Typically, this eosinophilic dermatosis, first described by Wells in 1971 [11], is a chronically recurrent, highly inflammatory condition that often heals spontaneously. In some patients, fever attacks and arthralgia are signs of systemic involvement. It is still controversial whether Wells syndrome is an independent, monocausal clinical condition or rather a reaction pattern, dominated by eosinophils, to different, ultimately unknown stimuli or danger signals. In fact, Wells syndrome is sometimes associated with other eosinophilic dermatoses such as eosinophilic fasciitis and eosinophilic granulomatosis with polyangiitis (EGPA).

Clinically, the main features are highly pruritic papules and plaques with a tendency to confluence and a clearly infiltrated and urticarial appearance, sometimes reminiscent of granuloma annulare. Occasionally, papulovesicles and even blisters can be found. Histopathologically, there is a mixed inflammatory infiltrate characterized by eosinophils and lymphocytes, often with marked edema of the papillary dermis. The characteristic flame figures develop over the course of one to three weeks.

About half of all patients with Wells syndrome exhibit a pronounced blood eosinophilia. The most important differential diagnoses are acute urticaria, urticarial vasculitis, Sweet syndrome, insect bite reactions and cellulitis. Therapeutically, the administration of systemic corticosteroids is clearly the first choice, with initial doses of 2 mg/kg body weight prednisone often being necessary to stop the disease activity [12]. Cyclosporin A and dapsone have also been shown to be effective in some patients [13]. The successful administration of the anti-IL-5 antibody mepolizumab in the treatment and relapse prophylaxis of Wells syndrome [14] once again underlines the central role of eosinophils in the disease process and represents an interesting therapeutic alternative in patients with a contraindication to the continuous administration of systemic corticosteroids.

This entity, also known as Gleich’s syndrome [15] is a rare disorder of unknown etiology which, similar to periodic autoinflammatory syndromes [16], is characterized by recurrent episodes of urticaria, fever, angioedema, weight gain and dramatic eosinophilia that occur at 3–4 week intervals and resolve with spontaneous diureses in the absence of therapy.

Systemic corticosteroids may accelerate this process [17].

This is a heterogeneous group of clinical conditions manifesting predominantly on the skin with three common features, namely (i) a hypereosinophilia of the peripheral blood of > 1500/µl persisting > 6 months and/or a pronounced tissue eosinophilia, (ii) damage or functional impairment of the affected tissues/organs attributable to the hypereosinophilia and (iii) the exclusion of other pathogenetic causes [18]. A distinction is made between two subtypes of HES: lymphocytic and myeloproliferative. In the former, there is an aberrant T-cell clone that causes the expansion and activation of eosinophilic granulocytes through the production and release of Th2 cytokines [19]. The latter variant is far more aggressive and also has a less favorable prognosis. It is caused by a gene deletion on chromosome 4, as a result of which the fusion gene FIP1L1-PDGFRA (=Fip1-like-1-platelet-derived growth factor receptor α) is created. This has tyrosine kinase activity and, thus, leads to myeloproliferation in the skin and also in internal organs.

Clinically, the lymphocytic variant of HES manifests itself predominantly, often even exclusively, on the skin. The appearance is extremely polymorphic and ranges from eczematous foci to wheals and angioedema (especially in the facial area) as well as from very itchy papulonodular lesions to palpable purpura, ulcerated plaques of the skin and oral mucosa and even erythroderma.

Histologically, all lesions exhibit interstitial and perivascular inflammatory infiltrates with a clear eosinophilic component in common. The aim of therapeutic measures must be to permanently reduce eosinophilia to a level of < 500/μl, and, thus, to prevent damage to internal organs.

In the treatment of the lymphocytic form of HES, systemic corticosteroids are the drug of first choice; dapsone, hydroxyurea, vincristine and etoposide are also occasionally used [18, 20]. According to several reports, the monoclonal anti-IL-5 antibody mepolizumab is also effective and long-lasting in the lymphocytic variant [21, 22]. In the myeloproliferative form, permanent remissions were achieved with the tyrosine kinase inhibitor imatinib [23].

DRESS is a severe hypersensitivity reaction to certain medications with obligatory skin manifestations as well as systemic symptoms such as fever, lymphadenopathy, leukocytosis with eosinophilia and/or atypical lymphocytes and liver dysfunction [24, 25]. The latency period from the time of taking the medication to the onset of clinical symptoms ranges from 2 to 8 weeks and is often associated with the reactivation of herpes viruses (HHV-6, EBV, or cytomegalovirus) [26]. Indeed, virus reactivation has been reported in up to 60% of patients with DRESS, but it is not specific for DRESS since it has also been observed, although less frequently, in other severe intolerance reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. In other words: a specific contribution of virus reactivation to DRESS has yet to be determined. [27] To establish the diagnosis DRESS, 3 criteria must be met, i.e. (i) skin symptoms, usually in the form of an itchy maculopapular rash, which can progress into erythroderma and, occasionally, also in the form of blisters or angioedema; (ii) inflammation/swelling of lymph nodes (> 2 cm in diameter) and/or internal organs (liver, kidney, lung, myocardium); and (iii) hematologic changes (pronounced eosinophilia or appearance of atypical lymphocytes). Together with abnormal liver and kidney function tests, these manifestations do not necessarily occur simultaneously, but often sequentially, with eosinophilia often lagging behind the hepatic pathology [13]. The most common triggers of DRESS are antiepileptic drugs, dapsone, sulfasalazine, sulfonamides, allopurinol and minocycline [28]. The disease often takes a severe, rarely (1.2–6.1%) even fatal course [29]. Therapeutic measures always include the immediate discontinuation of the triggering medication and, depending on the severity, the use of systemic (starting with 1 mg/kg body weight prednisone) or topical corticosteroids.

This refers to a polymorphic, eosinophil-rich inflammatory skin disease, which is invariably associated with underlying malignant hematological diseases (chronic lymphocytic leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, large B-cell lymphoma) [30, 31]. Clinically, there are usually itchy nodules and lumps, sometimes also vesicles and blisters, which are histopathologically based on a non-malignant lymphohistiocytic infiltrate with a pronounced eosinophilic component. Causes of tissue eosinophilia other than hematologic malignancy must be excluded. It is therefore a paraneoplastic disease that is often difficult to differentiate from insect bite reactions, hypereosinophilic syndromes, Wells syndrome and eosinophilic folliculitis [32]. As with so many other eosinophilic dermatoses, systemic corticosteroids are also effective in EDHM. The administration of dupilumab may be a therapeutic alternative [33].

This disease is also known as Shulman’s syndrome after its first describer [34] and is characterized by thickening of the cutaneous muscle fascia and by an inflammatory infiltrate in which lymphocytes, mononuclear phagocytes and eosinophilic granulocytes predominate. Sometimes the inflammatory process extends into the neighboring subcutaneous adipose tissue on one side and into the connective tissue septa of the muscles or the muscle tissue itself on the other.

The etiopathogenesis of the disease is only partially understood. One starting point for a better understanding of the disease may be the frequent co-occurrence of EF with certain autoimmune diseases such as SLE, Sjögren’s syndrome and thyroiditis. It is conceivable, but by no means proven, that an autoimmunologically triggered type 2 inflammation jumps from one organ/tissue to another. The resulting tissue eosinophilia then ultimately leads to toxic damage of connective tissue and muscles and, thus, also to fibrosis. Eosinophils themselves produce fibrogenic cytokines (e.g, TGF-β, IL-1, IL-6 and IL-13) and communicate directly with fibroblasts, stimulating them to produce fibronectin and type 1 collagen [35]. Finally, another important driver of fibrosis is the massive overproduction of an inhibitor of matrix metalloproteinase-1, called TIMP-1 (=tissue inhibitor of metalloproteinase-1), which leads to the accumulation of extracellular matrix proteins.

Infections (e.g., with borrelia), hematoproliferative diseases, severe physical stress and various medications (e.g., immune checkpoint inhibitors, anti-TNF-α antibodies, statins) have been blamed as triggers of EF; however, the way in which these factors exert their effect is unknown [36].

Clinically, there is usually an abrupt onset of symmetrical pitting edema and reddening of the flexor sides of the distal upper and lower extremities, which due to sclerosis of the deeper tissue layers give the appearance of orange peel skin (peau d’orange). The negative vein pattern (“groove sign”), a linear depression in the course of the superficial veins, is also very typical [37, 38]. In rare cases, the disease can spread to the muscular and skeletal layers of body. In turn some patients complain of pain in the adjacent muscles and joints and may develop carpal tunnel syndrome.

Although EF is often associated with morphea, i.e. localized cutaneous sclerosis, it is practically never associated with progressive systemic sclerosis. The absence of digital sclerosis and/or Raynaud’s phenomenon goes in line with it. Blood eosinophilia and polyclonal hypergammaglobulinemia are typical laboratory findings of EF. Disease-specific autoantibodies have not been described so far. Signs of activity are increases in (i) acute phase proteins,(ii) in serum aldolase and (iii) in the extent of inflammation and thickening of the fascia that can be detected by nuclear magnetic resonance imaging.

Similar to other eosinophilic diseases, systemic corticosteroids are also the focus of therapeutic efforts in EF, either in the form of several weeks of prednisone administration (starting with 0.5–1 mg/kg body weight) or as bolus therapy (125–500 mg methylprednisolone/day for 3–5 consecutive days). Methotrexate, azathioprine or mycophenolate mofetil are sometimes added to the therapeutic regimen [39]. Therapeutic success has also been achieved in some patients with the combined administration of methotrexate and high-dose intravenous immunoglobulins (HIVIG) [40] as well as with extracorporeal photopheresis.

Eosinophilic pustular folliculitis is a rare, chronic recurrent inflammatory dermatosis first described by Ise and Ofuji, which was originally regarded as a follicular variant of subcorneal pustulosis [41]. This disease should not be confused with papuloerythroderma [42], which was also attributed to Ofuji and in which the skin is predominantly infiltrated by Th2 and Th22 cells [43].

It is assumed that EFP is caused by an overexpression of prostaglandin D synthase in the tissue and that the resulting prostaglandin D2 (PGD₂) leads to an upregulation of eotaxin-3 in sebocytes, which is mediated by the peroxisome proliferator-activated receptor γ (PPARγ) [44].

In its classic variant, the disease is primarily found in Japanese men and manifests itself in the form of annular plaques composed of folliculocentric sterile papulopustules, which preferentially occur on the face. Histologically, there is a prominent eosinophilic spongiosis in the area of the hair/sebaceous gland unit [45]. There is also a variant associated with pronounced immunosuppression (e.g., advanced HIV infection) (IS-EPF), which predominantly affects the trunk. A further variant in infants (I-EPF) shows a benign, often self-limiting course. In comparison to the other variants, the scalp is predominantly affected and the relationship to the follicle is less pronounced [46, 47]. Moreover, the occurrence of a variant associated with malignant hematopoietic diseases has been described, which is characterized by a particularly severe pruritus [48]. All variants of EPF may or may not be accompanied by eosinophilia of the peripheral blood.

Oral non-steroidal anti-inflammatory drugs (NSAIDs) are the first line of treatment for EPF. Success has also been achieved in some patients with oral dapsone or minocycline, topical corticosteroids or tacrolimus and phototherapy [47].

Granuloma eosinophilicum faciei is a rare dermatosis that deserves the name “granuloma” at best because of its macroscopic appearance (nodular tissue formation), but not because of its histological appearance with nodular accumulation of inflammatory cells.

Clinically, reddish-brown to livid red papules, plaques and nodules with a smooth surface are seen together with an accentuation of the follicles and superficial telangiectasias. As the name suggests, the lesions occur almost exclusively on the face, preferably on the forehead, nose and cheeks [13]. Other skin areas may also be affected, but this is the exception [49].

Histopathologically one observes a predominantly perivascular, mesh-like fibrosis and an inflammatory infiltrate, which is separated from the overlying epidermis and adnexa by a connective tissue zone (“Grenzzone”). It is mainly composed of neutrophils, lymphocytes, plasma cells and also eosinophils. Occasionally, leukocytic diapedesis of the vessel wall and signs of leukocytoclasia are observed, but not the full picture of leukocytoclastic vasculitis [49]. Immunohistological examinations of lesional skin provided a possible clue about the etiopathogenesis of GF, as some research groups reported a predominance of IgG₄-positive plasma cells [50] . However, the data on this are contradictory [51]. Nevertheless, the hypothesis developed that GF is a cutaneous manifestation of IgG₄ disease/IgG₄-related disease. This disorder is characterized by fibrosis and accumulations of IgG₄-positive plasma cells in many organs (e.g. pancreas, bile ducts, thyroid gland, salivary glands, lungs, etc.) and poses a considerable therapeutic challenge in advanced stages [52].

In terms of differential diagnosis, GF is most similar to erythema elevatum et diutinum, which, however, occurs preferentially on the extremities [51]. In addition, rosacea, sarcoidosis, lymphomas and pseudolymphomas, cutaneous lupus erythematosus as well as infectious mycobacterial and mycotic processes should also be considered [13].

Treatment of GF is challenging and it is not uncommon for the foci of disease to prove resistant to various therapeutic modalities. Success has been achieved with dapsone, intralesional and systemic corticosteroids, chloroquine and topical tacrolimus, as well as with physicochemical (laser, cryotherapy) and surgical approaches [53, 54].

Although there is a high probability that these are two distinct entities, it cannot be ruled out with absolute certainty at the present time that they are different, partially overlapping manifestations of one and the same disease process. The reason for the latter hypothesis is that the lesions of both clinical pictures are characterized by an abundance of blood vessels and at the same time by a prominent lymphocytic component [13]. The etiopathogenesis of both clinical conditions is ultimately unknown. In particular, the question of whether or in which form vascular or lymphocytic proliferation should be considered the trigger of the disease process is controversial. Due to the fact that the endothelial cells in ALHE stain with an antibody against Wilms tumor 1, a marker molecule of vascular neoplasms, the current view is that ALHE is a benign vascular hyperplasia [55]. In contrast, Kimura’s disease with its more pronounced inflammatory infiltrate is regarded as a primary lymphoproliferative process.

Both ALHE and Kimura’s disease usually occur in young to adolescent as well as in middle aged individuals, more frequently in Asia, the former more often in women, the latter preferentially in men.

The clinical lesions are predominantly found in the head, neck and nape area; in ALHE in the form of mostly itchy, grouped reddish papules and nodules, in Kimura’s disease mainly in the form of subcutaneous swellings which, in contrast to ALHE, are often associated with regional lymph node swelling.

Histopathologically, ALHE is characterized by proliferating, prominent (epithelioid) endothelial cells in the dermis, often with cytoplasmic vacuoles. The inflammatory infiltrate consists mainly of lymphocytes, plasma cells and eosinophilic granulocytes. Lymphoid follicles are rarely found, in contrast to Kimura’s disease, where they predominate. Serum IgE elevations and blood eosinophilia are the exception in ALHE and the rule in Kimura’s disease.

The differential diagnoses of ALHE most often are pyogenic granuloma and Kaposi’s sarcoma, while Kimura’s disease is most likely mistaken as lymphoma and other processes underlying soft tissue swelling.

Surgical procedures, radiotherapy, laser treatment and cryotherapeutic measures as well as the administration of intralesional or systemic corticosteroids, intralesional chemotherapeutic agents, retinoids and IFN-α are valid therapeutic options for both conditions. [56, 57].

This is a systemic vasculitis of the small vessels first described in 1951 [58], which is associated with pronounced tissue and blood eosinophilia. It preferentially affects the respiratory tract, but also the heart, digestive tract, nervous system and even the skin can be involved.

The exact etiopathogenesis of the disease is not known. However, there is evidence that autoantibodies against a cytoplasmic antigen of neutrophils (so-called ANCA = anti-neutrophil cytoplasmic antibody) are pathogenetically significant, which is why EGPA is classified as an ANCA-associated vasculitis, together with granulomatosis with polyangiitis (GPA; formerly Wegener’s disease); and granulomatosis with polyangiitis (MPA) [59, 60].

EGPA is typically a disease of adulthood that usually begins with asthmatic symptoms (coughing attacks, wheezing, shortness of breath) and hay fever with sneezing fits. This is soon joined by general symptoms such as fever, fatigue and often generalized joint and muscle pain. Depending on the nature of the organs affected, symptoms such as cardiac arrhythmias, bleeding as a result of vascular ruptures such as melena, numbness and nerve pain eventually develop. The skin is affected in more than two thirds of all patients in the form of palpable purpura, extensive petechiae, hemorrhagic blisters, livedo reticularis, urticarial relapses and inflammatory nodules on the scalp and extremities [13]. Histopathologically, lesional skin shows an eosinophil-rich necrotizing vasculitis primarily of arterioles and venules as well as extravascular palisade granulomas with abundant eosinophils.

In contrast to the previous poor prognosis of EGPA, the administration of systemic glucocorticosteroids in combination with cyclophosphamide [61] or rituximab [62] has made it possible to halt progressive organ damage and, thus, to curb disease activity. In individual cases, therapeutic successes have also been reported with imatinib [63], and more recently with the anti-IL-5 antibody mepolizumab [64] and the antibody benralizumab, which targets the α chain of the IL-5 receptor [65].