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.

The COVID-19 pandemic now totaling 13,000,000 cases and over 571,000 deaths has continued to teach the medical, scientific and lay communities about viral infectious disease in the modern era. Among the many lessons learned for the medical community is the potential for transmissibility and host infectivity of the SARS-CoV-2 virus. Moreover, it has become clear that the virus can affect any organ including the circulatory system, directly via either tissue tropism or indirectly stemming from inflammatory responses in the form of innate immunity, leukocyte debris such as cell-free DNA and histones and RNA viral particles. The following review considers COVID-19-associated vasculitis and vasculopathy as a defining feature of a virus-induced systemic disease with acute, subacute and potential chronic health implications.

/pdf/covid-19-associated-vasculitis-and-vasculopathy-hwt1xk660q.pdf

COVID-19-associated vasculitis and vasculopathy.

Background Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months.
 Summary
 The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric “vasculitic” pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.

/pdf/skin-manifestations-associated-with-covid-19-current-4np4mdc1na.pdf

Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives.

A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous challenge to healthcare systems and affected communities. COVID-19 is caused by Severe Acute Respiratory Syndrome (SARS)-CoronaVirus-2 (CoV-2) that manifests as bronchitis, pneumonia, or a severe respiratory illness. SARS-CoV-2 infects human cells via binding a "spike" protein on its surface to angiotensin-converting enzyme 2 (ACE2) within the host. ACE2 is crucial for maintaining tissue homeostasis and negatively regulates the renin-angiotensin-aldosterone system (RAAS) in the humans. The RAAS is paramount for normal function in multiple organ systems including the lungs, heart, kidney, and vasculature. Given that SARS-CoV-2 internalizes via ACE2, the resultant disruption in ACE2 expression can lead to altered tissue function and exacerbate chronic diseases. The widespread distribution and expression of ACE2 across multiple organs is critical to our understanding of the varied clinical outcomes of COVID-19. This perspective review based on the current literature was prompted to show how disruption of ACE2 by SARS-CoV-2 can affect different organ systems.

https://journals.physiology.org/doi/pdf/10.1152/physiolgenomics.00087.2020

SARS-CoV-2, ACE2 expression, and systemic organ invasion.

The occurrence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVD-19), represents a catastrophic threat to global health. Protruding from the viral surface is a densely glycosylated spike (S) protein, which engages angiotensin-converting enzyme 2 (ACE2) to mediate host cell entry. However, studies have reported viral susceptibility in intra- and extrapulmonary immune and non-immune cells lacking ACE2, suggesting that the S protein may exploit additional receptors for infection. Studies have demonstrated interactions between S protein and innate immune system, including C-lectin type receptors (CLR), toll-like receptors (TLR) and neuropilin-1 (NRP1), and the non-immune receptor glucose regulated protein 78 (GRP78). Recognition of carbohydrate moieties clustered on the surface of the S protein may drive receptor-dependent internalization, accentuate severe immunopathological inflammation, and allow for systemic spread of infection, independent of ACE2. Furthermore, targeting TLRs, CLRs, and other receptors (Ezrin and dipeptidyl peptidase-4) that do not directly engage SARS-CoV-2 S protein, but may contribute to augmented anti-viral immunity and viral clearance, may represent therapeutic targets against COVID-19.

Can SARS-CoV-2 Virus Use Multiple Receptors to Enter Host Cells?

Routine clinical assays, such as conventional immunohistochemistry, often fail to resolve the regional heterogeneity of complex inflammatory skin conditions. We introduce MANTIS (Multiplex Annotated Tissue Imaging System), a flexible analytic pipeline compatible with routine practice, specifically designed for spatially resolved immune phenotyping of the skin in experimental or clinical samples. On the basis of phenotype attribution matrices coupled to α-shape algorithms, MANTIS projects a representative digital immune landscape while enabling automated detection of major inflammatory clusters and concomitant single-cell data quantification of biomarkers. We observed that severe pathological lesions from systemic lupus erythematosus, Kawasaki syndrome, or COVID-19–associated skin manifestations share common quantitative immune features while displaying a nonrandom distribution of cells with the formation of disease-specific dermal immune structures. Given its accuracy and flexibility, MANTIS is designed to solve the spatial organization of complex immune environments to better apprehend the pathophysiology of skin manifestations.

https://www.science.org/doi/pdf/10.1126/sciadv.adf9491?download=true

3D deconvolution of human skin immune architecture with Multiplex Annotated Tissue Imaging System

Dermpath & Clinic: Exogenous ochronosis.

Routine clinical assays, such as conventional immunohistochemistry, often fail to resolve the regional heterogeneity of complex inflammatory skin conditions. Here we introduce MANTIS (Multiplexed Annotated Tissue Imaging System), a flexible analytic pipeline compatible with routine practice, specifically-designed for spatially-resolved immune phenotyping of the skin in experimental or clinical samples. Based on phenotype attribution matrices coupled to α-shape algorithms, MANTIS projects a representative digital immune landscape, while enabling automated detection of major inflammatory clusters and concomitant single-cell data quantification of biomarkers. We observed that severe pathological lesions from systemic lupus erythematosus, Kawasaki syndrome or COVID-19-associated skin manifestations share common quantitative immune features, while displaying a non-random distribution of cells with the formation of disease-specific dermal immune structures. Given its accuracy and flexibility, MANTIS is designed to solve the spatial organization of complex immune environments to better apprehend the pathophysiology of skin manifestations.

/pdf/3-d-deconvolution-of-human-skin-immune-architecture-with-2bluy44c.pdf

3-D deconvolution of human skin immune architecture with Multiplex Annotated Tissue Imaging System (MANTIS)

211 cally significant based on the multivariate analysis adjusted for cancer and corticosteroid treatment. These results confirm findings regarding NLR and DM from previous studies [14, 15]. The cut-offs for NLR were 5.5 and 6.9 for cancer and OS, respectively. This study and the previous studies on NLR have several limitations that do not allow us to draw clear conclusions about the role of NLR as a biomarker for DM/PM, but it does seem to be a useful tool in the initial screening of patients. Studies with more patients are necessary to confirm the usefulness of NLR, with a larger number of patients and more variables for multivariate analysis in order to control confounding factors such as age, sex, immunosuppressive therapy, myositis-specific autoantibody profile and comorbidities. It is also important to analyse other outcomes, such as clinical subtype of DM, specific organ involvement, clinical course (monocyclic, polycyclic or continuous), and time to relapse. Sarcoidosis is a systemic granulomatous disorder, so named because it resembles sarcoma; the term was coined by Caesar Boeck. It is defined by the presence of non-caseating granulomata. Cutaneous manifestations can occur in more than 30% of patients and are quite variable. Lupus pernio, Darier-Roussy, Lofgren’s syndrome and Heerfordt’s syndrome are all clinical variants of the cutaneous manifestations of sarcoidosis. In this issue, Takako et al. [16] present a single-centre, retrospective analysis of the clinical features of cutaneous sarcoidosis in 95 Japanese patients. Sarcoidosis is a rare entity in Asians [17], therefore this article provides further information about the characteristics of sarcoidosis in this group of patients. As in other studies, there seemed to be a female predominance (male:female ratio of 1:3.5) [18]. The face and extremities were the most frequently involved sites and non-specific plaques or nodules were the most frequent morphology. It is important to remark that atypical lesions were relatively frequent, occurring in around 18% of the patients. This group encompasses different cutaneous presentations such as ichthyosiform, psoriasiform, lichenoid or ulcerative features. Interestingly, the cutaneous lesions were the initial symptom in 24 patients (25%). Scar-related lesions were observed in almost 15% of the patients, as in other studies. In summary, the clinical presentation of sarcoidosis in the Japanese population does not differ much from that of other ethnic groups. The dermatologist should keep in mind that sarcoidosis is a heterogenous disease, even in Japanese people. In almost 25% of the patients, the cutaneous manifestations are the initial symptom and this can be helpful for early diagnosis of systemic involvement.

Dermpath & Clinic: Lichen planus pemphigoides.

A 37-year-old man of skin type VI consulted our dermatology department for a nodule on the posterior surface of the right thigh, above the popliteal fossa, which had appeared with no obvious reason one year ago. The lesion was occasionally tender. Medical history was remarkable for sickle-cell anaemia. Physical examination showed a 6-mm firm pigmented nodule with a keratotic surface (figure 1A). There was no regional (inguinal) lymphadenopathy. Dermatoscopic examination revealed a bluish colour. The lesion was excised under local anaesthesia with the clinical diagnostic hypotheses of melanoma, blue naevus, keratotic papilloma and squamous cell carcinoma. Histopathological examination showed a slightly raised dermal tumour overlaid by a hyperkeratotic, acanthotic and papillomatous epidermis, showing an aspect of pseudoepitheliomatous hyperplasia (figure 1B, C). The tumour was made of a dense proliferation of epithelioid melanocytes with vesicular nuclei and visible nucleoli. These cells contained abundant cytoplasmic melanin deposits (figure 1D). No junctional activity was noted, although the epidermis contained melanin deposits and pigmented dendritic cell processes. On immunohistochemistry, the large majority of dermal melanocytes expressed the gp100/HMB-45 antigen. A few cells expressed MIB-1/Ki-67 antigen and/or p16 protein. These findings were diagnostic of pigmented epithelioid melanocytoma. Pigmented epithelioid melanocytoma (PEM), also referred to as epithelioid blue naevus, was previously described as “animal-type melanoma” because of the clinical and histological similarities with equine melanoma [1]. It is a rare melanocytic neoplasm of unknown pathogenesis affecting all racial groups, with a predilection for young patients, including children [2]. Clinically, PEM manifests usually as a slow-growing heavily pigmented (dark blue) papule or nodule with a homogenous blue colour on dermatoscopic examination [3]. PEM is either a pure tumour (as in the patient presented here), or can be a component of a combined naevus (in association with an adjacent common acquired naevus). In 30% of cases, PEM contains small junctional nests. Histopathological examination shows a mixture of dermal epithelioid and spindled melanocytes with heavy pigmentation, indistinguishable from epithelioid blue nevi associated with Carney complex [4]. The tumour cells express the melanocytic antigens, including gp100/HMB-45. Epidermal (occasionally pseudoepitheliomatous) hyperplasia is often present, as in our patient. Sentinel lymph node biopsy may reveal deposits of melanocytes within lymph nodes, simulating metastasis, but the evolution of PEM is usually indolent with no fatal outcome [4, 5]. A

/pdf/dermpath-clinic-pigmented-epithelioid-melanocytoma-3ogl3m4pm1.pdf

Dermpath & clinic: Pigmented epithelioid melanocytoma.

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