Eosinophilic Folliculitis

Eosinophilic folliculitis (EF) is a recurrent skin disorder of unknown etiology. In 1965, Ise and Ofuji reported a case of recurrent follicular pustules and eosinophilia in a Japanese woman.[1] Five years later, and after 3 additional cases, Ofuji named this skin condition eosinophilic pustular folliculitis (EPF).[2] Orfanos and Sterry argued that the name sterile eosinophilic pustulosis might be more appropriate because this lesion is not restricted to the hair follicle. Other names have also been proposed (eg, classic form of eosinophilic folliculitis, Ofuji disease, eosinophilic pustular dermatosis). Over the past 2 decades, the spectrum of eosinophilic folliculitis has expanded to pediatric populations, transplant recipients, and persons with HIV and hematopoietic disorders.

Eosinophilic folliculitis is a noninfectious eosinophilic infiltration of hair follicles. The 3 variants of eosinophilic folliculitis include classic eosinophilic pustular folliculitis, immunosuppression-associated eosinophilic folliculitis (mostly HIV-related), and infancy-associated eosinophilic folliculitis.[3]

Eosinophilic folliculitis has been classified as an AIDS-defining illness. In both children and adults, eosinophilic pustular folliculitis should be viewed as a possible cutaneous sign of immunosuppression. However, eosinophilic folliculitis may also develop in immunocompetent persons.

Eosinophilic pustular folliculitis in a patient infected with HIV. Note acneiform hyperpigmented papules. Photograph courtesy of Sarah A. Myers, MD.

Although the exact etiology of eosinophilic folliculitis remains obscure, studies have favored an autoimmune process directed against sebocytes or some component of sebum. Markers of acute inflammatory activation of the epithelia, such as ICAM-1 and MAC 387, are strongly positive in sebocytes of eosinophilic folliculitis lesions but only weakly reactive in the follicular epithelium. Antibody formation and the creation of immune complexes are believed to directly or indirectly mediate clinical manifestations. Patients with eosinophilic folliculitis create antibodies to the intercellular substance of the lower epidermis and the outer root sheath of the hair follicle. An abnormal Th2-type immune response to a follicular antigen, such as caused by Demodex species, may be responsible for HIV-associated eosinophilic folliculitis.

Frequency

United States

The prevalence of eosinophilic folliculitis is unknown.

International

The classic form is most closely linked with persons of Japanese descent.[4]

Mortality/Morbidity

Eosinophilic folliculitis is not disabling or life-threatening, but it may be intensely pruritic.

Race

Eosinophilic folliculitis is more common among Asian persons but also occurs among persons of Hispanic descent and in whites and blacks.

Sex

The male-to-female ratio of eosinophilic folliculitis is 5:1 in all 3 variants.

Classic type eosinophilic folliculitis was found to have no sexual predilection.[5]

HIV-associated eosinophilic folliculitis is more common among homosexual or bisexual men.

Age

Eosinophilic folliculitis is most common among persons aged 20-40 years.

In the pediatric population, eosinophilic folliculitis typically affects patients aged 5-10 months, although neonatal cases have been reported. A newborn was described with it.[6]

Eosinophilic folliculitis is a benign dermatologic disease; however, eosinophilic folliculitis is associated with advanced AIDS, and patients with HIV infection are at an increased risk of developing opportunistic infections.

Patients with eosinophilic folliculitis develop recurrent crops of sterile pustules and papules.

Pruritus develops in half of the patients, in some cases with considerable intensity.[7]

The clinical course of eosinophilic folliculitis is characterized by multiple cycles of exacerbations and remissions.

The individual skin lesions usually heal spontaneously a few months to several years after onset.

Eosinophilic folliculitis can become severe and persistent in certain populations (eg, persons infected with HIV) and may develop after mini-allogeneic bone marrow transplantation.[8]

Eosinophilic folliculitis typically appears as an area of erythematous papules and pustules. These involve the face in most (85%) affected patients. Occasionally, the papules do not evolve into macroscopic pustules.[9]

Eosinophilic pustular folliculitis in a patient infected with HIV. Note acneiform hyperpigmented papules. Photograph courtesy of Sarah A. Myers, MD.

Other locations include the back and the extensor surface of the upper extremities.

Eosinophilic pustular folliculitis in a patient who is HIV-positive. Note follicular-based excoriated papules and pustules on the trunk. Photograph courtesy of Sarah A. Myers, MD.

The papules gradually become confluent, creating indurate polycyclic plaques with a healing center and spreading periphery. Sometimes the plaques may be studded with papules and sterile pustules.[10] They ultimately fade away, leaving residual hyperpigmentation and scaling.

Atypical presentations or nonclassic forms of eosinophilic folliculitis occur in certain populations. Infantile eosinophilic folliculitis is characterized by erythematous papulopustules on the scalp as the primary area of involvement. Patients with HIV-associated eosinophilic folliculitis present with widespread urticarial lesions or large erythematous plaques with excoriations.

Involvement of mucosa and the palms and soles is rare.[11]

Although production of cytokines and chemotactic factors and expression of intercellular adhesion molecules are evidence of activation of the follicular sebaceous unit, the stimuli that provoke these changes are unknown. The cause of classic eosinophilic pustular folliculitis is unknown, although immune processes almost certainly play a key role in its pathogenesis.

Eosinophilic folliculitis may be associated with HIV infection, various drugs, and some lymphomas; it may be considered a nonspecific dermatopathologic pattern in such settings.[12] Drugs that have been associated with eosinophilic folliculitis are carbamazepine, allopurinol with or without timedium bromide, foscarnet, and various chemotherapeutic agents.[13, 14, 15, 16, 17, 18]

Many observations suggest a role for immunologic, infectious, and environmental factors.

Brenner et al described 3 cases of eosinophilic folliculitis associated with Pseudomonas infection of the hair follicles; the lesions improved with antipseudomonal treatment but recurred upon cessation of therapy.[19]

Other investigators have reported infectious associations, including dermatophyte infection, as well as infections due to larva migrans, Pityrosporum infection, retrovirus,[20] and hepatitis C virus infection.[21]

A linkage with pregnancy has been observed.[22]

In addition, eosinophilic folliculitis has been associated with various medical conditions, including lymphoma, Sézary syndrome,[23] leukemia,[24]  myelodysplastic syndrome, atopy, cutaneous angiosarcoma, and polycythemia vera.[25, 26, 27, 28, 29]

Eosinophilic folliculitis may also develop following bone marrow and solid organ transplantation.[30, 31] It may be considered a reaction related to immune dysregulation.

Eosinophilic folliculitis associated with wearing protective gear during the COVID-19 pandemic has been described[32] .

Eosinophilic folliculitis is a cutaneous disease without important sequelae. The only residual expression of the disease is cutaneous hyperpigmentation and scaling.

In patients with eosinophilic folliculitis, a CBC count reveals leukocytosis and eosinophilia.

Immunoelectrophoresis reveals elevated levels of immunoglobulin E (IgE), low levels of immunoglobulin G3 (IgG3), and low levels of immunoglobulin A (IgA) in pediatric eosinophilic folliculitis.

Culture of skin lesion reveals no consistent bacterial or fungal growth.

The CD4 count is usually less than 250-300 cells/µL in patients infected with HIV who have eosinophilic folliculitis.

A biopsy specimen is often necessary.[38]  Obtaining 2 punch biopsy specimens, to allow for both vertical and transverse sectioning, has been proposed to increase the sensitivity of finding the characteristic features of eosinophilic folliculitis.[39] The infundibulum of the hair follicle manifests eosinophilic spongiosis and pustulosis. The infiltrate often extends to the adjacent sebaceous gland. Although most follicles are preserved, some follicular walls are destroyed by the inflammatory infiltrate. The infiltrate is mainly composed of eosinophils with variable numbers of neutrophils and mononuclear cells. It also manifests a moderately dense, perivascular, and perifollicular inflammatory infiltrate comprised of eosinophils, lymphocytes (mainly CD4+), and macrophages. HIV-associated eosinophilic folliculitis has a more intense perivascular and diffuse inflammatory infiltration compared with that of the HIV-related pruritic papular eruption.[40]

Follicular mucinosis may be seen in lesions of eosinophilic folliculitis. Special stains are negative for micro-organisms. The lesions of the palms and soles have subcorneal and intraepidermal pustules, accompanied by a variable dermal inflammatory infiltrate. Basophils in cutaneous infiltrates of this disorder have been noted.[41]  

Eosinophilic folliculitis (low-power). Note eosinophilic spongiosis, particularly involving the infundibular region of the hair follicle.

Eosinophilic folliculitis (high-power). In addition to the abundant eosinophils, note the variable numbers of neutrophils and mononuclear cells.

Numerous topical and systemic therapies are available for eosinophilic folliculitis. Treatment modalities are chosen based on disease severity, patient preference (including cost and convenience), and response. Highly active antiretroviral therapy along with isotretinoin therapy is beneficial for eosinophilic folliculitis in the setting of HIV disease.[42] A new isotretinoin-loaded invasomal gel may be particularly effective.[43] Eosinophilic folliculitis may also respond well to systemic indomethacin,[44] which is considered first-line therapy in Japanese patients, in whom it has been found to be particularly effective among women.[4] A number of therapeutic options are delineated below. There are no generally accepted treatment protocols.[45, 46]

Topical corticosteroids are the mainstay of treatment for eosinophilic folliculitis. The mechanism of action of corticosteroids in eosinophilic folliculitis is not fully understood; the anti-inflammatory and immunosuppressive properties of these agents may contribute to their effect.

The potency of the steroid prescribed depends on the location of the skin lesions. In the scalp, potent steroids in alcohol solution, such as fluocinonide 0.05%, are frequently indicated. On the face and other sensitive body sites, a low-potency cream, such as hydrocortisone 1%, may suffice.

The typical regimen consists of twice-daily application of topical corticosteroids. This decreases the inflammation and plaques in most patients. Skin atrophy due to topical corticosteroid use is usually not a problem unless the medication is continuously applied after the skin has normalized. Severe flares may be treated with short courses of oral prednisone.

Fukamachi et al evaluated the therapeutic effectiveness of various treatments for eosinophilic pustular folliculitis in 20 patients.[47] Oral cyclosporine was markedly effective in all 11 patients treated with the drug, and topical tacrolimus ointment alleviated eosinophilic pustular folliculitis in 3 of 7 of the study participants. In addition to indomethacin or other oral nonsteroidal anti-inflammatory drugs (NSAIDs), oral cyclosporine and topical tacrolimus appeared to be beneficial in patients resistant to previous treatments. Others also recommend cyclosporine.[48]

Topical tacrolimus is a good option for both eosinophilic pustulosis of infancy and adult cases.[49, 50] Topical tacrolimus ointment 0.03% may produce rapid clearance in infants. Indomethacin is another option for refractory infantile eosinophilic pustular folliculitis.[51]

Retinoids, such as isotretinoin, inhibit sebaceous gland function and keratinization. Clinical improvement occurs in association with a reduction in sebum secretion. This effect is temporary and is related to the dose and duration of treatment. Monitoring for hypertriglyceridemia and hepatotoxicity is required. Common adverse effects include cheilitis and alopecia. Systemic retinoid therapy is teratogenic; it is indicated only in patients who have no reproductive potential. Alternatives include indomethacin and dapsone.

Ishiguro reported treatment outcomes of 20 patients with Ofuji disease, or classic eosinophilic pustular folliculitis. Eleven of the 20 patients were treated with oral indomethacin, with 8 and 3 of those patients showing complete and partial responses, respectively. In contrast, 12 of the 20 patients had previously been treated with topical steroids. Seven, 2, and 3 of the patients showed partial response, no response, and unknown responses, respectively; no complete responses were seen. In disease unresponsive to topical steroids and other treatments, oral indomethacin at doses of 50-75 mg/day in adults, if tolerated, may yield the highest complete response rate.[52]

In patients infected with HIV, treat mild eosinophilic folliculitis with topical steroids and oral antihistaminics. Treat moderate disease with oral itraconazole, isotretinoin, or phototherapy. Treat severe eosinophilic folliculitis with isotretinoin therapy for several months.

Potential treatments include oxyphenbutazone, colchicine, minocycline, oral metronidazole,[53] acitretin, cyclosporine A, UV-B therapy,[54, 55] interferon alfa-2b, tacrolimus,[56, 57, 58] doxycycline,[59] and radiation therapy.[60]

Cetirizine has shown benefit in the treatment of infantile eosinophilic folliculitis, but the condition recurred after therapy was stopped.[61]

Eosinophilic folliculitis associated with immune reconstitution inflammatory syndrome has been treated with thalidomide.[62]

Consider referral to a dermatologist in the following settings:

• If the diagnosis of eosinophilic folliculitis needs to be confirmed

• If the response to treatment is inadequate

• If the primary care physician is not familiar with the recommended treatment modality

• If the patient has widespread or severe eosinophilic folliculitis

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.[63]

Class Summary

These agents have both anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Prednisone

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage.

Class Summary

These agents decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. They modulate keratinocyte differentiation. They also reduce the risk of skin cancer in patients who have undergone renal transplant.

Isotretinoin (Amnesteem, Claravis, Sotret)

Retinoid acid derivative reduces size of sebaceous gland and decreases sebum production. Also regulates cell differentiation and proliferation.

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. The mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also exist (eg, inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, various cell-membrane functions).

Indomethacin (Indocin)

Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation; inhibits prostaglandin synthesis.

Class Summary

These agents may improve the clinical stage of the disease.

Dapsone

Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, thus inhibiting bacterial growth.

Class Summary

Treatment with oral cyclosporine might successfully control eosinophilic pustular folliculitis refractory to indomethacin. Oral cyclosporine has been shown to be markedly effective in patients treated with the drug, and topical tacrolimus ointment alleviated eosinophilic pustular folliculitis. Oral cyclosporine and topical tacrolimus may be beneficial in patients resistant to previous treatments. Others also recommend cyclosporine.

Topical tacrolimus is a good option for both eosinophilic pustulosis of infancy and adult cases. Topical tacrolimus ointment 0.03% may produce rapid clearance in infants.

A 13-year old girl with eosinophilic pustular folliculitis was treated with benralizumab, an antibody medication directed against the alpha-chain of the interleukin-5 receptor.[64]

Cyclosporine (Gengraf, Neoral, Sandimmune)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions. Suppresses mRNA expression of Th2 cytokines (interleukins 4 and 13) in peripheral blood mononuclear cells.

Pimecrolimus cream (Elidel)

Pimecrolimus cream is used for short-term treatment or for intermittent, long-term treatment in unresponsive or intolerant cases. It is available in a 1% cream.

This was the first nonsteroid cream approved in the United States for mild to moderate atopic dermatitis. It is derived from ascomycin, a natural substance produced by the fungus Streptomyces hygroscopicus var. ascomyceticus. Pimecrolimus cream selectively inhibits the production and release of inflammatory cytokines from activated T cells by binding to cytosolic immunophilin receptor macrophilin-12. The resulting complex inhibits phosphatase calcineurin, thus blocking T-cell activation and cytokine release. Cutaneous atrophy was not observed in clinical trials, a potential advantage over topical corticosteroids. Pimecrolimus cream is indicated only after other treatment options have failed.

Class Summary

Biologics may have a role, as a patient with eosinophilic pustular folliculitis was successfully treated with adalimumab.