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15 pages, 5047 KiB

Open AccessArticle

SARS-CoV-2 and Skin: New Insights and Perspectives

by Gerardo Cazzato, Eliano Cascardi, Anna Colagrande, Caterina Foti, Alessandra Stellacci, Maricla Marrone, Giuseppe Ingravallo, Francesca Arezzo, Vera Loizzi, Antonio Giovanni Solimando, Paola Parente, Eugenio Maiorano, Gennaro Cormio, Angelo Vacca and Leonardo Resta

Biomolecules 2022, 12(9), 1212; https://doi.org/10.3390/biom12091212 - 31 Aug 2022

Cited by 10 | Viewed by 2927

Abstract

The SARS-CoV-2 pandemic has disrupted global health systems and brought the entire globe to its knees. Although born as a disease of the respiratory system, COVID-19 can affect different parts of the body, including the skin. Reports of ongoing skin manifestations of COVID-19 [...] Read more.

The SARS-CoV-2 pandemic has disrupted global health systems and brought the entire globe to its knees. Although born as a disease of the respiratory system, COVID-19 can affect different parts of the body, including the skin. Reports of ongoing skin manifestations of COVID-19 have gradually multiplied, pushing researchers to investigate the etiopathogenic mechanisms underlying these phenomena in more depth. In an attempt to investigate the possible association between SARS-CoV-2, ACE2, TMPRSS2 and skin manifestations, we performed immunohistochemical investigations of the ACE2 receptor and TMPRSS2 in nine skin samples from SARS-CoV-2-positive patients compared to a cohort of healthy controls. Furthermore, after consulting public databases regarding ACE2 mRNA expression in various cell populations resident in the skin, we conducted a literature review aimed at outlining the current state of this topic. We did not find statistically different immuno-expression of ACE2 and TMPRSS2 between the group of SARS-CoV-2-positive patients (nine skin biopsies) and the control group. Regarding ACE2, major immunolabeling was present in the epidermal keratinocytes and, rarely, in the fibroblasts and in the adenomeres of the eccrine sweat glands. Regarding the immune expression of TMPRSS2, we found no significant differences between the two groups, with a weak immune staining only in some skin cytotypes. From the review of the literature, we isolated 35 relevant articles according to the inclusion criteria adopted. ACE2 appears to be a target of SARS-CoV-2, although, other receptor molecules may potentially be implicated, such as TMPRSS2. Future studies with large cases and different molecular investigative methods are needed to further elucidate the mechanisms underlying the skin manifestations of SARS-CoV-2. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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11 pages, 1938 KiB

Open AccessFeature PaperArticle

COVID-19 and the Brain: The Neuropathological Italian Experience on 33 Adult Autopsies

by Viscardo P. Fabbri, Mattia Riefolo, Tiziana Lazzarotto, Liliana Gabrielli, Giovanna Cenacchi, Carmine Gallo, Raffaele Aspide, Guido Frascaroli, Rocco Liguori, Raffaele Lodi, Caterina Tonon, Antonietta D’Errico and Maria Pia Foschini

Biomolecules 2022, 12(5), 629; https://doi.org/10.3390/biom12050629 - 25 Apr 2022

Cited by 10 | Viewed by 14337

Abstract

Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first [...] Read more.

Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first (February–April 2020) and the second/third (November 2020–April 2021) pandemic waves are described. In all the cases, SARS-CoV-2 RNA was searched. Pathological findings are described and compared with those presently published. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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17 pages, 5340 KiB

Open AccessArticle

Spectrum of Kidney Injury Following COVID-19 Disease: Renal Biopsy Findings in a Single Italian Pathology Service

by Alessandro Gambella, Antonella Barreca, Luigi Biancone, Dario Roccatello, Licia Peruzzi, Luca Besso, Carolina Licata, Angelo Attanasio, Mauro Papotti and Paola Cassoni

Biomolecules 2022, 12(2), 298; https://doi.org/10.3390/biom12020298 - 12 Feb 2022

Cited by 14 | Viewed by 3326

Abstract

The onset of coronavirus disease (COVID-19) as a pandemic infection, has led to increasing insights on its pathophysiology and clinical features being revealed, such as a noticeable kidney involvement. In this study, we describe the histopathological, immunofluorescence, and ultrastructural features of biopsy-proven kidney [...] Read more.

The onset of coronavirus disease (COVID-19) as a pandemic infection, has led to increasing insights on its pathophysiology and clinical features being revealed, such as a noticeable kidney involvement. In this study, we describe the histopathological, immunofluorescence, and ultrastructural features of biopsy-proven kidney injury observed in a series of SARS-CoV-2 positive cases in our institution from April 2020 to November 2021. We retrieved and retrospectively reviewed nine cases (two pediatric and seven adults) that experienced nephrotic syndrome (six cases), acute kidney injury (two cases), and a clinically silent microhematuria and leukocyturia. Kidney biopsies were investigated by means of light microscopy, direct immunofluorescence, and electron microscopy. The primary diagnoses were minimal change disease (four cases), acute tubular necrosis (two cases), collapsing glomerulopathy (two cases), and C3 glomerulopathy (one case). None of the cases showed viral or viral-like particles on ultrastructural analysis. Novel and specific histologic features on kidney biopsy related to SARS-CoV-2 infection have been gradually disclosed and reported, harboring relevant clinical and therapeutic implications. Recognizing and properly diagnosing renal involvement in patients experiencing COVID-19 could be challenging (due to the lack of direct proof of viral infection, e.g., viral particles) and requires a proper integration of clinical and pathological data. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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10 pages, 518 KiB

Open AccessArticle

Further Findings Concerning Endothelial Damage in COVID-19 Patients

by Monica Gelzo, Sara Cacciapuoti, Biagio Pinchera, Annunziata De Rosa, Gustavo Cernera, Filippo Scialò, Marika Comegna, Mauro Mormile, Gabriella Fabbrocini, Roberto Parrella, Gaetano Corso, Ivan Gentile and Giuseppe Castaldo

Biomolecules 2021, 11(9), 1368; https://doi.org/10.3390/biom11091368 - 16 Sep 2021

Cited by 7 | Viewed by 2160

Abstract

Systemic vascular damage with micro/macro-thrombosis is a typical feature of severe COVID-19. However, the pathogenesis of this damage and its predictive biomarkers remain poorly defined. For this reason, in this study, serum monocyte chemotactic protein (MCP)-2 and P- and E-selectin levels were analyzed [...] Read more.

Systemic vascular damage with micro/macro-thrombosis is a typical feature of severe COVID-19. However, the pathogenesis of this damage and its predictive biomarkers remain poorly defined. For this reason, in this study, serum monocyte chemotactic protein (MCP)-2 and P- and E-selectin levels were analyzed in 204 patients with COVID-19. Serum MCP-2 and P-selectin were significantly higher in hospitalized patients compared with asymptomatic patients. Furthermore, MCP-2 increased with the WHO stage in hospitalized patients. After 1 week of hospitalization, MCP-2 levels were significantly reduced, while P-selectin increased in patients in WHO stage 3 and decreased in patients in WHO stages 5–7. Serum E-selectin was not significantly different between asymptomatic and hospitalized patients. The lower MCP-2 levels after 1 week suggest that endothelial damage triggered by monocytes occurs early in COVID-19 disease progression. MCP-2 may also predict COVID-19 severity. The increase in P-selectin levels, which further increased in mild patients and reduced in severe patients after 1 week of hospitalization, suggests that the inactive form of the protein produced by the cleavage of the active protein from the platelet membrane is present. This may be used to identify a subset of patients that would benefit from targeted therapies. The unchanged levels of E-selectin in these patients suggest that endothelial damage is less relevant. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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12 pages, 6957 KiB

Open AccessArticle

HMGB1-TIM3-HO1: A New Pathway of Inflammation in Skin of SARS-CoV-2 Patients? A Retrospective Pilot Study

by Gerardo Cazzato, Anna Colagrande, Antonietta Cimmino, Gerolamo Cicco, Vincenza Sara Scarcella, Paola Tarantino, Lucia Lospalluti, Paolo Romita, Caterina Foti, Aurora Demarco, Sara Sablone, Pragnell Maria Victoria Candance, Sebastiano Cicco, Teresa Lettini, Giuseppe Ingravallo and Leonardo Resta

Biomolecules 2021, 11(8), 1219; https://doi.org/10.3390/biom11081219 - 16 Aug 2021

Cited by 11 | Viewed by 2994

Abstract

The SARS-CoV-2 pandemic has completely disrupted the health systems of the entire planet. From the earliest months, it became increasingly clear that in addition to affecting the upper airways and lungs, there were other organs that could be affected. Among these, the skin [...] Read more.

The SARS-CoV-2 pandemic has completely disrupted the health systems of the entire planet. From the earliest months, it became increasingly clear that in addition to affecting the upper airways and lungs, there were other organs that could be affected. Among these, the skin became a real “sentinel signal” to be able to even suspect COVID-19. Background: this study deals with a little-explored issue for now: the study of skin immunopathology in SARS-CoV-2 positive subjects ascertained using the most reliable methods available. Methods: we used skin biopsy samples from SARS-CoV-2 positive and negative patients, studying morphology (Hematoxylin-Eosin), T lymphocyte population (CD4 and CD8), three markers such as HMGB-1, TIM-3 and HO-1 by immunohistochemistry. Results: although the presence of the CD4 and CD8 T population did not differ statistically significantly, we found greater activation and release of HMGB-1 in skin samples from SARS-CoV-2 positive patients, greater immunolabeling for TIM-3 at the level of CD4 and CD8 and a reduced expression of Heme oxygenase 1. Conclusions: these results support the possibility that there is immune deregulation in SARS-CoV-2 positive patients who develop skin manifestations of various kinds. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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9 pages, 6289 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

SARS-CoV-2 and Skin: The Pathologist’s Point of View

by Gerardo Cazzato, Giulia Mazzia, Antonietta Cimmino, Anna Colagrande, Sara Sablone, Teresa Lettini, Roberta Rossi, Nadia Santarella, Rossella Elia, Eleonora Nacchiero, Michele Maruccia, Andrea Marzullo, Eugenio Maiorano, Giuseppe Giudice, Giuseppe Ingravallo and Leonardo Resta

Biomolecules 2021, 11(6), 838; https://doi.org/10.3390/biom11060838 - 04 Jun 2021

Cited by 12 | Viewed by 2797

Abstract

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million [...] Read more.

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real “sentinel” of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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16 pages, 2936 KiB

Open AccessEditor’s ChoiceArticle

Lower Gene Expression of Angiotensin Converting Enzyme 2 Receptor in Lung Tissues of Smokers with COVID-19 Pneumonia

by Francesca Lunardi, Francesco Fortarezza, Luca Vedovelli, Federica Pezzuto, Annalisa Boscolo, Marco Rossato, Roberto Vettor, Anna Maria Cattelan, Claudia Del Vecchio, Andrea Crisanti, Paolo Navalesi, Dario Gregori and Fiorella Calabrese

Biomolecules 2021, 11(6), 796; https://doi.org/10.3390/biom11060796 - 26 May 2021

Cited by 2 | Viewed by 2492

Abstract

Angiotensin-converting enzyme 2 (ACE-2) is the main cell entry receptor for severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), thus playing a critical role in causing Coronavirus disease 2019 (COVID-19). The role of smoking habit in the susceptibility to infection is still controversial. In this study [...] Read more.

Angiotensin-converting enzyme 2 (ACE-2) is the main cell entry receptor for severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), thus playing a critical role in causing Coronavirus disease 2019 (COVID-19). The role of smoking habit in the susceptibility to infection is still controversial. In this study we correlated lung ACE-2 gene expression with several clinical/pathological data to explore susceptibility to infection. This is a retrospective observational study on 29 consecutive COVID-19 autopsies. SARS-CoV-2 genome and ACE-2 mRNA expression were evaluated by real-time polymerase chain reaction in lung tissue samples and correlated with several data with focus on smoking habit. Smoking was less frequent in high than low ACE-2 expressors (p = 0.014). A Bayesian regression also including age, gender, hypertension, and virus quantity confirmed that smoking was the most probable risk factor associated with low ACE-2 expression in the model. A direct relation was found between viral quantity and ACE-2 expression (p = 0.028). Finally, high ACE-2 expressors more frequently showed a prevalent pattern of vascular injury than low expressors (p = 0.049). In conclusion, ACE-2 levels were decreased in the lung tissue of smokers with severe COVID-19 pneumonia. These results point out complex biological interactions between SARS-CoV-2 and ACE-2 particularly concerning the aspect of smoking habit and need larger prospective case series and translational studies. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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8 pages, 2567 KiB

Open AccessCase Report

Adventitial Microcirculation Is a Major Target of SARS-CoV-2-Mediated Vascular Inflammation

by Francesco Vasuri, Carmen Ciavarella, Salvatore Collura, Chiara Mascoli, Sabrina Valente, Alessio Degiovanni, Mauro Gargiulo, Miriam Capri and Gianandrea Pasquinelli

Biomolecules 2021, 11(7), 1063; https://doi.org/10.3390/biom11071063 - 20 Jul 2021

Cited by 10 | Viewed by 2320

Abstract

We report the case of a 77-year-old woman affected by coronavirus disease-19 (COVID-19) who developed an occlusive arterial disease of the lower limb requiring a left leg amputation. We studied the mechanisms of vascular damage by SARS-CoV-2 by means of a comprehensive multi-technique [...] Read more.

We report the case of a 77-year-old woman affected by coronavirus disease-19 (COVID-19) who developed an occlusive arterial disease of the lower limb requiring a left leg amputation. We studied the mechanisms of vascular damage by SARS-CoV-2 by means of a comprehensive multi-technique in situ analysis on the diseased popliteal arterial district, including immunohistochemistry (IHC), transmission electron microscopy (TEM) and miRNA analysis. At histological analyses, we observed a lymphocytic inflammatory infiltrate, oedema and endothelialitis of adventitial vasa vasorum while the media was normal and the intima had only minor changes. The vasa vasorum expressed the ACE2 receptor and factor VIII; compared with the controls, VEGFR2 staining was reduced. TEM analyses showed endothelial injury and numerous Weibel–Palade bodies in the cytoplasm. No coronavirus particle was seen. IL-6 protein and mRNA, together with miR-155-5p and miRs-27a-5p, which can target IL-6, were significantly increased compared with that in the controls. Our case report suggests an involvement of adventitial artery microcirculation by inflammation in the course of COVID-19. Without evident signs of current infection by SARS-CoV-2, endothelial cells show a spectrum of structural and functional alterations that can fuel the cardiovascular complications observed in people infected with SARS-CoV-2. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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