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.

Targetoid-like lesions and chilblain-like erythema manifested on hands and feet: A case of Rowell syndrome from China.

BACKGROUND: Rowell syndrome (RS) is an uncommon condition characterized by erythema multiforme (EM)-like lesions and lupus erythematosus. It is more common in females, and EM may be the first manifestation of the disease with positive autoantibodies, such as antinuclear antibody (ANA), SSA, SSB and rheumatoid factor. The pathogenesis of RS is unknown and is likely caused by drug induction, ultraviolet exposure and infection. METHOD: We describe a case of RS from China which presented as characteristic targetoid-like lesions and chilblain-like erythema on hands and feet. This is a case of RS in a female patient from the inpatient department of dermatology. RESULTS: A 41-year-old female with systemic lupus erythematosus exhibited chilblain-like erythema and characteristic EM lesions on her extremities. She tested positive for serum ANA (1:320) and anti-double-stranded DNA, as well as other autoantibodies. Systemic glucocorticoids and hydroxychloroquine worked effectively for her. CONCLUSION: The present case met diagnostic criteria of RS. Notably, there was a co-occurrence of facial butterfly erythema, chilblain-like erythema and EM lesions distributed on the limbs in this case.

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.

COVID 19-associated chilblain-like acral lesions among children and adolescents: an Italian retrospective, multicenter study.

BACKGROUND: Since the COVID-19 pandemic started, great interest has been given to this disease, especially to its possible clinical presentations. Besides classical respiratory symptoms, dermatological manifestations occur quite often among infected and non-infected patients, particularly in children. A prominent IFN-I response, that is generally higher in children compared to adults, may not only cause chilblain lesions, but it could also prevent infection and viral replication, thus justifying the negative swab results, as well as the absence of relevant systemic symptoms in positive cases. Indeed, reports have emerged describing chilblain-like acral lesions in children and adolescents with either proven or suspected infection. METHODS: Patients aged from 1 to 18 years old were enrolled in this study from 23 Italian dermatological units and were observed for an overall period of 6 months. Clinical pictures were collected along with data on the location and duration of skin lesions, their association with concomitant local and systemic symptoms, presence of nail and/or mucosal involvement, as well as histological, laboratory and imaging findings. RESULTS: One hundred thirty-seven patients were included, of whom 56.9% were females. Mean age was 11.97±3.66 years. The most commonly affected sites were the feet (77 patients, 56.2%). Lesions (48.5%) featured cyanosis, chilblains, blisters, ecchymosis, bullae, erythema, edema, and papules. Concomitant skin manifestations included maculo-papular rashes (30%), unspecified rashes (25%), vesicular rashes (20%), erythema multiforme (10%), urticaria (10%) and erythema with desquamation (5%). Forty-one patients (29.9%) reported pruritus as the main symptom associated with chilblains, and 56 out of 137 patients also reported systemic symptoms such as respiratory symptoms (33.9%), fever (28%), intestinal (27%), headache (5.5%), asthenia (3.5%), and joint pain (2%). Associated comorbid conditions were observed in 9 patients presenting with skin lesions. Nasopharyngeal swabs turned out positive in 11 patients (8%), whereas the remainder were either negative (101, 73%) or unspecified (25, 18%). CONCLUSIONS: COVID-19 has been credited as the etiology of the recent increase in acro-ischemic lesions. The present study provides a description of pediatric cutaneous manifestations deemed to be potentially associated with COVID-19, revealing a possible association between acral cyanosis and nasopharyngeal swab positivity in children and teenagers. The identification and characterization of newly recognized patterns of skin involvement may aid physicians in diagnosing cases of asymptomatic or pauci-symptomatic COVID patients.

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.

Early Cutaneous Manifestations of COVID-19: A Systematic Review and Public Health Implications.

INTRODUCTION: Cutaneous manifestations before other symptoms have great potential for early COVID-19 diagnosis to prevent surge. METHODS: We conducted a search of PubMed and Embase databases through April 11, 2021 to include 39 studies reporting skin manifestations occurring prior to any other COVID-19 symptoms in laboratory-confirmed cases. RESULTS: Ninety-seven patients were included. Urticarial (24.7%) and maculopapular (22.7%) lesions were most common, followed by pernio (17.5%), vesicular (14.4%), papulosquamous (8.2%), and purpuric (5.1%) lesions. Cutaneous to systemic symptom latency ranged from 2 to 20 days in cases that reported it (26%), while skin lesions were the only presentation in 23 cases (23.7%). Skin lesions were the only COVID-19 manifestation in 58.8% of pernio, 40% of vesicular, 16.6% of urticarial, 18.2% of maculopapular, and 12.5% of papulosquamous presymptomatic cases. Although sample size is limited, all purpuric cases developed other symptom(s) later. CONCLUSIONS: Pernio and purpuric lesions have been well-associated with COVID-19, but papulosquamous, vesicular, mild maculopapular, and urticarial lesions can easily be dismissed as unrelated to COVID-19. Pernio lesions are thought to be related to strong immune response and low contagiousness, while purpuric and vesicular cases are speculated to be related to higher SARS-CoV2 viral load, severity, and contagiousness. All rashes, even without other symptoms, should necessitate high level of suspicion for isolation or contact tracing.

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.

Pernio and early SARS-CoV-2 variants: natural history of a prospective cohort and the role of interferon.

Cases of new-onset pernio and recurrences in our cohort align tightly with trends in mean 7-day COVID-19 positivity in Wisconsin and mean temperature in Madison, Wisconsin by month.

Chilblain-like lesions onset during SARS-CoV-2 infection in a COVID-19-vaccinated adolescent: case report and review of literature.

BACKGROUND: COVID toes or chilblain-like skin lesions have been widely reported during COVID-19 pandemic. Most cases were described in patients with negative microbiological tests for SARS-CoV-2, therefore the possible relationship with SARS-CoV-2 infection, as well as with the nowadays broadly available mRNA-based vaccination, has not been fully elucidated.  CASE PRESENTATION: We here describe the case of a 14-year-old male who developed chilblain-like skin eruptions during SARS-CoV-2 infection despite two mRNA-based vaccine doses and review the clinical and epidemiological characteristics of chilblain-like lesions as a cutaneous presentation of COVID-19 in children. CONCLUSIONS: Most children and adolescent with COVID toes have a mild or asymptomatic SARS-CoV-2 infection. Our report aims to highlight the possible onset of these skin lesions in vaccinated children, if infection has occurred, and the potential use of systemic corticosteroids as a first line treatment. Additional evidence is required to better understand SARS-CoV-2 infection and cutaneous manifestations in children and determine the relationship between chilblain-like lesions and COVID-19 vaccination.

Chilblains in immune-mediated inflammatory diseases: a review.

Chilblains were first described over a hundred years ago as cutaneous inflammatory lesions, typically on the digits, occurring on cold exposure. Chilblains can be primary, or secondary to a number of conditions such as infections, including COVID-19, and immune-mediated inflammatory disorders (IMIDs) with SLE being the commonest. Chilblain lupus erythematosus (CHLE) was first described in 1888 as cold-induced erythematous lesions before the terms 'chilblains' or 'perniosis' were coined. Diagnostic criteria exist for both chilblains and CHLE. Histopathologically, CHLE lesions show interface dermatitis with perivascular lymphocytic infiltrate. Immunofluorescence demonstrates linear deposits of immunoglobulins and complement in the dermo-epidermal junction. This narrative review focuses on chilblains secondary to immune-mediated inflammatory disorders, primarily the epidemiology, pathogenesis and treatment of CHLE.