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Could human polyomaviruses cause grover disease?


DII small banner By Warren R. Heymann, MD
May 5, 2017


Grover Disease
Clinical images of a man with Grover disease. A, papulovesicular rash on the trunk evolving to crusts and keratotic erosions. B, Zoomed-in image. 
Credit: JAAD
My profound dermatologic experience in 1970 was the embarrassment I endured abruptly leaving Vincent Chiarello’s world history class at Martin Van Buren High School in Queens, New York. A horrific pustule violently ruptured during a lecture on King James — my submandibular scar persists (and obviously, so does the emotional scar). How was I to know that just a few miles away, in Floral Park, the private practitioner Ralph Wier Grover was simultaneously making dermatologic history by detailing the dermatosis that now bears his name?

I just read Dr. Grover’s original paper for the first time. It is a single-authored treatise confirming that the observations of a sole practitioner can have a profound influence on an entire discipline. The following is the abstract of the paper, “Transient Acantholytic Dermatosis” (1).
 
Six patients with an apparently unique, self-limited, primary acantholytic skin disease are described. The elementary lesions were pruritic, discrete, edematous papules or vesiculopapules which tended to appear first on the trunk, possibly as a Koebnerlike response to nonspecific irritation, such as ultraviolet light. The two youngest patients, aged 46 and 48, developed only localized manifestations which disappeared in a few weeks. The older patients, ranging from 56 to 74 years old, had disseminated eruptions which lasted several months. Although there was a strong histologic resemblance to Darier’s disease in three cases, and to Hailey-Hailey’s disease in the other three, clinical considerations seem to rule out both of these diagnoses. It is stressed that cytologic examination is most useful in recognizing the disease.
 
There are five classical histological presentations of Grover disease resembling Darier-White disease, pemphigus vulgaris, pemphigus foliaceus, Hailey-Hailey disease, or spongiotic dermatitis. The precise etiology of Grover disease is unknown. Most authorities consider it a syndrome with a strong relationship with exercise, heat, sunlight, and involvement of the eccrine apparatus in those confined to bed (2).

The tenth anniversary of Dr. Grover’s passing, May 25, 2008, is approaching (3). In honor of Dr. Grover, I would like to present a hypothesis on the etiology of this pruritic condition that affects so many.

Aside from the previously mentioned aggravating or precipitating conditions, it has become increasingly evident that immunologic aberrations may be at play. Grover disease has been observed in patients with solid and hematologic malignancies, organ transplantations, allogeneic hematopoietic stem cell transplantations (4), and the administration of ipiliumab (5).
 
Mammalian polyomaviruses establish persistent infections in healthy hosts and become pathogenic when the host becomes immunocompromised. There are at least 13 human polyomaviruses. Two of the skin-associated viruses, Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa–associated polyomavirus (TSPyV), have been associated with Merkel cell carcinoma and trichodysplasia spinulosa, respectively. MCPyV is the only polyomavirus known to cause cancer in humans, and TSPyV is the only human polyomavirus whose disease can be treated effectively, using topical cidofovir (6).

Ho et al detailed two patients, both immunosuppressed lung transplant recipients in their 70’s, with pruritic rashes, that histologically resembled “peacock plumage”, which were described as eosinophilic keratinocytes containing viral inclusions at different levels of the epidermis, and a stratum corneum with clusters of nucleated keratinocytes. The authors were able to confirm that human polyomavirus 7 was the culprit (7) Based on these findings, Nguyen et al screened biopsy specimens showing “peacock plumage” histology by polymerase chain reaction for HPyVs. Cases positive for HPyV6 or HPyV7 were then analyzed by immunohistochemistry, electron microscopy, immunofluorescence, quantitative polymerase chain reaction, and complete sequencing, including unbiased, next-generation sequencing. They identified 3 additional cases of HPyV6 or HPyV7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infected keratinocytes. High viral loads in lesional skin compared with normal-appearing skin and the identification of intact virions by both electron microscopy and next-generation sequencing supported a role for active viral infections in these skin diseases. The authors concluded that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a distinctive histologic pattern and described this entity as “HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses.” (8). Although clinically variable, the routine histology presented was strikingly reminiscent (to my eye) of the acantholytic dyskeratosis frequently exhibited in Grover disease.
 
UV radiation induces pro-inflammatory genes and causes immunosuppression by depleting the number and activity of the epidermal Langerhans cells (9). My hypothesis is that with age, known associations of Grover disease, especially ultraviolet light, cause subtle immunosuppression allowing the persistent HPyV6 or HPyV7 to proliferate and become pathogenic. Such viral proliferation could be the common denominator for the various cutaneous insults that result in the clinical lesions of Grover disease. To date, no such studies have been performed; in my opinion, they are worth doing. Grover disease adversely affects quality of life, may be persistent (despite the appellation “transient”), and can be difficult to treat. Wouldn’t it be wonderful to offer an antiviral agent such as cidofovir to ameliorate the disease? That would be the best way to honor Dr. Grover.

1. Grover RW. Transient acantholytic dermatosis. Arch Dermatol 1970; 101: 426-34.
2. Weaver J, Bergfeld. WF. Grover disease (transient acantholytic dermatosis). Arch Pathol Lab Med 2009; 133: 1490-4
3. Krivo JM, et al. In memoriam: Dr. Ralph Wier Grover. J Am Acad Dermatol 2010; 62: e3.
4. Lim PP, et al. Transient acantholytic dyskeratosis (Grover’s disease) after bone marrow transplantation. Australas J Dermatol 2016 June 30 [Epub ahead of print]
5. Uemura M, et al. A case report of Grover’s disease from immunotherapy – a skin toxicity induced by inhibition of CTLA-4 but not PD-1. J Immunother Cancer. 2016;4:55.
6. Imperiale MJ, Jiang M. Polyoma persistence. Annu Rev Virol 2016; 3: 517-32.
7. Ho J, et al. Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients. J Infect Dis 2015; 211: 1560-5.
8. Nguyen KD, et al. Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses. J Am Acad Dermatol 2017; 76: 932-40.
9. Bosch R, et al. Mechanisms of photoaging and cutaneous photocarcinogenesis, and photoprotective strategies with phytochemicals. Antioxidants (Basel) 2015; 26L 248-68.

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