Cutaneous manifestations of COVID-19.

COVID - 19 can be accompanied by a variety of cutaneous abnormalities, which mainly include vascular lesions chilblain - like lesions, livedo reticularis, purpura, ecchymosis, acral cyanosis, gangrene, etcand inflammatory lesionsdiffuse erythema, morbilliform exanthem, acute urticaria, varicella- like exanthem, etc. Some types of skin lesions may be the first symptom or the only clinical manifestation of COVID-19.Copyright © 2022 Chinese Journal of Dermatology. All rights reserved.

Prevalence of phalangeal bone marrow edema on MRI before and during the COVID-19 pandemic and correlation with chilblain skin lesions.

OBJECTIVE: The purpose of this study is to establish the prevalence bone marrow edema of the phalanges of the feet and hands before and during the COVID-19 pandemic on MRI studies and correlate with clinically chilblain skin lesions and epidemiological data. METHODS: This observational retrospective study. In patients with confirmed bone marrow edema of the phalanges, epidemiological data and clinical findings were collected, including the history of current or remote COVID-19 infection and vaccination status. The two-proportion test was used to compare the frequency of bone marrow edema in the phalanges before and during the pandemic, and the comparison between the categories variables was performed using the one-proportion test. RESULTS: Of the total of 7215 patients, only 20 presented isolated bone marrow edema of the digits in MRI studies; 2 (0.05%) were found two years before the pandemic's beginning, and 18 (0.64%) after the pandemic's onset, demonstrating an increase of 13-fold in this period. 16 were women with a mean age of 40.3 years and 4 were men with a mean age of 53.5 years. The most frequently reported clinical symptoms by the patients were pain (85.0%), and erythema of the skin (45.0%). Of the 18 patients found after the pandemic's onset, only 27.8% had COVID-19 infections confirmed by RT-PCR before the imaging study, and all cases were mild. CONCLUSION: This study demonstrated a significant increase in the prevalence of bone marrow edema of the phalanges after the onset of the COVID-19 pandemic, particularly in middle-aged and younger women.

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.

Cutaneous manifestations of COVID⁃19

COVID ⁃ 19 can be accompanied by a variety of cutaneous abnormalities, which mainly include vascular lesions （chilblain ⁃ like lesions, livedo reticularis, purpura, ecchymosis, acral cyanosis, gangrene, etc）and inflammatory lesions（diffuse erythema, morbilliform exanthem, acute urticaria, varicella⁃ like exanthem, etc）. Some types of skin lesions may be the first symptom or the only clinical manifestation of COVID⁃19. © 2022 Chinese Journal of Dermatology. All rights reserved.

COVID-associated non-vasculitic thrombotic retiform purpura of the face and extremities: A case report.

SARS-CoV-2 infection can manifest many rashes. However, thrombotic retiform purpura rarely occurs during COVID-19 illness. Aggressive anti-COVID-19 therapy with a high-dose steroid regimen led to rapid recovery. This immunothrombotic phenomenon likely represents a poor type 1 interferon response and complement activation on the endothelial surface in response to acute infection.

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.

Epidemiology and clinical evolution of non-multisystem inflammatory syndrome (MIS-C) dermatological lesions in pediatric patients affected by SARS-CoV-2 infection: A systematic review of the literature.

COVID-19 can present with a range of skin manifestations, some of which specific of the pediatric age. The aim of this systematic literature review was to determine the type, prevalence, time of onset, and evolution of cutaneous manifestations associated with COVID-19 in newborns, children, and adolescents, after excluding multisystem inflammatory syndrome in children (MIS-C). PubMed, Tripdatabase, ClinicalTrials, and Cochrane Library databases were searched using an ad hoc string for case reports/series and observational studies, published between December 2019 and February 2022. Study quality was assessed using the STROBE and CARE tools. Seventy-three (49 case reports/series and 24 studies) out of 26,545 identified articles were included in the analysis. Dermatological lesions were highly heterogeneous for clinical presentation, time of onset, and association with other COVID-19 manifestations. Overall, they mainly affected the acral portions, and typically presented a favorable outcome. Pseudo-chilblains were the most common. CONCLUSIONS: Mucocutaneous manifestations could be the only/predominant and early manifestation of COVID-19 that could precede other more severe manifestations by days or weeks. Therefore, physicians of all disciplines should be familiar with them. WHAT IS KNOWN: • A variety of cutaneous manifestations have been reported in association with COVID-19. • Urticaria, maculopapular, or vesicular rashes can occur at any age, while chilblains and erythema multiforme are more common in children and young patients. WHAT IS NEW: • Skin lesions related to SARS-CoV-2 infection often show a peculiar acral distribution. • Mucocutaneous lesions of various type may be the only/predominant manifestation of COVID-19; they could present in paucisymptomatic and severely ill patients and occur at different stages of the disease.

"COVID toes": A true viral phenomenon or a diagnosis without a leg to stand on?

"COVID toes" is the colloquial name of chilblain-like lesions thought to be a sequela of COVID-19 infection. Over two years and approximately 300 publications later, this association remains controversial. Here, we summarize key clinical, serological, biological, histological, and immunological evidence that supports and rejects this relationship and discuss alternate theories underlying the pathogenesis of chilblain-like lesions.

Pandemic chilblains: Are they SARS-CoV-2-related or not?

The exact etiopathology of chilblains observed during the Coronavirus Disease 2019 (COVID-19) pandemic is still unclear. Initially, SARS-CoV-2 appeared as the obvious causing agent, but two years of various investigations have failed to convincingly support its direct implication. Most affected individuals have no detectable virus, no anti-SARS-CoV-2 antibodies and no symptoms of COVID-19. Analyses of skin biopsies similarly failed to unambiguously demonstrate presence of the virus or its genome. In a recent hypothesis, SARS-CoV-2 would cause the lesions before being promptly eliminated by unusually strong type I interferon responses. With others, we feel that environmental factors have not been sufficiently considered, in particular cold exposure related to unprecedented containment measures. The cause of pandemic chilblains remains a stimulating puzzle which warrants further investigation.

Cutaneous manifestation of COVID-19: What have we learned an year into the pandemic?

Coronavirus disease-19 (COVID-19) is an emerging health situation caused by the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). The ongoing COVID-19 pandemic which emerged from the Chinese city of Wuhan in December 2019 has spread to over 188 countries and infected over 100 million people across the globe in over one year. Most common symptoms of COVID-19 include fever and respiratory illness. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported from different geographical regions. The exact incidence or prevalence of COVID-19 associated skin manifestation remains largely unknown and the pathophysiological mechanisms are still unclear. In this article, we have attempted to give a comprehensive overview of what has been learned an year into the pandemic on the epidemiology, clinical and histopathological features, pathophysiological mechanisms and clinical management of COVID-19 associated cutaneous manifestations.

Caracterización de las manifestaciones cutáneas por infección de SARS COV- 2 en pacientes de América Latina

RESUMEN Introducción. En 2019 surgió el coronavirus SARS-CoV-2, causante del COVID-19, ocasionando una pandemia que se extendió rápidamente alrededor del mundo;en casos graves, este, puede desencadenar un síndrome de tormenta de citoquinas, y conllevar a la muerte. Las manifestaciones cutáneas pueden asociarse a la expresión del receptor ACE2 en queratinocitos, estas, se han descrito en la literatura de diversos países. La presente revisión busca documentar las presentaciones cutáneas que se han descrito en pacientes con COVID-19 en América Latina. Metodología. Realizamos una búsqueda en nueve bases de datos de artículos en español, portugués e inglés, hasta el 10 de marzo del 2021, utilizando los términos: «Skin», «Cutaneous manifestations», «COVID 19», «SARS-COV-2», asociándolos al nombre de los países Latinoamericanos. Se obtuvieron los datos básicos de los pacientes incluidos, luego se creó una tabla en Microsoft Excel para analizar y comparar datos. Resultados. Se identificaron 22 publicaciones de nueve países. Obtuvimos información de 92 pacientes, predominantemente de sexo femenino y edad promedio de 31,6 años. Fueron documentadas 99 lesiones dermatológicas, en orden de frecuencia correspondieron a rash, habones, petequias-púrpura y pápulas. En 70 pacientes se describió el segmento corporal afectado, principalmente el tronco, miembros inferiores y superiores. Encontramos 39 fotografías y 5 histopatologías. Los tratamientos más formulados fueron corticoides, antipalúdicos e interferón recombinante. Conclusiones. Se observan diferencias en las manifestaciones cutáneas del COVID-19, entre las publicaciones latinoamericanas respecto a los demás países. Parece haber un patrón propio, donde predomina el rash eritematoso con habones, mientras que la pseudo-perniosis fue menos representativa. Introduction In 2019, the SARS-CoV-2 coronavirus emerged, producing COVID-19, which caused a pandemic that spread rapidly around the world;in severe cases, it can trigger cytokine storm syndrome and lead to death. Cutaneous manifestations can be associated with the expression of the ACE2 receptor in keratinocytes, these have been described in the literature from different countries. This review seeks to document the skin presentations that have been described in patients with COVID-19 in Latin America. Methodology. We researched in nine databases for articles in Spanish, Portuguese and English, until March 10, 2021, using the terms: “Skin”, “Cutaneous manifestations”, “COVID-19”, “SARS-COV-2”, associating them with Latin American countries. Basic data was obtained from the patients, then a table was created in Microsoft Excel to analyze and compare this data. Results 22 publications from nine countries were identified. We obtained information from 92 patients, predominantly female with an average age of 31.6 years. 99 dermatologic lesions were documented, in order of frequency: rash, wheals, petechiae-purpura and papules. In 70 patients the affected body segment was described, mainly the trunk, lower and upper limbs. We found 39 photographs and 5 histopathologies. The most indicated treatments were corticosteroids, antimalarials and recombinant interferon. Conclusions Differences can be observed in the description of cutaneous manifestations caused by COVID-19, between Latin American publications and the ones found in other countries. There seems to be a specific pattern with a predominance of erythematous rash with wheals, while pseudo-perniosis was less representative.

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.

Cutaneous Complications of mRNA and AZD1222 COVID-19 Vaccines: A Worldwide Review.

Because of the increasing emergence of cutaneous reactions from COVID-19 vaccines worldwide, we investigated the published reports of these complications. We searched the PubMed, Google Scholar, and Scopus databases and the preprint server bioRxiv for articles on cutaneous complications linked to mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and AZD1222 (AstraZeneca-Oxford University) vaccines published until 30 September 2021. Eighty studies describing a total of 1415 reactions were included. Cutaneous reactions were more prevalent in females (81.6%). Delayed large local reactions were the most common complication (40.4%), followed by local injection site reactions (16.5%), zoster (9.5%), and urticarial eruptions (9.0%). Injection site and delayed large local reactions were predominantly caused by the mRNA-1273 vaccine (79.5% and 72.0%, respectively). BNT162b2 vaccination was more closely linked to distant reactions (50.1%) than mRNA-1273 (30.0%). Zoster was the most common distant reaction. Of reactions with adequate information for both vaccine doses, 58.3% occurred after the first dose only, 26.9% after the second dose only, and 14.8% after both doses. Overall, a large spectrum of cutaneous reaction patterns occurred following the COVID-19 vaccination. Most were mild and without long-term health implications. Therefore, the occurrence of such dermatologic complications does not contraindicate subsequent vaccination.

Cutaneous reactions to COVID-19 vaccines: A review.

Background: The increasing number of reports on cutaneous reactions following COVID-19 vaccination has led to growing concerns among certain groups. Objective: We reviewed the published reports of cutaneous lesions after COVID-19 vaccination. Methods: We conducted a literature search for original and review articles published between January 1, 2020, and September 27, 2021. Results: Eleven cutaneous reactions associated with COVID-19 vaccines were determined; the most prevalent reactions were local injection site reactions, delayed local reactions, urticaria, angioedema, and morbilliform eruptions. There were more reports on skin reactions following the administration of messenger RNA-based vaccines than on those following the administration of adenoviral vector or inactivated whole-virus vaccines, in part, due to their higher administration rate. Most reported skin reactions occurred after the first vaccine dose. Limitations: A reporting bias could not be excluded, and skin biopsy results were not available for most included individuals. Moreover, given that the included trials focused on vaccine efficacy, there was a lack of details concerning cutaneous reactions and participant information. Conclusion: Not all cutaneous reactions observed after COVID-19 vaccination are hypersensitivity reactions. Different cutaneous reactions may reflect underlying immune responses to the vaccines. A large majority of COVID-19 vaccination reactions were mild and self-limiting, and people should be encouraged to complete their vaccination regimen.

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.