The skin as a critical window in unveiling the pathophysiologic principles of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is a single-stranded RNA virus whose sequence is known. COVID-19 is associated with a heterogeneous clinical phenotype ranging from asymptomatic to fatal disease. It appears that access to nasopharyngeal respiratory epithelia expressing angiotensin-converting enzyme (ACE) 2, the receptor for SARS-CoV-2, is followed by viral replication in the pulmonary alveolar septal capillary bed. We have demonstrated in earlier studies that incomplete viral particles, termed pseudovirions, dock to deep subcutaneous and other vascular beds, potentially contributing to the prothrombotic state and systemic complement activation that characterizes severe and critical COVID-19. A variety of skin eruptions have been described in the setting of SARS-CoV-2 infection and more recently, after COVID-19 vaccination. The vaccines deliver a laboratory-synthesized mRNA that encodes a protein that is identical to the spike glycoprotein of SARS-CoV-2, allowing the production of immunogenic spike glycoprotein that will then elicit T cell and B cell adaptive immune responses. In this contribution, we review an array of cutaneous manifestations of COVID-19 that provide an opportunity to study critical pathophysiologic mechanisms that underlie all clinical facets of COVID-19, ranging from asymptomatic/mild to severe and critical COVID-19. We classify cutaneous COVID-19 according to underlying pathophysiologic principles. In this regard we propose three main pathways: (1) complement mediated thrombotic vascular injury syndromes deploying the alternative and mannan binding lectin pathways and resulting in the elaboration of cytokines like interleukin 6 from endothelium in the setting of severe and critical COVID-19 and (2) the robust T cell and type I interferon-driven inflammatory and (3) humoral-driven immune complex mediated vasculitic cutaneous reactions observed with mild and moderate COVID-19. Presented are novel data on cutaneous vaccine reactions that manifest a clinical and morphologic parallel with similar eruptions observed in patients with mild and moderate COVID-19 and in some cases represent systemic eczematoid hypersensitivity reactions to a putative vaccine-based antigen versus unmasking subclinical hypersensitivity due to immune enhancing effects of the vaccine. Finally, we demonstrate for the first time the localization of human synthesized spike glycoprotein after the COVID-19 vaccine to the cutaneous and subcutaneous vasculature confirming the ability of SARS-CoV-2 spike glycoprotein to bind endothelium in the absence of intact virus.

A retrospective study on the prevalence of anti-phospholipid antibodies, thrombotic events and cutaneous signs of vasculopathy in 173 hospitalized COVID-19 patients.

BACKGROUND: Hypercoagulability is a risk factor of thromboembolic events in COVID-19. Anti-phospholipid (aPL) antibodies have been hypothesized to be involved. Typical COVID-19 dermatological manifestations of livedo reticularis and digital ischemia may resemble cutaneous manifestations of anti-phospholipid syndrome (APS). OBJECTIVES: To investigate the association between aPL antibodies and thromboembolic events, COVID-19 severity, mortality, and cutaneous manifestations in patients with COVID-19. METHODS: aPL antibodies [anti-beta2-glycoprotein-1 (B2GP1) and anti-cardiolipin (aCL) antibodies] were titered in frozen serum samples from hospitalized COVID-19 patients and the patients' clinical records were retrospectively analyzed. RESULTS: 173 patients were enrolled. aPL antibodies were detected in 34.7% of patients, anti-B2GP1 antibodies in 30.1%, and aCL antibodies in 10.4%. Double positivity was observed in 5.2% of patients. Thromboembolic events occurred in 9.8% of patients, including 11 pulmonary embolisms, 1 case of celiac tripod thrombosis, and six arterial ischemic events affecting the cerebral, celiac, splenic, or femoral-popliteal arteries or the aorta. aPL antibodies were found in 52.9% of patients with vascular events, but thromboembolic events were not correlated to aPL antibodies (adjusted OR = 1.69, p = 0.502). Ten patients (5.8%) had cutaneous signs of vasculopathy: nine livedo reticularis and one acrocyanosis. No significant association was observed between the presence of cutaneous vasculopathy and aPL antibodies (p = 0.692). CONCLUSIONS: Anti-phospholipid antibodies cannot be considered responsible for hypercoagulability and thrombotic events in COVID-19 patients. In COVID-19 patients, livedo reticularis and acrocyanosis do not appear to be cutaneous manifestations of APS.

To Trap a Pathogen: Neutrophil Extracellular Traps and Their Role in Mucosal Epithelial and Skin Diseases.

Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of extracellular traps. Neutrophil extracellular traps (NETs) are a microbicidal mechanism that involves neutrophil death. Since their discovery, in vitro and in vivo neutrophils have been challenged with a range of stimuli capable of inducing or inhibiting NET formation, with the objective to understand its function and regulation in health and disease. These networks composed of DNA and granular components are capable of immobilizing and killing pathogens. They comprise enzymes such as myeloperoxidase, elastase, cathepsin G, acid hydrolases and cationic peptides, all with antimicrobial and antifungal activity. Therefore, the excessive formation of NETs can also lead to tissue damage and promote local and systemic inflammation. Based on this concept, in this review, we focus on the role of NETs in different infectious and inflammatory diseases of the mucosal epithelia and skin.

How to Manage COVID-19 Vaccination in Immune-Mediated Inflammatory Diseases: An Expert Opinion by IMIDs Study Group.

Since March 2020, the outbreak of Sars-CoV-2 pandemic has changed medical practice and daily routine around the world. Huge efforts from pharmacological industries have led to the development of COVID-19 vaccines. In particular two mRNA vaccines, namely the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna), and a viral-vectored vaccine, i.e. ChAdOx1 nCoV-19 (AstraZeneca), have recently been approved in Europe. Clinical trials on these vaccines have been published on the general population showing a high efficacy with minor adverse events. However, specific data about the efficacy and safety of these vaccines in patients with immune-mediated inflammatory diseases (IMIDs) are still lacking. Moreover, the limited availability of these vaccines requires prioritizing some vulnerable categories of patients compared to others. In this position paper, we propose the point of view about the management of COVID-19 vaccination from Italian experts on IMIDs and the identification of high-risk groups according to the different diseases and their chronic therapy.

Cutaneous Manifestations Related to COVID-19 Immune Dysregulation in the Pediatric Age Group.

PURPOSE OF REVIEW: At the juncture of the COVID-19 pandemic, the world is currently in an early phase of collecting clinical data and reports of its skin manifestations, and its pathophysiology is still highly conjectural. We reviewed cutaneous manifestations associated with COVID-19 in the pediatric age group. RECENT FINDINGS: Children infected by SARS-CoV-2 usually develop milder respiratory symptoms, but cutaneous manifestations seem a little more prevalent than in adults. These skin features of infection by the coronavirus can be similar to those produced by other common viruses, but there are also reports of cases with more heterogeneous clinical pictures, which have made their classification difficult. To date, the more frequently reported skin variants featured in pediatric cases are purpuric (pseudo-chilblain, necrotic-acral ischemia, hemorrhagic macules, and/or cutaneous necrosis), morbilliform/maculopapular, erythema multiforme, urticarial, vesicular, Kawasaki-like, and miscellaneous (highly variable in both frequency and severity). Their pathophysiological mechanism is still elusive and is likely to be the result of the complex involvement of one or more mechanisms, like direct virus-induced skin damage, vasculitis-like reactions, and/or indirect injury as a consequence of a systemic inflammatory reaction. In this review, we presented and discussed clinical cases as examples of different cutaneous responses reported in some children with SARS-CoV-2 infection, differential diagnosis considerations, and a preliminary conceptual approach to some of their probable associated pathologic mechanisms.

An evidence-based guide to SARS-CoV-2 vaccination of patients on immunotherapies in dermatology.

Immune-mediated diseases and immunotherapeutics can negatively affect normal immune functioning and, consequently, vaccine safety and response. The COVID-19 pandemic has incited research aimed at developing a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. As SARS-CoV-2 vaccines are developed and made available, the assessment of anticipated safety and efficacy in patients with immune-mediated dermatologic diseases and requiring immunosuppressive and/or immunomodulatory therapy is particularly important. A review of the literature was conducted by a multidisciplinary committee to provide guidance on the safety and efficacy of SARS-CoV-2 vaccination for dermatologists and other clinicians when prescribing immunotherapeutics. The vaccine platforms being used to develop SARS-CoV-2 vaccines are expected to be safe and potentially effective for dermatology patients on immunotherapeutics. Current guidelines for the vaccination of an immunocompromised host remain appropriate when considering future administration of SARS-CoV-2 vaccines.

Cutaneous Sarcoidosis.

Sarcoidosis is a chronic, multisystem, inflammatory disorder of unknown etiology that is characterized by noncaseating granulomas that impair normal organ functioning. Sarcoidosis predominantly affects the lungs, but the skin is often cited as the second most frequently involved organ. Cutaneous manifestations of sarcoidosis are highly variable and ongoing research seeks to better understand the relationship between clinical morphology and disease prognosis. Skin findings in patients with sarcoidosis can be "specific," in which sarcoidal granulomas infiltrate the skin, or they can represent a "nonspecific" reactive inflammatory process, as is seen in calcinosis cutis and erythema nodosum. Cutaneous sarcoidosis can be the initial presenting sign or develop later in the course of the disease. In some patients, the skin will be the most involved and impactful organ system and will drive therapy. In other cases, the skin will be an incidental or minor finding, but may be easily accessible for biopsy to confirm the diagnosis. There are many potential therapies for sarcoidosis, though no one therapy is universally effective.

Chilblain-like acral lesions during the COVID-19 pandemic ("COVID toes"): Histologic, immunofluorescence, and immunohistochemical study of 17 cases.

BACKGROUND: During the coronavirus disease 2019 pandemic, several acral chilblain-like lesions were observed in young patients with suspected, but mostly unconfirmed, infection with severe acute respiratory syndrome coronavirus 2. The histopathologic aspect of these lesions is as yet poorly known. OBJECTIVE: To investigate the pathologic features of chilblain-like lesions. METHODS: Biopsies were obtained from 17 cases of chilblain-like lesions during the coronavirus disease 2019 pandemic in France and were studied by routine histologic examination, immunohistochemistry, and direct immunofluorescence. The patients had suspected but unconfirmed infection with severe acute respiratory syndrome coronavirus 2 (negative nasopharyngeal polymerase chain reaction and serologic test results). RESULTS: Chilblain-like lesions showed many features in common with those reported in idiopathic and autoimmune-related chilblains, including epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine sweat gland lymphocytic (predominantly CD3/CD4+) inflammation, and frequent vascular changes (endothelialitis, microthromboses, fibrin deposition, and immunoreactant deposits on vessels). CONCLUSIONS: Chilblain-like lesions show histopathologic features similar to those of idiopathic and autoimmune-related chilblains, with a high rate of vascular changes and direct immunofluorescence positivity. The role of severe acute respiratory syndrome coronavirus 2 in the development of these puzzling lesions remains to be elucidated.

COVID-19 and immunosuppressive therapy in dermatology.

Coronavirus 2019 (COVID 19) was first detected in December 2019 in China. It has become a pandemic. With concern about therapies that may decrease immunity and enhance the severity of an individual's COVID-19 infection, leading to a possibly fatal outcome, use of immunosuppressants has become an important concern. This work focuses on management of various skin diseases individuals lacking immunity to COVID-19 but requiring a systemic immunosuppressant, keeping in view the challenge of the COVID 19 pandemic and that our knowledge of this virus and its effects on the immune system are incomplete including knowledge as to an individual's immunity after COVID-19 infection.

Patients with specific skin disorders who are affected by COVID-19: What do experiences say about management strategies? A systematic review.

In patients with specific dermatologic disorders who are affected by new corona virus, we know little about disease course (underlying disease and new onset infection), and the most proper management strategies include both issues that are what this systematic review targets. Databases of PubMed, Scopus, Google Scholar, Medscape, and Centre of Evidence-Based Dermatology, coronavirus dermatology resource of Nottingham University searched completely up to May 15, 2020, and initial 237 articles were selected to further review and finally 9 articles (including 12 patients) entered to this study. From 12 patients with chronic underlying dermatologic disease treated with systemic therapies, only 1 patient required Intensive Care Unit admission, the others have been treated for mild-moderate symptoms with conventional therapies. The biologic or immunosuppressive/immunomodulator agents have been ceased during the course of disease. The course of coronovirus diseases 2019 (COVID-19) and its management was as similar as normal populations. Their underlying dermatologic disease were exacerbating from mild to moderate. Their treatment has been continued as before, after the symptoms improved. Exacerbation of patients underlying dermatologic disease was mild to moderate. Discontinuing the treatment in the acute period of COVID and the restart after recovery may prevent severe recurrence and disturbing cytokine storms in these patients.

Cutaneous manifestations and considerations in COVID-19 pandemic: A systematic review.

COVID-19 had a great impact on medical approaches among dermatologist. This systematic review focuses on all skin problems related to COVID-19, including primary and secondary COVID-related cutaneous presentations and the experts recommendations about dermatological managements especially immunomodulators usage issues. Search was performed on PubMed, Scopus, Embase and ScienceDirect. Other additional resources were searched included Cochrane, WHO, Medscape and coronavirus dermatology resource of Nottingham university. The search completed on May 3, 2020. Three hundred seventy-seven articles assigned to the inclusion and exclusion groups. Eighty-nine articles entered the review. Primary mucocutaneous and appendageal presentations could be the initial or evolving signs of COVID-19. It could be manifest most commonly as a maculopapular exanthamatous or morbiliform eruption, generalized urticaria or pseudo chilblains recognized as "COVID toes" (pernio-like acral lesions or vasculopathic rashes). During pandemic, Non-infected non-at risk patients with immune-medicated dermatologic disorders under treatment with immunosuppressive immunomodulators do not need to alter their regimen or discontinue their therapies. At-risk o suspected patients may need dose reduction, interval increase or temporary drug discontinuation (at least 2 weeks). Patients with an active COVID-19 infection should hold the biologic or non-biologic immunosuppressives until the complete recovery occur (at least 4 weeks).

Infection risk of dermatologic therapeutics during the COVID-19 pandemic: an evidence-based recalibration.

Recommendations were made recently to limit or stop the use of oral and systemic immunotherapies for skin diseases due to potential risks to the patients during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic. Herein, we attempt to identify potentially safe immunotherapies that may be used in the treatment of cutaneous diseases during the current COVID-19 pandemic. We performed a literature review to approximate the risk of SARS-CoV-2 infection, including available data on the roles of relevant cytokines, cell subsets, and their mediators in eliciting an optimal immune response against respiratory viruses in murine gene deletion models and humans with congenital deficiencies were reviewed for viral infections risk and if possible coronaviruses specifically. Furthermore, reported risk of infections of biologic and non-biologic therapeutics for skin diseases from clinical trials and drug data registries were evaluated. Many of the immunotherapies used in dermatology have data to support their safe use during the COVID-19 pandemic including the biologics that target IgE, IL-4/13, TNF-α, IL-17, IL-12, and IL-23. Furthermore, we provide evidence to show that oral immunosuppressive medications such as methotrexate and cyclosporine do not significantly increase the risk to patients. Most biologic and conventional immunotherapies, based on doses and indications in dermatology, do not appear to increase risk of viral susceptibility and are most likely safe for use during the COVID-19 pandemic. The limitation of this study is availability of data on COVID-19.