Background Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized. Objective To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines. Methods A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination. Results From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions. Limitations Registry analysis does not measure incidence. Morphologic misclassification is possible. Conclusions We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination.

https://scholarlycommons.henryford.com/cgi/viewcontent.cgi?article=1559&context=dermatology_articles

Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases.

Background Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established Objectives To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue Methods We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one Results Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy Conclusions Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2 Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19 Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19 Linked Comment: Wetter Br J Dermatol 2020; 183:611

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjd.19327

SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases

In contrast to other respiratory viruses, children have less severe symptoms when infected with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we discuss proposed hypotheses for the age-related difference in severity of coronavirus disease 2019 (COVID-19).Factors proposed to explain the difference in severity of COVID-19 in children and adults include those that put adults at higher risk and those that protect children. The former include: (1) age-related increase in endothelial damage and changes in clotting function; (2) higher density, increased affinity and different distribution of angiotensin converting enzyme 2 receptors and transmembrane serine protease 2; (3) pre-existing coronavirus antibodies (including antibody-dependent enhancement) and T cells; (4) immunosenescence and inflammaging, including the effects of chronic cytomegalovirus infection; (5) a higher prevalence of comorbidities associated with severe COVID-19 and (6) lower levels of vitamin D. Factors that might protect children include: (1) differences in innate and adaptive immunity; (2) more frequent recurrent and concurrent infections; (3) pre-existing immunity to coronaviruses; (4) differences in microbiota; (5) higher levels of melatonin; (6) protective off-target effects of live vaccines and (7) lower intensity of exposure to SARS-CoV-2.

https://adc.bmj.com/content/archdischild/106/5/429.full.pdf

Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections.

The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.

/pdf/endothelial-dysfunction-in-covid-19-a-position-paper-of-the-169tkxai3m.pdf

Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science.

Multisystem inflammatory syndrome (MIS-C) is a pediatric hyperinflammation disorder caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It has now been reported from several countries the world over. Some of the clinical manifestations of MIS-C mimic Kawasaki disease (KD) shock syndrome. MIS-C develops 4-6 weeks following SARS-CoV-2 infection, and is presumably initiated by adaptive immune response. Though it has multisystem involvement, it is the cardiovascular manifestations that are most prominent. High titres of anti-SARS-CoV-2 antibodies are seen in these patients. As this is a new disease entity, its immunopathogenesis is not fully elucidated. Whether it has some overlap with KD is still unclear. Current treatment guidelines recommend use of intravenous immunoglobulin and high-dose corticosteroids as first-line treatment. Mortality rates of MIS-C are lower compared to adult forms of severe COVID-19 disease.

/pdf/severe-covid-19-multisystem-inflammatory-syndrome-in-7xivbdyol5.pdf

Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: immunological mechanisms, clinical manifestations and management.

BACKGROUND: Different skin manifestations of COVID-19 are being reported. Acral lesions on the hands and feet, closely resembling chilblains, have been recognized during the peak incidence of the COVID-19 pandemic. MATERIAL AND METHODS: A retrospective review of 22 children and adolescents with chilblain-like lesions seen over a short period of time in the Emergency Department of a children's hospital during the peak incidence of COVID-19 in Madrid, Spain. RESULTS: All patients had lesions clinically consistent with chilblains of the toes or feet, with three also having lesions of the fingers. Pruritus and mild pain were the only skin symptoms elicited, and only 10 had mild respiratory and/or GI symptoms. None had fever. Coagulation tests, hemogram, serum chemistry, and lupus anticoagulant were normal in all patients tested. One out of 16 tested cases had elevated D-dimer results, but without systemic symptoms or other laboratory anomalies. SARS-CoV-2 PCR tested in 19 cases was positive in just one case. Skin biopsies obtained in six patients were consistent with chilblains. On follow-up, all cases showed spontaneous marked improvement or complete healing. CONCLUSION: Acute chilblains were observed during COVID-19 pandemic in children and teenagers. It is a mildly symptomatic condition with an excellent prognosis, usually requiring no therapy. Etiopathogenesis remains unknown.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/pde.14215

Chilblains in children in the setting of COVID-19 pandemic.

During examination of cases of chilblains in children and adolescents, we identified four patients who also showed skin lesions similar to erythema multiforme (EM). They had no other known triggers for EM. One of them had a positive PCR for SARS-CoV-2, while the other three were negative. Skin biopsies from two patients showed features not typical of EM, such as deep perivascular and perieccrine infiltrate and absence of necrosis of keratinocytes. Immunohistochemistry for SARS-CoV/SARS-CoV-2 spike protein showed granular positivity in endothelial cells and epithelial cells of eccrine glands in both biopsies. All patients had an excellent outcome, and had minimal or no systemic symptoms. The coincidence of EM, a condition commonly related to viruses, and chilblains in the setting of COVID-19, and the positivity for SARS-CoV/SARS-CoV-2 spike protein by immunohistochemistry strongly suggest a link between EM-like lesions and SARS-CoV-2.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/pde.14246

Erythema multiforme-like lesions in children and COVID-19.

Cutaneous drug reactions in the pediatric population.

Background
Cyclosporin A (CSA) is an immunosuppressant agent widely used in severe atopic dermatitis (AD). However, experience in children is limited.

Objectives
To assess the efficacy and adverse events of CSA therapy in children.

Methods
Retrospective study of children with severe AD treated with CSA between January 2009 and December 2015.

Results
Data from 63 patients were collected. Mean age at the beginning of treatment was 8.4 years (±3.6). The median starting dose was 4.27 (±0.61) mg/kg/day. After four weeks of treatment, the outcome was excellent in 35% of cases, good in 29%, and poor in 36% of the patients. The response was better in patients without eosinophilia (p 6 months) was observed in 13 patients (20%).

Limits
This is a retrospective review. The follow-up period is limited.

Conclusions
Our data confirm that CSA is efficacious and acts rapidly in the majority of children with severe AD. CSA therapy can provide sustained remission in some patients. CSA seems to be well tolerated in children, but strict monitoring is mandatory.

This article is protected by copyright. All rights reserved.

Lucero Noguera-Morel

Papers

SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases

Chilblains in children in the setting of COVID-19 pandemic.

Erythema multiforme-like lesions in children and COVID-19.

Cutaneous drug reactions in the pediatric population.

Cyclosporine A for severe atopic dermatitis in children. efficacy and safety in a retrospective study of 63 patients.