did we miss them? Nat Rev Immunol 2013;13:75-87. 9. Molofsky AB, Nussbaum JC, Liang HE, van Dyken SJ, Cheng LE, Mohapatra A, et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 2013;210:535-49. 10. Lee JJ, Protheroe CA, Luo H, Ochkur SI, Scott GD, Zellner KR, et al. Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice. J Allergy Clin Immunol 2015;135:477-87.

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200. Approach to the patient with unexplained eosinophilia. In: Mahoney DH Jr, Bochner BS, Eds. UpToDate. Available from: https://www.uptodate.com/. Accessed April 7, 2018. 201. Butt NM, Lambert J, Ali S, Beer PA, Cross NC, Duncombe A, et al. Guideline for the investigation and management of eosinophilia. Br J Haematol 2017; 176:553-72. 202. Khoury P, Bochner BS. Consultation for elevated blood eosinophils: clinical presentations, high value diagnostic tests, and treatment options. J Allergy Clin Immunol Pract 2018;6:1446-53. 203. Starr J, Pruett JH, Yunginger JW, Gleich GJ. Myiasis due to hypoderma lineatum infection mimicking the hypereosinophilic syndrome. Mayo Clin Proc 2000;75:755-9. 204. Pukkila-Worley R, Nardi V, Branda JA. Case records of the Massachusetts General Hospital. Case 28-2014. A 39-year-old man with a rash, headache, fever, nausea, and photophobia. N Engl J Med 2014;371:1051-60. 205. Marcos LA, Terashima A, Dupont HL, Gotuzzo E. Strongyloides hyperinfection syndrome: an emerging global infectious disease. Trans R Soc Trop Med Hyg 2008;102:314-8. 206. Ghosh K, Ghosh K. Strongyloides stercoralis septicaemia following steroid therapy for eosinophilia: report of three cases. Trans R Soc Trop Med Hyg 2007;101:1163-5. 207. Krishnamurthy R, Dincer HE, Whittemore D. Strongyloides stercoralis hyperinfection in a patient with rheumatoid arthritis after anti-TNF-alpha therapy. J Clin Rheumatol 2007;13:150-2. 208. Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH. Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 2002;359:1577-8. 209. Klion AD. How I treat hypereosinophilic syndromes. Blood 2015;126:1069-77. 210. Kamisawa T, Okazaki K. Diagnosis and treatment of IgG4-related disease. Curr Top Microbiol Immunol 2017;401:19-33. 211. Bochner BS, Gleich GJ. What targeting eosinophils has taught us about their role in diseases. J Allergy Clin Immunol 2010;126:16-25. 212. Fulkerson PC, Rothenberg ME. Targeting eosinophils in allergy, inflammation and beyond. Nat Rev Drug Discov 2013;12:117-29. 213. Kiwamoto T, Kawasaki N, Paulson JC, Bochner BS. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol Ther 2012;135:327-36. 214. Gauvreau GM, O’Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 2014;370:2102-10. 215. Legrand F, Klion AD. Biologic therapies targeting eosinophils: current status and future prospects. J Allergy Clin Immunol Pract 2015;3:167-74. 216. Radonjic-Hoesli S, Valent P, Klion AD, Wechsler ME, Simon HU. Novel targeted therapies for eosinophil-associated diseases and allergy. Annu Rev Pharmacol Toxicol 2015;55:633-56. 217. Gotlib J. Tyrosine kinase inhibitors and therapeutic antibodies in advanced eosinophilic disorders and systemic mastocytosis. Curr Hematol Malig Rep 2015;10:351-61. 218. Kuang FL, Klion AD. Biologic agents for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol Pract 2017;5:1502-9. 219. O’Sullivan JA, Carroll DJ, Cao Y, Salicru AN, Bochner BS. Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 2018;141:1774-85.e7. 220. Dworetzky SI, Hebrank GT, Archibald DG, Reynolds IJ, Farwell W, Bozik ME. The targeted eosinophil-lowering effects of dexpramipexole in clinical studies. Blood Cells Mol Dis 2017;63:62-5. 221. Gleich GJ, Klion AD, Lee JJ, Weller PF. The consequences of not having eosinophils. Allergy 2013;68:829-35. 222. Lambrecht BN, Hammad H. The immunology of the allergy epidemic and the hygiene hypothesis. Nat Immunol 2017;18:1076-83. 223. Lucarini V, Ziccheddu G, Macchia I, La Sorsa V, Peschiaroli F, Buccione C, et al. IL-33 restricts tumor growth and inhibits pulmonary metastasis in melanoma-bearing mice through eosinophils. Oncoimmunology 2017;6: e1317420. 224. Varricchi G, Galdiero MR, Loffredo S, Lucarini V, Marone G, Mattei F, et al. Eosinophils: the unsung heroes in cancer? Oncoimmunology 2018;7:e1393134.

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ONLINE REPOSITORY TABLE E1. Histopathological patterns with eosinophil-related inflammation in different cutaneous compartments Epidermis Eosinophilic Connective tissue in dermis Eosinophilic Blood vessels in dermis Eosinophilic Hair follicles in dermis Eosinophilic Subcutaneous fat Eosinophilic Fascia Eosinophilic Muscle Eosinophilic  Each pattern may be found in various diseases  Overlapping patterns in one disease are common  Patterns may change as a disease develops/persists

spongiosis cellulitis vasculitis folliculitis panniculitis fasciitis myositis

TABLE E2. Cutaneous presentations with differential diagnoses of eosinophil-related diseasesE1 Cutaneous signs/symptom

Angioedema/dermographism/edema/urticaria

Blisters and/or ulceration

Dermatitis/eczema/pruritus

Erythema/pruritus

Eosinophil-related disease diagnostic differential

Cellulitis Drug reaction Eosinophilia myalgia and toxic oil syndromes Eosinophilic cellulitis (Wells syndrome) Erysipelas Hereditary angioedema Hypereosinophilic syndromes Immunodeficiency syndromes Insect bite or sting Mast cell disease Parasitic infection Urticaria Urticarial vasculitis Aphthous stomatitis Behçet syndrome Drug reaction Erythema multiforme Herpes simplex infection Hypereosinophilic syndromes Immunobullous disease Incontinentia pigmenti Insect bite or sting Lichen planus Lesions in diseases in the box above (angioedema/dermographism/edema/urticaria) may blister Atopic dermatitis Contact dermatitis Drug reaction Ectoparasite infestation Fungal infection Hypereosinophilic syndromes Immunodeficiency syndromes Parasitic infection Drug reaction Ectoparasite infestation Hypereosinophilic syndromes Sézary syndrome Seborrheic dermatitis (continued)

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TABLE E2. (Continued) Cutaneous signs/symptom

Fibrosis/sclerosis

Hyperpigmentation

Nodules/papules/plaques/pustules

Various, miscellaneous disease-associated

Eosinophil-related disease diagnostic differential

IgG4-related diseases Eosinophilia myalgia and toxic oil syndromes Eosinophilic fasciitis Morphea Adrenal insufficiency (Addison disease) Drug reaction Hemochromatosis Hyperthyroidism Acne, including acne neonatorum Acropustulosis Epithelioid angiosarcoma Epithelioid hemangioendothelioma Erythema toxicum neonatorum Folliculitis Follicular mucinosis Fungal infection Hypereosinophilic syndromes IgG4-related diseases Angiolymphoid hyperplasia with eosinophilia Granuloma faciale Kimura disease Kaposi sarcoma Lichen planus Lupus erythematosus Mast cell disease Morphea Mycosis fungoides Nodules, eosinophilia, rheumatism, dermatitis, and swelling Palmar-plantar pustular psoriasis Pityriasis lichenoides chronica Pyogenic granuloma T-cell lymphoma Vasculitis Asthma Crohn disease Erythema multiforme Fungal infection Immunodeficiency syndromes including hyper IgE syndromes Reactive arthritis (formerly Reiter syndrome) Sarcoidosis Syphilis Ulcerative colitis

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TABLE E3. Eosinophil-related cutaneous diseases; clinical cluesE2 Diagnosis

Allergic contact dermatitis Angiolymphoid hyperplasia with eosinophilia

Annular erythema of infancy Arthropod bite and sting reactions

Atopic dermatitis Autoimmune bullous dermatoses

Drug eruptions

Eosinophilic dermatosis of hematologic malignancy (eosinophilic dermatosis of myeloproliferative disease)

Eosinophilic fasciitis (Shulman syndrome) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

Eosinophilic (pustular) folliculitis

Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy Eosinophilic vasculitis Eosinophilic ulcer of the oral mucosa

Epidermolysis bullosa acquisita (also see above, autoimmune bullous dermatoses) Erythema toxicum neonatorum Granuloma faciale

Hypereosinophilic dermatitis of Nir-Westfried

Clinical clues

History of exposure; distribution pattern; positive patch test Single or multiple nodules of face, scalp, and ears; vascular proliferation with prominent endothelial cells, and mixed mainly lymphocytic inflammation, with eosinophils Annular or serpiginous nonpruritic plaques in infants Primarily involves exposed skin; spiders, ticks, fleas, mites, and mosquitoes; exaggerated reactions in patients with chronic lymphocytic leukemia History of atopy; pruritus; flexural and extremity accentuation Pemphigoid (particularly bullous pemphigoid, pemphigoid gestationis), pemphigus, linear IgA bullous dermatosis, epidermolysis bullosa acquisita and less often dermatitis herpetiformis; initial phase of bullous pemphigoid and pemphigoid gestationis may be urticarial Eosinophilic spongiosis, eosinophil-rich subepidermal bulla, mixed superficial dermal inflammation including eosinophils; eosinophilic spongiosis may be a marker for immunobullous disease, particularly pemphigus and pemphigoid, but more often correlates with a clinical diagnosis of dermatitis Drug history, especially new drugs within previous 2 wk Eosinophils observed in many types of drug eruptions but absent in approximately 50% of cases and present in many nonedrug-related dermatoses—therefore, an unreliable marker of drug etiology Often in setting of chronic lymphocytic leukemia but reported in patients with other hematologic malignancies Considered an insect bite-like reaction but without history of bites, presenting as pruritic, papules, nodules, and sometimes vesicles Superficial and deep dermal lymphohistiocytic inflammation with eosinophils Sudden onset of symmetrical induration of skin and subcutaneous tissues of the limbs with “peau d’orange” texture, peripheral blood eosinophilia Palpable purpura and tender papulonodules; asthma and peripheral blood eosinophilia; peripheral neuropathy, cardiac involvement and glomerulonephritis may be present; cutaneous small-vessel vasculitis; prominent IgG4 and IgE responses HIV variant: HIVþ patient with severe pruritus and papules on the face and upper trunk Ofuji’s disease: Japanese patient with chronic, recurrent follicular pustules in a seborrheic distribution with tendency to form circinate plaques Pediatric: follicular pustules on the scalp of an infant Local and generalized pruritus, erythematous papules, sometimes with vesicles Pruritic urticarial and purpuric papules; angioedema, juvenile temporal arteritis; histopathologic reaction pattern rather than specific dermatosis Rapidly enlarging nodule that develops ulceration; tongue most common site; in addition to eosinophils, brisk lymphocytic infiltrate with the component of CD30-positive cells and occasional clone suggests inclusion in the spectrum of CD30þ lymphoproliferative disorders Rare, acquired subepithelial immunobullous disease of skin and mucous membranes Newborn with erythematous macules, papules, and pustules, often with prominent erythematous flare; involving trunk Solitary to few, asymptomatic, red-brown to violaceous plaques on face, most common in middle-aged white men, IgG4-related disease; nasal mucosal variant termed eosinophilic angiocentric fibrosis Pruritic, papular eruption with peripheral eosinophilia; often dapsone-responsive (continued)

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TABLE E3. (Continued) Diagnosis

Hypereosinophilic syndromes

Incontinentia pigmenti Itchy red bump disease (papular dermatitis) Juvenile temporal arteritis Juvenile xanthogranuloma

Kimura disease

Langerhans cell histiocytosis (especially eosinophilic granuloma)

Lymphoproliferative disorders, including mycosis fungoides, lymphomatoid papulosis, anaplastic large cell lymphoma

Mastocytosis Nummular dermatitis Oid-oid disease (exudative discoid and lichenoid chronic dermatosis of Sulzberger and Garbe) Pachydermatous eosinophilic dermatitis

Papular eruption of blacks Papuloerythroderma of Ofuji

Parasitic infestations Pemphigoid variants (also see above, autoimmune bullous dermatoses)

Clinical clues

Cutaneous lesions include pruritic erythematous papules or nodules as well as urticaria and angioedema in primary and secondary variants; mucosal ulcers are associated with an aggressive course and splinter hemorrhages and/or nailfold infarcts indicate thromboembolic disease and constitute a medical emergency. Vesicles and bullae along Blaschko lines in neonate (stage I); blood eosinophilia; eosinophilic spongiosis; and keratinocyte dyskeratosis Markedly pruritic pink to red papules; may be associated with eczematous patches and/or dermographism Large-vessel eosinophilic vasculitis of children or young adults Yellow to red-brown papules or nodules on the head and neck, upper trunk or proximal extremities; early lesions may have numerous eosinophils Head/neck masses, peripheral eosinophilia, increased serum IgE; deep dermal and subcutaneous nodular lymphoid infiltrates with component of eosinophils Disseminated pink and yellow-brown papules (often with crusts), nodulo-ulcerative periorificial lesions; infiltrate of Langerhans histiocytes with variable, sometime prominent eosinophilic component Patches, plaques, or nodules; in mycosis fungoides, eosinophils often in the tumor stage but uncommon in the patch stage disease; a minor component of various cutaneous peripheral T-cell lymphomas and lymphomatoid papulosis; prominent in eosinophil-rich neutrophil-rich variant of anaplastic large cell lymphoma Pink-tan to red-brown macules, papules, and plaques that urticate with stroking (Darier sign) Discrete round eczematous plaques on the extremities; pruritic Middle-aged, predominantly Jewish, men; pruritic lesions commonly involving genitals; progressive stages: discoid / exudative / lichenified; peripheral blood eosinophilia South African black teenage girls with generalized pruritic papules, hypertrophic genital lesions and peripheral blood eosinophilia; dapsone-responsive; possibly a variant of hypereosinophilic dermatitis of Nir-Westfried Young, black men with intensely pruritic papules on the trunk and upper arms Widespread red-brown papules and/or confluent erythroderma sparing skin folds (“deck-chair sign”) in elderly men, blood eosinophilia, lymphopenia, high IgE, possible underlying T-cell lymphoma, gastric carcinoma, or other malignancy. Cysticercosis, dirofilariasis, larva migrans, myiasis, onchocerciasis, tungiasis, schistosomiasis, and others Bullous pemphigoid: Elderly patients, pruritic tense blisters, urticarial plaques, and itching without primary lesions, Pemphigoid gestationis: Pregnant patient; urticarial papules, plaques, and bullae of abdomen, including periumbilical. Other pemphigoid variants Flaccid vesicles and crusted erosions; distribution depends on subtype

Pemphigus variants (also see above, autoimmune bullous dermatoses) Polymorphic eruption of pregnancy Primigravida in third trimester; urticarial papules, and plaques, (also referred to as pruritic urticarial papules and plaques of pregnancy) especially in striae Pruritic papular eruption of HIV disease Symmetrical pruritic nonfollicular papules; HIV infection; may be an exaggerated reaction to arthropod antigens without recognized bites Pseudolymphoma Association with arthropod bite or drug (especially phenytoin) Scabies Marked nocturnal pruritus; webspace, umbilical, and groin involvement Seabather’s eruption (larvae of Linuche unguiculata and Pruritic papules in distribution of swimsuit covering; occurs after Edwardsiella lineata and other larval cnidarians) ocean swimming Swimmer’s itch or cercarial dermatitis Pruritic papules on uncovered skin; occurs after fresh-water swimming (larvae of avian and mammalian schistosome species)

(continued)

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TABLE E3. (Continued) Diagnosis

Urticaria Urticarial allergic eruption Urticarial dermatitis

Urticarial vasculitis

HIV, Human immunodeficiency virus.

TABLE E4. Cutaneous eruptions/lesion types in drug reactionsE3 Acanthosis nigricans Acneiform lesions Acute generalized exanthematous pustulosis Alopecia Angioedema Aphthous stomatitis Black hairy tongue Bullous eruptions Erythema multiforme and Stevens-Johnson syndrome Erythema nodosum Exanthemas Exfoliative dermatitis Fixed drug eruption Gingival hyperplasia Lichen planus-like (lichenoid) eruption Lupus erythematosus Onycholysis Pemphigus vulgaris Photosensitivity Pigmentation Pityriasis rosea-like eruption Pruritus Psoriasis Purpura Raynaud’s phenomenon Toxic epidermal necrolysis Urticaria Vasculitis Xerostomia

Clinical clues

Pruritic, migratory, transient (lasting <24 h) wheals Annular or gyrate urticarial plaques that persist >24 h Very pruritic, eczematous and/or urticarial, often excoriated papules, and plaques of trunk and proximal extremities, particularly of the elderly; persist for d to wk; often accompanied by excoriated papules; minimally responsive to topical glucocorticoids and oral antihistamines Lesions may burn rather than itch and persist >24 h; associated with autoimmune connective tissue disease and decrease in complement levels

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REFERENCES E1. Leiferman KM. Eosinophil-associated diseases with dermatologic manifestations. In: Callen JP, Jorizzo JL, editors. Dermatological Signs of Systemic Disease. Philadelphia, PA: Elsevier; 2017. E2. Leiferman KM, Peters MS. Eosinophil-associated dermatoses. In: Bolognia JL, Schaffer JV, Cerroni L, editors. Dermatology. Philadelphia, PA: Elsevier; 2017: 440-52. E3. McKenna JK, Leiferman KM. Dermatologic drug reactions. Immunol Allergy Clin North Am 2004;24:399-423.

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