Pruritic Papulopustular Eruptions and a Chronic Cough
A 34-year-old Indian American male presents with a 6-month history of pruritic papulopustular eruptions on his bilateral elbows, hands, and legs.
The patient has no significant past medical history except for chronic lower back pain with a partial laminectomy in 2008. Other surgeries include a right knee ACL reconstruction in 2002.
He denies a history of tobacco and illicit drug use, but does drink alcohol socially. He is a professional and has a heterosexual orientation. The patient’s family history includes a father with hypertension and hyperlipidemia, but is otherwise noncontributory.
The patient has a significant travel history. He is a physician who regularly travels internationally for medical mission trips and for pleasure. As a result, the patient is current on all his childhood and other immunizations including hepatitis A and B, tetanus, typhoid, yellow fever, and meningitis. His travels for the year prior to presentation include 1-month medical missions to Lesotho, Africa, and Belize and non-medical trips to Brazil (3 weeks) and St. Martin (1 week).
The patient’s most recent 1-month medical mission trip was to Manchay, Peru—a rural village in the Lambayeque province in February 2008. He states that the pruritic papulopustular eruptions began 1 week into his visit. He observed several of the local Peruvians presenting with extreme pruritis and similar eruptions. The eruptions start as papular 3 mm to 5 mm lesions, which are extremely pruritic and transform into vesicular papules with no associated purulence. When the lesions are unroofed, they form craters. The only causative association he can make is with the gnat-like flying black insects that infested the village.
Review of systems is non-contributory, however, the patient admits to a chronic, productive cough with no associated fever or chills that ailed him for 6 weeks after his return from Lesotho, Africa.
Physical exam is benign except for multiple, 1 mm to 2 mm pruritic papulopustular lesions on the extensor regions of his bilateral elbows and knees with scattered lesions over his arms and hands.
Diagnostic and Laboratory Findings
Laboratory testing shows a normal basic metabolic panel. The patient’s white blood cell count with differential is essentially within normal limits. Granulocytes, lymphocytes, and eosinophils are all normal with only a slight elevation in monocytes to 8.0%. Additional laboratory testing includes negative RPR, Lyme antibody, and HIV-1 and HIV-2 antibody tests.
What's Your Diagnosis?
(Answer and discussion on next page)
Eosinophilic folliculitis (EF) is an unusual chronic and relapsing dermatitis of unknown etiology first described in 1965. The first case, a Japanese woman, had recurrent episodes of pruritic follicular pustules on the face and back with a peripheral eosinophilia. Later reports of 3 further cases lead to naming the condition eosinophilic pustular folliculitis (EPF). Most of the early cases are seen in immunocompetent Japanese. Subsequent examples of EPF are also reported in other immunocompetent patient populations, however, most subsequent patients with EPF are immunosuppressed and positive for human immunodeficiency virus (HIV).1-4
Eosinophilic folliculitis is a noninfectious eosinophilic infiltration of hair follicles, though the lesion is not restricted to the hair follicle.1 EF may be seen in association with bacterial and fungal infection, drug reactions, and hematological disorders.2 There are 3 variants: classic eosinophilic pustular folliculitis (also called Ofuji’s disease), immunosuppression-associated EF, and infancy-associated EF. This skin disorder has been classified as an AIDS-defining illness, and in both children and adults, this disorder is viewed as a possible cutaneous sign of immunosuppression.1
EPF is a type of dermatosis characterized by recurrent clusters of extremely pruritic, follicular, sterile papules, and pustules. These lesions gradually extend peripherally and have a tendency for central healing. The eruptions occur mainly on the face, upper back, and extensor surfaces of the upper extremities and are often accompanied by peripheral blood eosinophilia. The histopathological features of this disease include a predominant infiltration by eosinophils in and around hair follicles with some degree of spongiosis.5
This case is an example of EPF in an immunocompetent patient and an example of unusual illnesses that can be seen in travel medicine.
Classic EPF can cause severe and intractable pruritus and is generally chronic and persistent. Most cases are reported from Japan and are not associated with any systemic disorder, except peripheral blood eosinophilia, present in 25% to 80% of patients.6 Several documented cases over the years illustrate that the disease affects anyone.7
Although the overwhelming majority of EPF cases are found in patients with HIV, the prevalence in the United States is unknown. EPF is not disabling or life-threatening, but the intense pruritis—seen in only half of the patients with the disease—may lead an inflicted patient to believe otherwise. Men are affected more frequently than women in all 3 variants of EPF with a male-to-female ratio of 5:1. EPF is most common among persons 20 to 40 years old.1,7,8
The clinical course is characterized by multiple cycles of exacerbations and remissions. The disease manifests as chronic and recurrent annular clusters of sterile follicular papules and pustules. The papules gradually become confluent, creating indurate polycyclic plaques with a healing center and spreading periphery. Individual clusters last for 7 to 10 days and ultimately fade away leaving residual hyperpigmentation and scaling, but tend to relapse every 3 to 4 weeks. The individual skin lesions usually heal spontaneously a few months to several years after onset and usually heal without scarring, but often with post-inflammatory hyperpigmentation.1,7
The distribution of EPF typically affects seborrheic skin areas such as the face (85% of cases), back, and extensor surface of the arms. Involvement of the trunk (59%) and the extremities, palms, and soles is also seen, despite the fact that follicles are not found in either palms or soles. Mild to moderate leukocytosis with eosinophilia is seen in up to 35% of patients.6,7,9
The pathogenesis of EPF is unknown, although immune processes are thought to play a key role. It is not known if eosinophils play a primary role or whether they are present as part of an allergic response to an unknown stimulus, and why they have a predilection for the infundibular region of the hair follicle.2 Regardless, causal connections with immunologic, infectious, and environmental factors have been postulated. In addition to HIV, reported infectious associations include Pseudomonas, dermatophyte infection, larva migrans, Pityrosporum infection, Demodex folliculorum and Demodex brevis mite infections, toxocariasis, Leptotrichia buccalis bacteria, retrovirus, and hepatitic C virus infection. Associated causal medications include carbamazepine, minocycline, allopurinol, timepidium bromide, and indeloxazine. In addition, EPF has been associated with various medical conditions, including lymphoma, leukemia, myelodysplastic syndrome, atopy, and polycythemia vera. EF may also develop following bone marrow transplantation.1,2,7,10-12
Whereas the clinical presentation may vary, the histological pattern is similar in all forms of EPF. There is a predominantly lymphocytic and eosinophilic folliculocentric infiltrate, sometimes with small numbers of macrophages and neutrophils. Spongiosis also occurs at the outer root sheath, greatest at the isthmus, and is accompanied by an eosinophilic infiltrate in the early stages. In later stages, a pustule forms in the follicular canal—from the subcorneal region to the entry point of the sebaceous gland.5,8,10
Histologically, the differential diagnoses for EPF include the various conditions classified under the eosinophilic dermatoses. Although there are usually distinguishing histologic features present, the importance of close clinicopathologic correlation cannot be overemphasized. Arthropod bite reactions often have a prominent eosinophilic component as part of the mixed inflammatory cellular dermal infiltrate. Epidermal spongiosis and dermal edema are often present as well.8 Other differential diagnosis for EPF include: acneiform eruptions, follicular eczema, bacterial, fungal, viral or dermatophytic folliculitis, pustular psoriasis, popular urticaria, graft-versus-host disease, subcorneal pustular dermatosis (Sneddon-Wilkinson disease), strongyloidiasis, and alopecia mucinosis.1,7,12
There is no consistently effective treatment nor have there been controlled trials of treatments of EPF. A wide range of medications is used to treat EPF. Topical corticosteroids are usually the first treatment option for all 3 types of EPF. The “gold standard” is ultraviolet therapy with UVB (6-9 treatments, cumulative dose: 243-1225 mJ) and sporalen plus UVA therapy. The limitation is that the effect is lost as soon as the treatment is discontinued. The utilization and efficacy of other therapies seem to depend on the variant of EPF. In classic EPF, the kind found most often in Japanese male adults, indomethacin is the first line treatment.9
The mechanism of action of corticosteroids in EPF is not fully understood, but 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. Additionally, a mild to moderate potency should be used in children. 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 at a dosage of 1 mg/kg per day.1,7,9
Indomethacin is usually recommended as the first choice of treatment in classic EPF because of the short time required to achieve a good result, usually within 1-2 weeks.6 Treatment dose is 75 mg/d and is usually combined with a topical corticosteroid.5 Indomethacin is the most effective treatment for HIV seronegative EPF patients in Japan.4,6 Research suggests that this cyclooxygenase inhibitor reduces the synthesis of eosinophil chemotactic factors and normalizes the dysregulated cytokine production seen in EPF.6,11 Although treatment is effective, indomethacin can induce peptic ulcers.6
Other options include itraconazole (100 mg to 400 mg/d), metronidazole (250 mg three times a day)4, doxicycline (100 mg/d for 21 days every month for 2 months),3 and permethrin 5% cream.10 Antihistamines are often incorporated into the treatment regimen because of the intense pruritus that often accompanies it. Cetirizine at a dosage of 20 mg/d to 40 mg/d and cyproheptadine at a dosage of 2 mg/d to 4 mg/d appear to be most effective. Ionizing radiation has shown efficacy in treating chronic EPF unresponsive to other treatment. In addition, transdermal nicotine patches have been reported to improve EPF.1,7,9
Topical tacrolimus is a new immunosuppressive agent successfully used to treat atopic dermatitis and several inflammatory skin diseases and is a viable treatment option for EPF. Reported cases show successful treatment of EPF with topical tacrolimus ointment (0.1%) twice daily for 2 weeks. Tacrolimus is a macrolide immunosuppressive agent that exerts its effect by inhibiting T-cell activation in a manner similar to that of cyclosporine. However, tacrolimus inhibits cytokines 10-fold to 100-fold more potently than cyclosporine. Tacrolimus also reportedly inhibits histamine release and cytokine production.3,13
Outcome of the Case
Multiple treatment modalities resulted in little improvement in the pruritis or the number of skin lesions. Initial treatment included topical steroids in combination with diphenhydranmine and loratidine, which aided in the reduction of the pruritis but did little to resolve the lesions. The patient also used multiple other topical medications including several applications of permethrin, clotrimazole, and mupirocin. Oral medications included trimethoprim/sulfamethoxazole for 10 days and 2 courses of prednisone tapered from a 60 mg dose over 15 days. With the oral steroids, the pruritis lost intensity and the lesions began to resolve but immediately reappeared at the termination of the steroids.
After multiple treatment failures, the patient had a 5 mm punch biopsy from the right extensor region of his arm. The biopsy showed eosinophilic spongiosis and associated EF with unusual features. The microscopic examination showed hyperkeratosis, parakeratosis, and loculated serum in the stratum corneum. The epidermis was acanthotic. A superficial and deep predominantly perivascular lymphplasmacytic inflammatory infiltrate admixed with scattered eosinophils was present in the dermis.
Dilated vascular channels were present in the tips of some dermal papillae. Increased fibrosis was present in the superficial dermis. Deeper levels showed mildly to moderately atypical keratinocytes in the lower epidermis. Some solar elastosis were present. Lymphocytes, neutrophils, and scattered eosinophils were present in a follicular lumen. PAS staining was positive for budding yeast forms compatible with Pityrosporum species in the stratum corneum. No unequivocal hyphal or speudohyphal fungal elements was identified.
Warthin-Starry silver staining was negative for unequivocal spirochete organisms. Mucicarmine staining was non-contributory. There are scattered eosinophils and lymphoid cells in the epidermis in association with spongiosis. Eosinophils was observed in follicular epithelium.
The pathologist noted that the presence of plasma cells in a biopsy from this site is unusual and raised the histiologic possibility of a connective tissue disorder, a plasma dyscrasia, Lyme disease, syphilis, and other disorders with plasma cells.
Treatment with indomethacin and tacrolimus ointment was considered in this patient. ■
1.Janniger C. Eosinophilic folliculitis. eMedicine Dermatology. 2008. Available at http://emedicine.medscape.com/article/217266-overview.
2.Fraser SJ, Benton EC, Roddie PH, et al. Eosinophilic folliculitis: an important differential diagnosis after allogeneic bone-marrow transplant. Clin Experiment Dermatol. 2009;34:369-371.
3.Brazzelli V, Barbagallo T, Prestinari F, et al. HIV seronegative eosinophilic pustular folliculitis successfully treated with doxicycline. J European Acad Dermatol Venereol. 2004;18:467-470.
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11.Gesierich A, Herzog S, Grunewald S, et al. Eosinophilic folliculitis in a Caucasian patient: association with toxocariasis? J Eur Acad Dermatol Venereol. 2006;20:1317-1321.
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