Hyperpigmentation Associated with the Use of Topical Cidofovir for Treatment of Trichodysplasia Spinulosa in an Immunosuppressed Adult: Case Report and Review of the Literature

Trichodysplasia spinulosa (TS) is a rare, infectious skin disease seen in severely immunocompromised hosts. This unusual disease is caused by infection with the polyoma virus, a small DNA virus in the polyomaviridae virus family. Multiple treatments exist including oral acitretin, valganciclovir, lefludomide, topical cidofovir, physical extraction, and modification of immunosuppressive medications. Clinically, TS is characterized by follicular papules, keratin spicules, and alopecia most classically in a midfacial distribution. Since its discovery in 2010, no standard of treatment has been established. Proper diagnosis and treatment is crucial to prevent painful and potentially disfiguring lesions.


INTRODUCTION
Trichodysplasia spinulosa (TS) is a rare, opportunistic infectious skin disease caused by the polyoma virus. Clinically, TS is characterized by follicular papules, keratin spicules, and alopecia most classically in a midfacial distribution. Since its discovery in 2010, no standard of treatment has been established, though use of oral acitretin, valganciclovir, lefludomide, topical cidofovir, physical extraction, and modification of immunosuppressive medications have been reported in the literature. We describe the case of a 52-year old female with a painful midfacial eruption and alopecia of the bilateral eyebrows ultimately diagnosed with TS and treated with topical cidofovir 3%. Though the TS eruption resolved, treatment resulted in hyperpigmentation of the affected area. Hyperpigmentation associated with cidofovir use has been reported in cases of molluscum contagiosum, however no such association has been described in the treatment of TS to our knowledge. Therefore, we report this case to highlight an underreported adverse effect of topical cidofovir in the setting of this rare disease.
Laboratory findings were notable for a white blood cell count of 3,200 (4,000-11,000), Hemoglobin of 10.5 (12-15.5 Physical exam was significant for multiple skin colored, erythematous, firm papules, with spicules on the mid-face. Concomitant eyebrow alopecia was also appreciated. The patient endorsed occasional pain but no pruritus, burning or other symptoms. The differential diagnosis included acne vulgaris, trichodysplasia spinulosa, lichen spinulosus, trichoepitheliomas, colloid milium, and milia. She was treated for presumed acne vulgaris with salicyclic acid chemical peels, adalapene gel, benzoyl peroxide wash, and ultimately oral isotretinoin; however this resulted in no significant improvement. A curettage biopsy subsequently demonstrated dilated, distended hair follicles within the dermis, without obvious shaft formation ( Figure 1). The hair shaft was effaced and lacked true hair formation. Follicles were filled with abnormal, dense keratinization and excessive inner root sheath production. No outer root sheath or hair bulb papillae were present (Figures 2  and 3). The constellation of findings was most consistent with a diagnosis of trichodysplasia spinulosa. The patient was treated with once daily compounded topical cidofovir 3% cream (with Versabase ® Cream). After 8 months of therapy, the facial eruption completely resolved, however residual hyperpigmentation of the affected area was noted at the one-year follow-up. Ingredients of the cream base were reviewed with the compounding pharmacy and included the common contact allergens methylchloroisothiazolinone, methylisothiazolinone, ethylhexyl stearate, cyclopentasiloxane, sorbitol, aloe barbadensis leaf juice, tocopheryl acetate, and disodium EDTA. In order to rule out contact dermatitis, the patient underwent patch testing with the topical cidofovir cream and specifically methylchloroisothiazolinone and methylisothiazolinone. However, the results were negative for hypersensitivity. The patient discontinued topical cidofovir cream, which resulted in mild improvement of hyperpigmentation but recurring TS lesions. She chose to resume topical cidofovir, and the hyperpigmentation persists at the16month follow-up.     1 This rare disease is known to affect immunocompromised hosts, most commonly after solid organ transplant. One recent review of 20 patients with TS found it to be associated with solid organ transplants in 13 cases and with leukemia or non-Hodgkin lymphoma in 7 cases.
TS is very rarely diagnosed in patients with HIV, perhaps because the degree of immunosuppression seen in patients treated with highly active antiretroviral therapy (HAART) is not sufficient for disease progression. Still, TSPyV was found to be elevated on the skin of men with known HIV compared to controls. 3 The current case is unique in that TS was diagnosed in an immunocompromised patient in the setting of both HIV infection and post-transplantation immunotherapy.
Clinically TS presents with follicular, erythematous, hyperkeratotic papules most often located on the central face, however it may also be found on the trunk and upper extremities. Skin thickening and alopecia have also been noted. 4 Histologically, TS is characterized by abnormal hair follicles often without a formed hair shaft. Excessive and disorganized inner root sheath cells, intraepithelial viral inclusions, and nucleated eosinophils containing excess trichohyaline can also be appreciated. 5 Management of TS is challenging, as this disease entity is newly described and rare. Treatment options include topical cidofovir, topical acitretin, oral leflunomide, and manual extraction of keratin spicules (table  I). This case highlights the safe use of topical cidofovir in a patient with a history of renal disease and transplant, though the oral antiviral counterpart is associated with nephrotoxicity. Furthermore, this case highlights hyperpigmentation as a rare adverse event associated with the use of topical cidofovir.
Post-inflammatory hyperpigmentation was reported after the use of topical cidofovir for the treatment of molluscum contagiosum in 6 out of 14 patients with HIV. 6 However, after a thorough review of the literature in Pubmed, this case is the first to our knowledge to highlight a similar outcome in the setting of polyoma virus infection. Though the patient presented here did not test positive for contact dermatitis related to the topical cidofovir, it should be noted that the preservative ingredients found in topical cidofovir base, mainly methylchloroisothiazolinone and methylisothiazolinone, have been increasingly associated with a delayed hypersensitivity reaction. 7 Dermatologists should be aware of this potentially common adverse event and counsel patients with TS accordingly.
TS is a rare disease that affects immunosuppressed individuals. Topical cidofovir appears to be the most commonly used treatment (Table I). However, this unique case highlights a new and unreported adverse effect of hyperpigmentation in the setting of TS. Dermatologists should be aware of this potential consequence and counsel patients appropriately. Minimal improvement of TS lesions after use of 20mg acitretin daily and tretinoin 0.05% daily, in a patient who ultimately improved due to recovered immune function. 12 Limited evidence of efficacy.

Oral Leflunomide
Tyrosine kinase inhibitor, which inhibits replication of DNA viruses.
Modification of immunosuppressive medications and leflunomide 100 mg daily orally for 5 days, followed by 40 mg daily for 1 month resulted in resolutions of lesions after 3 months. 13 None reported.

Oral Valganciclovir
Gancylcovir competitively inhibits dGTP incorporated in viral DNA, thereby inhibiting viral replication.
Successful resolution of TS lesions in a case report with the use of 900mg valganciclovir BID. 14 None reported.

Manual Extraction
Physical removal of facial TS papules. Successful resolution in a child after 2 months of repeated manual extraction. 15 Pain associated with manual extraction.