Patient Recovery from COVID-19 Infections: Follow-Up of Hair, Nail, and Cutaneous Manifestations.

BACKGROUND: COVID-19 is a pandemic disease worldwide. Although cutaneous manifestations may present in affected patients, there have been limited studies on the cutaneous findings and hair and nail abnormalities after discharge. OBJECTIVE: To establish the cutaneous manifestations, hair and scalp disorders, and nail abnormalities in patients who recovered from COVID-19 infections. METHODS: A retrospective chart review and telephone interviews were conducted to determine the cutaneous manifestations, hair and scalp disorders, and nail abnormalities of patients aged over 18 years who were diagnosed with COVID-19 infections at Siriraj Hospital, Bangkok, Thailand, between January and June 2020. RESULTS: Ninety-three patients with prior COVID-19 infections participated in the study. The COVID-19 severity had been mild for most (71%). Cutaneous manifestations were reported in 8 patients (8.6%), with the common skin conditions being maculopapular rash and urticaria. The onsets of the skin conditions were before admission (1%), during admission (4.3%), and after discharge (3.2%). Increased hair shedding was also reported in 22 patients (23.7%), with a female predominance. Three patients were affected during admission, while the others were affected after discharge. The patients with moderate, severe, and critical COVID-19 infections experienced significantly more hair shedding than those with asymptomatic and mild diseases. Only 2 patients with mild COVID-19 disease reported nail abnormalities (chromonychia and brittle nails). CONCLUSIONS: Cutaneous manifestations, hair disorders, and nail abnormalities can occur in patients with COVID-19 after their discharge from hospital. Patients should therefore be followed up in anticipation of dermatological problems.

Recent developments in trichodysplasia spinulosa disease.

Trichodysplasia Spinulosa (TS) is a rare proliferative skin disease that occurs primarily in immunocompromised patients, specifically organ transplant recipients. TS is characterized by uncontrolled inner root sheath cell proliferation and folliculocentric papular eruption that can progress to disfiguring leonine facies when left untreated. TS presents with distinct histological features including the presence of large eosinophilic, trichohyaline granules within hyperproliferating inner root sheath cells of the hair bulb. The discovery of the Trichodysplasia Spinulosa Polyomavirus (TSPyV) and recent studies highlighting the role of TSPyV tumor antigens in cell proliferation pathways have provided new insight into the mechanisms of TS development. In this review, we discuss the expansion of our understanding of TS, specifically over the past 5 years. We summarize novel cases of TS and recent developments in the mechanisms underlying TSPyV-mediated disease progression. We also evaluate advancements in diagnostic methods and treatment options. As the incidence of TS continues to rise, it is becoming critical for clinicians to understand the clinical features of TS and emerging research regarding pathogenesis and therapeutics for early treatment of this potentially disfiguring disease.

Viremia and viruria of trichodysplasia spinulosa-associated polyomavirus before the development of clinical disease in a kidney transplant recipient.

Trichodysplasia spinulosa (TS) is a rare disease associated with immunosuppression and induced by a polyomavirus denominated Tricodisplasia Polyomavirus (TSPyV). We report a case of TS 6 months after kidney transplantation in a 65 years-old woman under immunosuppression therapy with prednisone, mycophenolate and tacrolimus. The patient developed follicular papules on the face with a thickening of the skin and alopecia of the eyebrows, leading to distortion of the face and a leonine appearance characteristic of the disease. The skin biopsy confirmed the clinical diagnosis and the presence of TSPyV DNA in the skin was detected. Staining for SV40 was positive. Immunosuppression was changed: mycophenolate was withdrawn, tacrolimus reduced and everolimus added. Intravenous cidofovir and later on leflunomide were added. Although the literature has reported clinical success with topical cidofovir, we were unable to use it because this drug is not available. There was an improvement of skin lesions and on cosmetic appearance. The patient had three rejections (one clinically diagnosed and two other biopsy proven), progressed with renal failure and graft loss. Retrospective analysis of stored urine and blood samples detected TSPyV DNA in some of those samples two months before the TS clinical development. This case highlights the TSPyV detection in blood and urine samples before the development of skin lesions.

Detection of Beta-Human Papillomavirus in a Child With Polyomavirus-Associated Trichodysplasia Spinulosa.

Viral associated trichodysplasia spinulosa (VATS) is a rare cutaneous eruption characterized by folliculocentric papules, keratin spicules, and alopecia associated with trichodysplasia spinulosa-associated polyomavirus (TSPyV) infection. We report a case of a 6-year-old male child who presented with a generalized papular eruption during chemotherapy for acute lymphoblastic leukemia. The papules were tested for human papillomavirus (HPV) DNA by nested polymerase chain reaction (PCR) and TSPyV using PCR and gene sequencing studies. The lesions were positive for TSPyV by PCR combined with sequencing and showed high copy number with real-time PCR, and beta-papillomavirus was identified by PCR and sequencing. Immunohistochemistry revealed inner root sheath keratinocytes expressing nuclear HPV L1 capsid antigen. To our knowledge, this is the first case of concomitant productive HPV and TSPyV infection in a VATS-affected patient. The presence of HPV may be coincidental, however, further studies are needed to establish whether specific HPV genotypes influence the development of abnormal inner root sheath trichohyalin granules found in VATS.

Dysregulation of the MEK/ERK/MNK1 signalling cascade by middle T antigen of the trichoydsplasia spinulosa polyomavirus.

BACKGROUND: Trichodysplasia spinulosa (TS) is a disfiguring folliculocentric cutaneous disease caused by infection with the trichodysplasia spinulosa polyomavirus (TSPyV). The TSPyV genome contains splice variants encoding the middle tumour (mT) antigen, although the potential role for TSPyV mT antigen in disease development remains unknown. OBJECTIVE: The current study was designed to investigate the mechanistic properties of TSPyV mT antigen, which may further our understanding of TS pathogenesis and provide insight into potential therapies. METHODS: A lentiviral packaging system was used to create an inducible cell line expressing TSPyV mT antigen. Proteins were extracted, separated by SDS-PAGE and subjected to Western blot analysis. Co-immunoprecipitation experiments and mutational analyses were also performed to evaluate protein-protein interactions of mT antigen. RESULTS: We describe a novel mechanism of action for mT antigen that involves hyperactivation of MEK, ERK and MNK1. Our findings suggest that dysregulation of these key signalling molecules depends upon TSPyV mT antigen interaction with protein phosphatase 2A (PP2A) via intact Zn binding motifs. CONCLUSION: Given that PP2A interaction and MEK/ERK/MNK1 phosphorylation are associated with high levels of cell proliferation and inflammation, our findings provide new evidence that TSPyV mT antigen may contribute to the pro-proliferative conditions that lead to TS development.

Leflunomide for the treatment of trichodysplasia spinulosa in a liver transplant recipient.

Trichodysplasia spinulosa (TS) is a rare dermatologic complication associated with the immunosuppressive therapy used in solid organ transplantation. The distinctive clinical manifestation of this condition is spiny follicular papules on the face, ears, extremities, and trunk. Histopathologically, abnormally maturing hair follicles with hyperkeratotic material are noted. The condition is produced by the trichodysplasia spinulosa-associated polyomavirus. Treatment of this condition in the past has entailed a reduction in immunosuppression, topical agents such as cidofovir or retinoids, or oral valganciclovir. Herein, we report a case of generalized TS treated successfully with leflunomide.

Folliculocentric Herpes: A Clinicopathological Study of 28 Patients.

BACKGROUND: The cutaneous manifestations of herpes infection are primarily in the context of active infection and of the post-herpetic zosteriform eruption. The former manifests cytopathic alterations diagnostic of herpes. The latter includes lichen planus-like and granuloma annulare-like eruptions and lymphocytoma cutis. METHODS: We encountered skin biopsies from 28 patients whose acute or chronic herpetic or post-herpetic zosteriform lesions manifested folliculocentricity. The clinical appearance of the lesions was correlated with the histopathologic and immunohistochemical features of paraffin-embedded skin biopsies to determine the specific viral etiology. A history of underlying medical disease was noted if present. RESULTS: There were 16 men and 12 women with a folliculocentric eruption occurring after a known herpetic eruption or manifesting cytopathic changes and/or immunohistochemical findings compatible with herpes virus in lesional skin biopsies. Underlying immune dysregulatory states were present in most cases, namely, malignancy, anticonvulsant or antidepressant therapy, diabetes mellitus, psoriasis, Crohn disease, and other conditions. All biopsies demonstrated dense lymphohistiocytic infiltrates in or around hair follicles with variable necrosis, while active infections also showed cytopathic and/or immunohistochemical evidence of herpetic alterations, most commonly varicella zoster. Other features included interfollicular interface dermatitis, lymphocytic eccrine hidradenitis, neuritis, and folliculocentric vasculitis. CONCLUSIONS: Cutaneous herpetic eruptions can evoke a predominantly folliculocentric mononuclear cell reaction and vasculitis; there is an association with underlying endogenous and/or iatrogenic immune dysregulation. Most cases are secondary to reactivation of varicella zoster. The histomorphology suggests a role for cell-mediated immunity. Antigenic homology of an endogenous 72-kd heat shock protein in follicles with that of a herpetic heat shock protein, in concert with an intrafollicular proliferative response of γ-δ T lymphocytes, may explain the follicular localization and composition of the infiltrate.

Emerging differential roles of the pRb tumor suppressor in trichodysplasia spinulosa-associated polyomavirus and Merkel cell polyomavirus pathogeneses.

BACKGROUND: Merkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS) are two proliferative cutaneous diseases caused by the Merkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa-associated polyomavirus (TSPyV) respectively. Recently, studies have elucidated a key role of the small tumor (sT) antigen in the proliferative pathogenic mechanisms of MCPyV and likely TSPyV. While both sT antigens have demonstrated a capacity in regulating cellular pathways, it remains unknown whether MCPyV and TSPyV sT antigens contribute similarly or differentially to cell proliferation. OBJECTIVES: The present study aims to explore the proliferative potential of MCPyV and TSPyV sT antigens by investigating their regulatory effects on the retinoblastoma protein (pRb) tumor suppressor. STUDY DESIGN: Inducible cell lines expressing MCPyV sT or TSPyV sT were created using a lentiviral packaging system. Cellular proteins were extracted and subjected to SDS-PAGE followed by Western blot detection and densitometric analysis. RESULTS: Expression of TSPyV sT markedly enhanced the phosphorylation of pRb in Western blot experiments. In contrast, expression of MCPyV sT did not alter pRb phosphorylation under the same experimental conditions. Densitometric analysis revealed that TSPyV sT antigen expression nearly doubled the ratio of phosphorylated to total pRb (P<0.001, Student's T-test), while MCPyV sT antigen expression did not cause significant change in pRb phosphorylation status. CONCLUSION: Given that hyperphosphorylation of pRb is associated with dysregulation of the cell cycle, S-phase induction, and increased cell proliferation, our findings support an important role of TSPyV-mediated pRb deactivation in the development of TS. The observation that the pRb tumor suppressor is inactivated by TSPyV sT but not MCPyV sT provides further insights into the distinct pathobiological mechanisms of MCC and TS.

New findings about trichodysplasia spinulosa-associated polyomavirus (TSPyV)--novel qPCR detects TSPyV-DNA in blood samples.

A new real-time PCR assay for trichodysplasia spinulosa-associated polyomavirus (TSPyV) DNA detection was designed, and blood samples from kidney transplant recipients and healthy individuals were screened. TSPyV-DNA was not detected in blood from healthy individuals, but 26.8% of kidney recipients presented TSPyV-DNA. This is the first report of TSPyV viremia.

Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients.

Trichodysplasia spinulosa (TS) is a rare skin disease, caused by a specific polyomavirus, occurring in immunocompromised patients. The pathophysiological mechanisms of TS are not yet fully understood. By using polymerase chain reaction and skin biopsy immunostaining we report evidence, in a paediatric case, of follicular keratinocytes being the primary target of trichodysplasia spinulosa-associated polyomavirus.

Trichodysplasia Spinulosa in a 20-Month-Old Girl With a Good Response to Topical Cidofovir 1%.

Trichodysplasia spinulosa (TS) is a rare entity, characterized by a follicular digitate keratosis predominantly affecting the face and variable degrees of hair loss, most severely facial hair, that occurs in immunosuppressed individuals, and is considered to be a viral infection caused by a human polyomavirus, the "TS-associated polyomavirus." Histologically it is characterized by hair follicles with excessive inner root-sheath differentiation and intraepithelial viral inclusions. Correlation of these findings with clinical features is required for diagnosis. Treatment with antiviral agents appears to be the most effective. We report the occurrence of TS in a 20-month-old girl with multivisceral transplantation due to short-bowel syndrome secondary to intestinal atresia and gastroschisis. The patient was treated with cidofovir 1% cream, with significant improvement and without any adverse effects. We describe the youngest patient, to our knowledge, with TS.

Spiny Papules in an Immunosuppressed Child.

Trichodysplasia spinulosa is a rare folliculocentric polyomavirus infection observed in the setting of immunosuppression. We report a 7-year-old boy with pre-B-cell lymphoblastic leukemia who presented with folliculocentric spiny papules on the face. Histologic evaluation revealed hypertrophic bulbs, an expanded inner root sheath, and numerous brightly eosinophilic trichohyalin granules. We present this case to raise awareness of this rare but recognizable entity and to highlight the availability of appropriate diagnostic and therapeutic modalities.

Seroprevalence of trichodysplasia spinulosa-associated polyomavirus in Japan.

BACKGROUND: Trichodysplasia spinulosa-associated polyomavirus (TSV) was identified in, and shown to be the probable cause of, trichodysplasia spinulosa, a rare skin disease. To date, serological analyses have revealed that TSV infection is common among adults in the general population of Europe and Australia. However, there have been no reports of TSV in Asia. OBJECTIVE: To study the prevalence of TSV infection in Japan. STUDY DESIGN: TSV-VP1 expressed in a recombinant baculovirus expression system in an insect cell line, Tn5, self-assembled into virus-like particles. Overall, 1000 serum samples were examined by enzyme-linked immunosorbent assays using virus-like particles of TSV as antigen. Participants ranged in age from 0 to 94 years. RESULTS: Overall, 629 of 1000 serum samples (62.9%) were positive for anti-TSV antibodies. The seropositive rate increased with age and the seroprevalence of TSV significantly increased from 17.1% (25/146) in children aged from 0 to 4 years to 78.7% (472/600) in adults aged over 20 years (odds ratio = 0.056, 95% confidence interval = 0.035-0.900, P = 0.000, Chi-squared test). TSV seropositivity was not different between sera obtained in 1980 and 2012, and was not associated with sex. Competitive assay demonstrated that TSV antibodies did not cross-react with BK virus or Merkel cell polyomavirus. CONCLUSIONS: These results provide evidence that TSV circulates widely in the Japanese population, with primary exposure occurring mainly at early childhood, similar to that previously reported in other countries.