Vascular cutaneous manifestations of COVID-19 and RNA viral pathogens: a systematic review.

BACKGROUND: COVID-19, the widely recognized and highly contagious respiratory tract infection, has had a substantial impact on the field of dermatology since its emergence in 2019. SARS-CoV-2, the causative virus of COVID-19, is classified as an RNA virus. Various skin-related symptoms have been reported in patients with COVID-19, most notably the distinctive purple-red acral rash resembling chilblain lesions, commonly referred to as 'COVID toe'; similarly, skin-related symptoms have been observed in connection with other RNA viruses. OBJECTIVES: To explore the relationship between RNA viruses and their associated vascular cutaneous manifestations vs. those observed in patients infected with SARS-CoV-2. METHODS: A systematic literature review was conducted using PubMed and medical subject heading terms related to RNA viruses and related skin manifestations. RESULTS: In total, 3994 patients diagnosed with COVID-19 presenting with skin rashes were included. Chilblain-like lesions were most frequently observed (30.2%), followed by erythematous maculopapular/morbilliform rashes (9.1%) and urticarial rashes (4.7%). Of 8362 patients diagnosed with RNA viruses, more than half of the skin findings reported were erythematous/maculopapular/morbilliform rashes (52.3%), followed by unspecified (11.3%) and purpuric rashes (10.6%). CONCLUSIONS: When comparing RNA viral infections with COVID-19 infection, we observed similarities in the reported skin manifestations and their presumed pathways, with many implicated in the proinflammatory response. Owing to the wide range of cutaneous symptoms associated with RNA viruses and our currently limited understanding of the underlying mechanisms, additional research is warranted to investigate the pathology behind viral-induced skin lesions.

Chilblain-Like Eruption Unveiling Cutaneous Aleukemic Relapse of Acute Myeloid Leukemia.

ABSTRACT: Leukemia cutis corresponds to skin infiltration by malignant hematopoietic cells. It is most commonly reported in acute myeloid leukemia, particularly in subtypes with a monocytic component. Its clinical manifestations are extremely variable, and histopathologic diagnosis of cutaneous leukemic infiltrates may be challenging. We report the first case of cutaneous, that is, extramedullary, aleukemic relapse of acute myeloid leukemia within an unusual chilblain-like eruption that imposed a challenging clinical and histopathologic diagnosis. Primary chilblains are uncommon in the elderly, and a systemic underlying cause should be thoroughly investigated. In patients presenting with atypical chilblains (ie, persistent chilblains developing even without exposure to cold temperatures and/or refractory to therapy) and with a history of hematologic disorders such as leukemias, histopathologic examination is crucial to identify leukemic or aleukemic phases of relapse of underlying leukemia and initiate timely treatment.

Vincristine-Induced Acrocyanosis and Erythema Pernio.

INTRODUCTION: Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy. CASE DESCRIPTION: A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient's oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient's symptoms and the appearance of his feet had markedly improved. DISCUSSION: Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient's history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.

Chilblain-Like Lesions (CLL) Coinciding With the SARS-CoV-2 Pandemic in Children: A Systematic Review.

Chilblain-like lesions (CLL) coinciding with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have been described in the literature. Available reviews of the literature suggest that CLL are associated with younger age, an equal sex ratio, negative testing for SARS-CoV-2, and mild to no extracutaneous manifestations (ECM) associated with COVID-19 infection. This systematic review aims to provide a summary of reports of CLL associated with the early SARS-CoV-2 pandemic in children to clarify the prevalence, clinical characteristics, and resolution outcomes of these skin findings. Sixty-nine studies, published between May 2020 and January 2022, met inclusion criteria and were summarized in this review, representing 1,119 cases of CLL. Available data showed a slight male predominance (591/1002, 59%). Mean age was 13 years, ranging from 0 to 18 years. Most cases had no ECM (682/978, 70%). Overall, 70/507 (14%) of patients tested positive for COVID-19 using PCR and/or serology. In the majority the clinical course was benign with 355/415 (86%) of cases resolving, and 97/269 (36%) resolving without any treatment. This comprehensive summary of pediatric CLL suggests these lesions are rarely associated with COVID-19 symptoms or test positivity.

Cilostazol as a Treatment for COVID Toes: A Case Report.

During the Coronavirus Disease 2019 (COVID-19) pandemic, skin lesions resembling those seen in pernio (chilblains) have been observed in patients with COVID-19 infection. The term "COVID toes" has been used when there is toe involvement. We describe the case of a fully vaccinated, 56-year-old woman with no prior diagnosis of COVID-19 who developed pernio-like lesions many months after being vaccinated. Her skin lesions resolved after treatment with cilostazol, suggesting that this medication may be a viable treatment for pernio in the setting of COVID-19 infection.

Chilblain-like lesions coinciding with the SARS-CoV-2 pandemic.

Chilblain-like lesions (CLL) coinciding with SARS-CoV-2 infection have been described. Previous systematic reviews suggest CLL are associated with younger age, an equal sex ratio, negative testing for SARS-CoV-2, and mild to no extracutaneous symptoms. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines on CLL coinciding with SARS-CoV-2 to clarify the demographic characteristics, clinical features, and resolution outcomes of these skin findings. One hundred twenty-eight studies, published between March 2020 and January 2022, met inclusion criteria and were summarized in this review, representing 4,982 cases of CLL. Available data showed a slight female predominance (55%, n = 2,471 of 4,472). The mean age was 25 years, ranging from 0 to 95 years. Most cases were not associated with extracutaneous signs and symptoms (63%, n = 1,649 of 2,636). Overall, 19% (n = 347 of 1,838) of patients tested positive for SARS-CoV-2 using polymerase chain reaction, serology, or tissue biopsy. Clinical course was generally benign with 80% (n = 979 of 1,224) of cases resolving and 47% (n = 204 of 432) resolving without receiving treatment. This review provides a comprehensive summary of CLL associated with SARS-CoV-2. CLL occurred at a mean age of 25 years with a slight female predominance. The majority had negative COVID-19 testing, no extracutaneous signs and symptoms, and resolution without recurrence.

Chilblains observed during the COVID-19 pandemic cannot be distinguished from classic, cold-related chilblains

Background: Type 1 interferon (IFN-I) response induced by SARS-CoV-2 has been hypothesized to explain the association between chilblain lesions (CL) and SARS-CoV-2 infection. Objective: To explore direct cytopathogenicity of SARS-CoV-2 in CL and to focus on IFN-I expression in patients with chilblains. Materials & Methods: A monocentric cohort of 43 patients presenting with CL from April 2020 to May 2021 were included. During this period, all CL were, a priori, considered to be SARS-CoV-2-related. RT-qPCR on nasopharyngeal swabs and measurements of anti-SARS-CoV-2 antibodies were performed. Anti-SARS-CoV-2 immunostainings as well as SARS-CoV-2 RT-qPCR were performed on biopsy specimens of CL and controls. Expression of MX1 and IRF7 was analysed on patients' biopsy specimens and/or PBMC and compared with controls and/or chilblains observed before the pandemic. Serum IFN-α was also measured. Results: RT-qPCR was negative in all patients and serological tests were positive in 11 patients. Immunostaining targeting viral proteins confirmed the lack of specificity. SARS-CoV-2 RNA remained undetected in all CL specimens. MX1 immunostaining was positive in CL and in pre-pandemic chilblains compared to controls. MX1 and IRF7 expression was significantly increased in CL specimens but not in PBMC. Serum IFN-α was undetected in CL patients. Conclusion: CL observed during the pandemic do not appear to be directly related to SARS-CoV-2 infection, either based on viral cytopathogenicity or high IFN-I response induced by the virus.

RNAscope in situ hybridization and RT-PCR for detection of SARS-CoV-2 in chilblain-like lesions: A clinical, laboratory and histopathological study.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, an increasing number of chilblain-like lesions (ChLL) have been increasingly reported worldwide. To date, the causal link between ChLL and SARS-CoV-2 infection has not been unequivocally established. METHODS: In this case series, we present demographic, clinical, laboratory, and histopathological information regarding 27 young patients with a clinical diagnosis of ChLL who referred to the Dermatology Unit of Papa Giovanni XXIII Hospital, Bergamo, Italy, from 1 April 2020 to 1 June 2020. RESULTS: The mean age was 14.2 years, and 21 patients (78%) experienced mild systemic symptoms a median of 28 days before the onset of cutaneous lesions. ChLL mostly involved the feet (20 patients - 74%). Among acral lesions, we identified three different clinical patterns: (i) chilblains in 20 patients (74%); (ii) fixed erythematous macules in 4 children (15%); (iii) erythrocyanosis in 3 female patients (11%). Blood examinations and viral serologies, including parvovirus B19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and coxsackievirus were normal in all. Three patients (11%) underwent nasopharyngeal swab for RT-PCR for SARS-CoV-2 showing only 1 positive. Histopathological examinations of 7 skin biopsies confirmed the clinical diagnosis of chilblains; vessel thrombi were observed only in 1 case. Our findings failed to demonstrate the direct presence of SARS-CoV-2 RNA in skin biopsies, both with real-time polymerase chain reaction (RT-PCR) and RNAscope in situ hybridization (ISH). LIMITATIONS: Limited number of cases, unavailability of laboratory confirmation of COVID-19 in all patients, potential methodological weakness, and latency of skin biopsies in comparison to cutaneous lesions onset. CONCLUSIONS: These observations may support the hypothesis of an inflammatory pathogenesis rather than the presence of peripheral viral particles. Although, we could not exclude an early phase of viral endothelial damage followed by an IFN-I or complement-mediated inflammatory phase. Further observations on a large number of patients are needed to confirm this hypothesis.

Chilblain or perniosis-like skin lesions in children during the COVID-19 pandemic: A systematic review of articles.

COVID toes or chilblain-like skin lesions represent a widespread and specific skin presentation mostly in the feet that may be attributed to COVID-19 infection. They may last for several months. We conducted this study to investigate chilblain-like lesions in children during the COVID-19 pandemic, any predisposition, location, clinical course, and prognosis. We searched Google Scholar, Scopus, and Medline (PubMed) databases using the following keywords: "Coronavirus" OR "COVID-19" AND "Chilblains" OR "Pernio" OR "Perniosis" OR "Children" OR "Cutaneous" OR "skin." The inclusion criteria were: (a) Studies that described the specific vascular skin lesion. (b) Studies that included patients aged >1 month till 18 years. (c) Case reports, case series, retrospective or prospective cohort studies, case-control studies. A total of 28 articles were included. The total number of children with chiblain-like lesions (CLL) was 433. The mean age of children presenting CLL during the COVID-19 pandemic was estimated as 12.58 ± 2.15. Of note, 53.6% of them were male. The nasopharyngeal SARS-CoV-2 RT-PCR test and anti-SARS-CoV-2 antibodies were mostly negative for the virus. In conclusion, it is crucial to be familiar with various presentations of COVID-19 infection and their clinical significance to approach the earliest diagnosis, immediate treatment, estimate the prognosis, and finally isolate the patients to prevent spreading. Chilblain-like lesions as a possible cutaneous presentation of COVID-19 in children may last several months with the indolent course.

A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review.

BACKGROUND: The abundance of publications of COVID-19-induced chilblains has resulted in a confusing situation. METHODS: This is a prospective single-institution study from 15 March to 13 May 2020. Thirty-two patients received PCR nasopharyngeal swabs. Of these, 28 patients had a thoracic CT-scan, 31 patients had blood and urine examinations, 24 patients had skin biopsies including immunohistochemical and direct immunofluorescence studies, and four patients had electron microscopy. RESULTS: COVID-19-induced chilblains are clinically and histopathologically identical to chilblains from other causes. Although intravascular thrombi are sometimes observed, no patient had a systemic coagulopathy or severe clinical course. The exhaustive clinical, radiological, and laboratory work-up in this study ruled-out other primary and secondary causes. Electron microscopy revealed rare, probable viral particles whose core and spikes measured from 120 to 133 nm within endothelium and eccrine glands in two cases. CONCLUSION: This study provides further clinicopathologic evidence of COVID-19-related chilblains. Negative PCR and antibody tests do not rule-out infection. Chilblains represent a good prognosis, occurring later in the disease course. No systemic coagulopathy was identified in any patient. Patients presenting with acral lesions should be isolated, and chilblains should be distinguished from thrombotic lesions (livedo racemosa, retiform purpura, or ischemic acral necrosis).

Long-term Outcome of Chilblains Associated with SARS-CoV-2.

Numerous cases of chilblains have been observed in the course if the COVID-19 pandemic. The aims of this study were to provide comprehensive follow-up data for patients reporting chilblains, and to determine the risk factors for incomplete recovery. Patients referred to 5 hospitals in France between March and May 2020 for chilblains were surveyed on December 2020. A teleconsultation was offered. Among 82 patients reporting chilblains, 27 (33%) reported complete recovery, 33 (40%) had recurrences of chilblains after their hands and feet had returned to normal, and 22 (27%) developed persistent acral manifestations, mostly acrocyanosis, with or without further recurrences of chilblains. Most recurrences of chilblains occurred during the following autumn and winter. A past history of chilblains was not associated with recurrences or persistent acral manifestations. Women had a significantly higher risk of developing recurrences or persistent acral manifestations (odds ratio 1.30; 95% confidence interval 1.06-1.59). In conclusion, two-thirds of patients reporting chilblains at the start of the COVID-19 pandemic experienced persistent or recurrent acral manifestations after a 10-month follow-up.

Prognosis of rash and chilblain-like lesions among outpatients with COVID-19: a large cohort study.

In a large regional observational cohort study of adult (≥ 18 years), outpatients with COVID-19, prevalence, characteristics, and outcome of patients with rash and/or chilblain-like lesions (CLL), compared with population without cutaneous features, were studied. In total, 28,957 outpatients were included; the prevalence of rash and CCL were 9.5% and 3.7%, respectively. Presence of rash was significantly associated with presence of asthenia, shivers or myalgia, respiratory and gastro-intestinal symptoms, and anosmia/ageusia. The presence of CCL was associated with chest pain, chest oppression, nausea/vomiting, and anosmia/ageusia. Patients with CCL were significantly less prone to an unfavourable outcome (hospitalization or death).

An unusual case of T-cell prolymphocytic leukemia mimicking a cutaneous vasculitis.

T-cell prolymphocytic leukemia (T-PLL) is an aggressive post-thymic T-cell malignancy, which accounts for 2% of mature lymphocytic leukemias in adults. Though typically presenting with a brief history of B symptoms, hepatosplenomegaly, and marked lymphocytosis, erythematous or nodular skin rashes involving the trunk or limbs may be seen in 25% to 30% of patients, as well as a purpuric rash in a periorbital distribution. Cutaneous involvement typically presents in the context of patients with an established history of T-PLL, but it can less frequently present as an initial symptom heralding the diagnosis. An unusual case of T-PLL is described, presenting initially as palmoplantar ulcerated nodules with an initial biopsy suggestive of perniosis, followed by rapid progression of dark violaceous and bright red papules throughout the body after initiation of obinutuzumab. The diagnosis of T-PLL was subsequently fully supported by the clinical, laboratory, cytologic, and immunophenotypic findings. This case highlights the importance of a multidisciplinary team approach to address such rare and atypical presentations.

Idiopathic perniosis presenting as acral purpuric lesions: Clustering of cases before COVID-19 pandemic and their comparison with chilblain like lesions reported in the literature.

Perniosis/chilblains are the acral inflammatory skin lesions developing in susceptible individuals as an abnormal reaction to cold. In the absence of a discernible cause, it is labeled as idiopathic perniosis (IP). With the ongoing COVID-19 pandemic, there was an upsurge of reports of chilblain like lesions (CLL) especially in young patients possibly implicated to the SARS-CoV-2 virus. Twelve clinically suspected and histopathologically confirmed cases of IP seen from November 2019 through February 2020 were retrospectively recruited. Clinical, dermoscopic, and histopathological characteristics of these were reviewed and compared with CLL reported in the literature. Mean age of patients was 26.58 ± 15.18 years with an equal male to female ratio. Characteristic histopathology findings were spongiosis (100%), dermal edema (100%), perivascular lymphocytic infiltrate (100%) with peri-eccrine accentuation (66.7%), keratinocyte necrosis (50%), focal basal vacuolar damage (58.3%), and lymphocytic vasculitis (58.3%). Significant dermoscopy findings were variable background color ranging from dull red and violaceous to copper red and brown orange, coiled vessels (44.4%) and orange-red structureless areas (63.9%). Lesions over palms and soles preferentially had white dots/clods and lines (38.9%). There appears no exclusive histopathological as well as dermoscopy features of CLL and IP, yet certain clues can be appreciated. Keratinocyte necrosis and severe dermal edema favors IP, whereas fibrin thrombi with involvement of both superficial and deep dermal vessels favor CLL. Dermoscopically presence of irregular, linear or branching vessels, red/purple dots and clods and gray brown reticule supports CLL while white dots/clods and lines supports IP.

Histopathologic Features of Chilblainlike Lesions Developing in the Setting of the Coronavirus Disease 2019 (COVID-19) Pandemic.

CONTEXT.­: During the coronavirus disease 2019 pandemic, several studies have described a distinctive cutaneous manifestation with a clinical picture resembling chilblains or chilblain lupus in young patients. OBJECTIVE.­: To report the histopathologic description of a series of chilblainlike lesions appearing in the context of the severe acute respiratory syndrome coronavirus 2 epidemic. DESIGN.­: The study included 13 patients with cutaneous acral lesions resembling chilblains occurring in the setting of suspected severe acute respiratory syndrome coronavirus 2 infection with available skin biopsy. RESULTS.­: Two main histopathologic patterns were observed: a chilblainlike histopathologic pattern (10 of 13 cases; 77%) and a thrombotic vasculopathy pattern (3 of 13 cases; 23%). The chilblainlike histopathologic pattern featured a superficial and deep perivascular infiltrate of lymphocytes of varying intensity. This infiltrate was sometimes peri-eccrine and alterations of eccrine glands were present in most cases. Vacuolar alteration of the basal layer of the epidermis was found in a majority of patients. Lichenoid interface dermatitis was rarely present. The thrombotic vasculopathy pattern featured an absent or mild inflammatory infiltrate, multiple intraluminal fibrin thrombi, and ischemic epidermal necrosis. In both patterns, no true vasculitis was observed. No patient tested positive for severe acute respiratory syndrome coronavirus 2 by polymerase chain reaction, possibly because these lesions may represent late cutaneous manifestations of the disease or are associated with an early effective immune response. CONCLUSIONS.­: The relationship of chilblainlike lesions to severe acute respiratory syndrome coronavirus 2 requires further investigations. Histopathologic features mimic chilblains, chilblain lupus, and, less frequently, a thrombotic vasculopathy. Response to viral infection might trigger diverse mechanisms leading to the 2 histopathologic patterns described.