Pathophysiology

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15/01/2021 Correspondence
Assessing the importance of interleukin-6 in COVID-19

THE LANCET

Authors
Luke Y C Chen Ryan L Hoiland Sophie Stukas Cheryl L Wellington Mypinder S Sekhon

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14/01/2021 News
COVID’s toll on smell and taste: what scientists do and don’t know

NATURE

Authors
Michael Marshall

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11/01/2021 Articles
A novel ACE2 isoform is expressed in human respiratory epithelia and i...

A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection

NATURE

Authors
Cornelia Blume, Claire L. Jackson, Cosma Mirella Spalluto, Jelmer Legebeke, Liliya Nazlamova, Franco Conforti, Jeanne-Marie Perotin, Martin Frank, John Butler, Max Crispin, Janice Coles, James Thompson, Robert A. Ridley, Lareb S. N. Dean, Matthew Loxham, Stephanie Reikine, Adnan Azim, Kamran Tariq, David A. Johnston, Paul J. Skipp, Ratko Djukanovic, Diana Baralle, Christopher J. McCormick, Donna E. Davies, Jane S. Lucas, Gabrielle Wheway, Vito Mennella

Abstract
Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma membrane, resulting in viral RNA genome delivery into the host. Despite ACE2’s critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.

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30/12/2020 Articles
NIH study uncovers blood vessel damage and inflammation in COVID-19 pa...

NIH study uncovers blood vessel damage and inflammation in COVID-19 patients’ brains but no infection

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A.

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21/12/2020 Articles
The SARS-CoV-2 RNA–protein interactome in infected human cells

NATURE

Authors
Nora Schmidt, Caleb A. Lareau, Hasmik Keshishian, Sabina Ganskih, Cornelius Schneider, Thomas Hennig, Randy Melanson, Simone Werner, Yuanjie Wei, Matthias Zimmer, Jens Ade, Luisa Kirschner, Sebastian Zielinski, Lars Dölken, Eric S. Lander, Neva Caliskan, Utz Fischer, Jörg Vogel, Steven A. Carr, Jochen Bodem, Mathias Munschauer

Abstract
Characterizing the interactions that SARS-CoV-2 viral RNAs make with host cell proteins during infection can improve our understanding of viral RNA functions and the host innate immune response. Using RNA antisense purification and mass spectrometry, we identified up to 104 human proteins that directly and specifically bind to SARS-CoV-2 RNAs in infected human cells. We integrated the SARS-CoV-2 RNA interactome with changes in proteome abundance induced by viral infection and linked interactome proteins to cellular pathways relevant to SARS-CoV-2 infections. We demonstrated by genetic perturbation that cellular nucleic acid-binding protein (CNBP) and La-related protein 1 (LARP1), two of the most strongly enriched viral RNA binders, restrict SARS-CoV-2 replication in infected cells and provide a global map of their direct RNA contact sites. Pharmacological inhibition of three other RNA interactome members, PPIA, ATP1A1, and the ARP2/3 complex, reduced viral replication in two human cell lines. The identification of host dependency factors and defence strategies as presented in this work will improve the design of targeted therapeutics against SARS-CoV-2.

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16/12/2020 Articles
The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice

NATURE

Authors
Elizabeth M. Rhea, Aric F. Logsdon, Kim M. Hansen, Lindsey M. Williams, May J. Reed, Kristen K. Baumann, Sarah J. Holden, Jacob Raber, William A. Banks, Michelle A. Erickson

Abstract
It is unclear whether severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019, can enter the brain. Severe acute respiratory syndrome coronavirus 2 binds to cells via the S1 subunit of its spike protein. We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood–brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver. Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake but had variable effects on uptake by the olfactory bulb, liver, spleen and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the blood–brain barrier by adsorptive transcytosis and that murine angiotensin-converting enzyme 2 is involved in brain and lung uptake, but not in kidney, liver or spleen uptake.

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12/12/2020 Communication
IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fa...

IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients

CELLS

Authors
Léonie A. N. Staats, Hella Pfeiffer, Jasmin Knopf, Aylin Lindemann, Julia Fürst, Andreas E. Kremer, Holger Hackstein, Markus F. Neurath, Luis E. Muñoz, Susanne Achenbach, Moritz Leppkes, Martin Herrmann, Georg Schett, Ulrike Steffen

Abstract
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.

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09/12/2020 Press Release
COVID-19 neutralizing antibodies predict disease severity and survival

CELL

Authors
Wilfredo F. Garcia-Beltran, Evan C. Lam, Michael G. Astudillo, Diane Yang, Tyler E. Miller, Jared Feldman, Blake M. Hauser, Timothy M. Caradonna, Kiera L. Clayton, Adam D. Nitido, Mandakolathur R. Murali, Galit Alter, Richelle C. Charles, Anand Dighe, John A. Branda, Jochen K. Lennerz, Daniel Lingwood, Aaron G. Schmidt, A. John Iafrate, Alejandro B. Balazs

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09/12/2020 Articles
Decreased serum level of sphingosine-1-phosphate: a novel predictor of...

Decreased serum level of sphingosine-1-phosphate: a novel predictor of clinical severity in COVID-19

EMBO PRESS

Authors
Giovanni Marfia, Stefania Navone, Laura Guarnaccia, Rolando Campanella, Michele Mondoni, Marco Locatelli, Alessandra Barassi, Laura Fontana, Fabrizio Palumbo, Emanuele Garzia, Giuseppe Ciniglio Appiani, Davide Chiumello, Monica Miozzo, Stefano Centanni, Laura Riboni

Abstract

The severity of coronavirus disease 2019 (COVID-19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine-1-phosphate (S1P) along with severity markers, in COVID-19 patients. One hundred eleven COVID-19 patients and forty-seven healthy subjects were included. The severity of COVID-19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil-to-lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C-reactive protein (CRP), and D-dimer. Serum S1P level was inversely associated with COVID-19 severity, being significantly correlated with CRP, LDH, ferritin, and D-dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient's outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID-19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID-19.

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07/12/2020 Research
Metabolic reprogramming and epigenetic changes of vital organs in SARS...

Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2 induced systemic toxicity

JCI INSIGHT

Authors
Shen Li, Feiyang Ma, Tomohiro Yokota, Gustavo Garcia Jr., Amelia Palermo, Yijie Wang, Colin Farrell, Yu-Chen Wang, Rimao Wu, Zhiqiang Zhou, Calvin Pan, Marco Morselli, Michael A. Teitell, Sergey Ryazantsev, Gregory A. Fishbein, Johanna ten Hoeve, Valerie A. Arboleda, Joshua Bloom, Barbara J. Dillon, Matteo Pellegrini, Aldons J. Lusis, Thomas G. Graeber, Vaithilingaraja Arumugaswami, Arjun Deb

Extra-pulmonary manifestations of COVID-19 are associated with a much higher mortality rate. Yet, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2 induced severe systemic toxicity and multi-organ involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery followed by systemic administration of SARS-CoV-2. The animals develop a profound phenotype within 7 days with severe weight loss, morbidity and failure to thrive. We demonstrate there is metabolic suppression of oxidative phosphorylation and the tri-carboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia and splenic atrophy mirroring human COVID-19 phenotypes. Animals had a significantly lower heart rate and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. We perform metabolomic profiling of peripheral blood and identify a panel of TCA cycle metabolites that serve as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, that affects expression of immune response genes and could in part contribute to COVID-19 pathogenesis. Our model suggests that SARS-CoV-2 induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19. 

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30/11/2020 Articles
Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervou...

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

NATURE

Authors
Jenny Meinhardt, Josefine Radke, Carsten Dittmayer, Jonas Franz, Carolina Thomas, Ronja Mothes, Michael Laue, Julia Schneider, Sebastian Brünink, Selina Greuel, Malte Lehmann, Olga Hassan, Tom Aschman, Elisa Schumann, Robert Lorenz Chua, Christian Conrad, Roland Eils, Werner Stenzel, Marc Windgassen, Larissa Rößler, Hans-Hilmar Goebel, Hans R. Gelderblom, Hubert Martin, Andreas Nitsche, Walter J. Schulz-Schaeffer, Samy Hakroush, Martin S. Winkler, Björn Tampe, Franziska Scheibe, Péter Körtvélyessy, Dirk Reinhold, Britta Siegmund, Anja A. Kühl, Sefer Elezkurtaj, David Horst, Lars Oesterhelweg, Michael Tsokos, Barbara Ingold-Heppner, Christine Stadelmann, Christian Drosten, Victor Max Corman, Helena Radbruch, Frank L. Heppner

Abstract
The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural–mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.

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26/11/2020 Articles
HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry

NATURE

Authors
Congwen Wei, Luming Wan, Qiulin Yan, Xiaolin Wang, Jun Zhang, Xiaopan Yang, Yanhong Zhang, Chen Fan, Dongyu Li, Yongqiang Deng, Jin Sun, Jing Gong, Xiaoli Yang, Yufei Wang, Xuejun Wang, Jianmin Li, Huan Yang, Huilong Li, Zhe Zhang, Rong Wang, Peng Du, Yulong Zong, Feng Yin, Wanchuan Zhang, Nan Wang, Yumeng Peng, Haotian Lin, Jiangyue Feng, Chengfeng Qin, Wei Chen, Qi Gao, Rui Zhang, Yuan Cao, Hui Zhong

Abstract
Responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through binding of the viral spike protein (SARS-2-S) to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). Here we show that the high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitates ACE2-dependent entry of SARS-CoV-2. We find that the S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components to enhance viral uptake in vitro. SR-B1 expression facilitates SARS-CoV-2 entry into ACE2-expressing cells by augmenting virus attachment. Blockade of the cholesterol-binding site on SARS-2-S1 with a monoclonal antibody, or treatment of cultured cells with pharmacological SR-B1 antagonists, inhibits HDL-enhanced SARS-CoV-2 infection. We further show that SR-B1 is coexpressed with ACE2 in human pulmonary tissue and in several extrapulmonary tissues. Our findings reveal that SR-B1 acts as a host factor that promotes SARS-CoV-2 entry and may help explain viral tropism, identify a possible molecular connection between COVID-19 and lipoprotein metabolism, and highlight SR-B1 as a potential therapeutic target to interfere with SARS-CoV-2 infection.

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25/11/2020 Brief Report
Visceral fat is associated to the severity of COVID-19

METABOLISM CLINICAL AND EXPERIMENTAL

Authors
Guillaume Favre, Kevin Legueult, Christian Pradier, Charles Raffaelli, Carole Ichai, Antonio Iannelli, Alban Redheuil, Olivier Lucidarme, Vincent Esnaulta

Abstract

Background

Excess visceral fat (VF) or high body mass index (BMI) is risk factors for severe COVID-19. The receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expressed at higher levels in the VF than in the subcutaneous fat (SCF) of obese patients.

Aim

To show that visceral fat accumulation better predicts severity of COVID-19 outcome compared to either SCF amounts or BMI.

Methods

We selected patients with symptomatic COVID-19 and a computed tomography (CT) scan. Severe COVID-19 was defined as requirement for mechanical ventilation or death. Fat depots were quantified on abdominal CT scan slices and the measurements were correlated with the clinical outcomes. ACE 2 mRNA levels were quantified in fat depots of a separate group of non-COVID-19 subjects using RT-qPCR.

Results

Among 165 patients with a mean BMI of 26.1 ± 5.4 kg/m2, VF was associated with severe COVID-19 (p = 0.022) and SCF was not (p = 0.640). Subcutaneous fat was not different in patients with mild or severe COVID-19 and the SCF/VF ratio was lower in patients with severe COVID-19 (p = 0.010). The best predictive value for severe COVID-19 was found for a VF area ≥128.5 cm2 (ROC curve), which was independently associated with COVID-19 severity (p < 0.001). In an exploratory analysis, ACE 2 mRNA positively correlated with BMI in VF but not in SCF of non-COVID-19 patients (r2 = 0.27 vs 0.0008).

Conclusion

Severe forms of COVID-19 are associated with high visceral adiposity in European adults. On the basis of an exploratory analysis ACE 2 in the visceral fat may be a trigger for the cytokine storm, and this needs to be clarified by future studies.

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25/11/2020 Brief Report
Clinical, Laboratory, and Interferon-Alpha Response Characteristics of...

Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic

JAMA

Authors
Thomas Hubiche, Nathalie Cardot-Leccia, Florence Le Duff, Barbara Seitz-Polski, Pascal Giordana, Christine Chiaverini, Valérie Giordanengo, Géraldine Gonfrier, Vincent Raimondi, Olivier Bausset, Zoubir Adjtoutah, Margaux Garnier, Fanny Burel-Vandenbos, Bérengère Dadone-Montaudié, Véréna Fassbender, Aurélia Palladini, Johan Courjon, Véronique Mondain, Julie Contenti, Jean Dellamonica, Georges Leftheriotis, Thierry Passeron

Abstract
Importance Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown.

Objective To perform a systematic clinical, histologic, and biologic assessment in a cohort of patients with chilblain-like lesions occurring during the COVID-19 pandemic.

Design, Setting, and Participants In this prospective case series carried out with a COVID-19 multidisciplinary consultation group at the University Hospital of Nice, France, 40 consecutive patients presenting with chilblain-like lesions were included.

Main Outcomes and Measures Patients underwent a thorough general and dermatologic examination, including skin biopsies, vascular investigations, biologic analyses, interferon-alpha (IFN-α) stimulation and detection, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) and serologic analysis.

Results Overall, 40 consecutive patients with chilblain-like lesions were included. Most patients were young, with a median (range) age of 22 (12-67) years; 19 were male and 21 were female. The clinical presentation was highly reproducible with chilblain-like lesions mostly on the toes. Bullous and necrotic evolution was observed in 11 patients. Acrocyanosis or cold toes were reported in 19 (47.5%) cases. Criteria compatible with COVID-19 cases were noted in 11 (27.5%) within 6 weeks prior to the eruption. The real-time PCR (rt-PCR) testing results were negative in all cases. Overall, SARS-CoV-2 serology results were positive in 12 patients (30%). D-dimer concentration levels were elevated in 24 (60.0%) cases. Cryoglobulinemia and parvovirus B19 serologic results were negative for all tested patients. The major histologic findings were features of lymphocytic inflammation and vascular damage with thickening of venule walls and pericyte hyperplasia. A significant increase of IFN-α production after in vitro stimulation was observed in the chilblain population compared with patients with mild-severe acute COVID-19.

Conclusions and Relevance Taken together, our results suggest that chilblain-like lesions observed during the COVID-19 pandemic represent manifestations of a viral-induced type I interferonopathy.

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23/11/2020 Case Report
Insulin Treatment Is Associated with Increased Mortality in Patients w...

Insulin Treatment Is Associated with Increased Mortality in Patients with COVID-19 and Type 2 Diabetes

CELL METABOLISM

Authors
Bo Yu, Chenze Li, Yang Sun, Dao Wen Wang

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23/11/2020 Articles
Diagnosis, Management, and Pathophysiology of Arterial and Venous Thro...

Diagnosis, Management, and Pathophysiology of Arterial and Venous Thrombosis in COVID-19

JAMA

Authors
Gregory Piazza, David A. Morrow

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17/11/2020 News
Can Autoimmune Antibodies Explain Blood Clots in COVID-19?

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
Francis Collins

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17/11/2020 Original Research
Incidence of VTE and Bleeding Among Hospitalized Patients With Coronav...

Incidence of VTE and Bleeding Among Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis

SCIENCE

Authors
David Jiménez, Aldara García-Sanchez, Parth Rali, Alfonso Muriel, Behnood Bikdeli, Pedro Ruiz-Artacho, Raphael Le Mao, Carmen Rodríguez, Beverley J. Hunt, Manuel Monreal

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13/11/2020 Articles
JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates infl...

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality

SCIENCE

Authors
Justin Stebbing, Ginés Sánchez Nievas, Marco Falcone, Sonia Youhanna, Peter Richardson, Silvia Ottaviani, Joanne X. Shen, Christian Sommerauer, Giusy Tiseo, Lorenzo Ghiadoni3, Agostino Virdis, Fabio Monzani, Luis Romero Rizos, Francesco Forfori, Almudena Avendaño-Céspedes, Salvatore De Marco, Laura Carrozzi, Fabio Lena, Pedro Manuel Sánchez-Jurado, Leonardo Gianluca Lacerenza, Nencioni Cesira, David Caldevilla-Bernardo, Antonio Perrella, Laura Niccoli, Lourdes Sáez Méndez, Daniela Matarrese, Delia Goletti, Yee-Joo Tan, Vanessa Monteil, George Dranitsaris, Fabrizio Cantini, Alessio Farcomeni, Shuchismita Dutta, Stephen K. Burley, Haibo Zhang, Mauro Pistello, William Li, Marta Mas Romero, Fernando Andrés Pretel, Rafaela Sánchez Simón-Talero, Rafael García-Molina, Claudia Kutter, James H. Felce, Zehra F. Nizami, Andras G. Miklosi, Josef M. Penninger, Francesco Menichetti, Ali Mirazimi, Pedro Abizanda, Volker M. Lauschke

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12/11/2020 Research
Assessment of SARS-CoV-2 RNA Test Results Among Patients Who Recovered...

Assessment of SARS-CoV-2 RNA Test Results Among Patients Who Recovered From COVID-19 With Prior Negative Results

JAMA

Authors
Flora Marzia Liotti, Giulia Menchinelli, Simona Marchetti, Brunella Posteraro, Francesco Landi, Maurizio Sanguinetti, Paola Cattani

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10/11/2020 News
Coronaviruses hijack lysosomes to exit cells

NIH (NATIONAL INSTITUTES OF HEALTH)

Authors
NIH (NATIONAL INSTITUTES OF HEALTH)

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06/11/2020 Articles
Tissue-resident CD8+ T cells drive age-associated chronic lung sequel...

Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia

SCIENCE

Authors
Nick P. Goplen, Yue Wu, Young Min Son, Chaofan Li, Zheng Wang, In Su Cheon, Li Jiang, Bibo Zhu, Katayoun Ayasoufi, Eduardo N. Chini, Aaron J. Johnson, Robert Vassallo, Andrew H. Limper, Nu Zhang, Jie Sun

Abstract
Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.

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03/11/2020 Articles
Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallm...

Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology

THE LANCET

Authors
Rossana Bussani, Edoardo Schneider, Lorena Zentilin , Chiara Collesi, Hashim Ali, Luca Braga, Maria Concetta Volpe, Andrea Colliva, Fabrizio Zanconati, Giorgio Berlot, Furio Silvestri, Serena Zacchigna, Mauro Giacca

Abstract
Background
COVID-19 is a deadly pulmonary disease with peculiar characteristics, which include variable clinical course and thrombophilia. A thorough understanding of the pathological correlates of the disease is still missing.

Methods
Here we report the systematic analysis of 41 consecutive post-mortem samples from individuals who died of COVID-19. Histological analysis is complemented by immunohistochemistry for cellular and viral antigens and the detection of viral genomes by in situ RNA hybridization.

Findings
COVID-19 is characterized by extensive alveolar damage (41/41 of patients) and thrombosis of the lung micro- and macro-vasculature (29/41, 71%). Thrombi were in different stages of organization, consistent with their local origin. Pneumocytes and endothelial cells contained viral RNA even at the later stages of the disease. An additional feature was the common presence of a large number of dysmorphic pneumocytes, often forming syncytial elements (36/41, 87%). Despite occasional detection of virus-positive cells, no overt signs of viral infection were detected in other organs, which showed non-specific alterations.

Interpretation
COVID-19 is a unique disease characterized by extensive lung thrombosis, long-term persistence of viral RNA in pneumocytes and endothelial cells, along with the presence of infected cell syncytia. Several of COVID-19 features might be consequent to the persistence of virus-infected cells for the duration of the disease.

Funding
This work was supported by a King's Together Rapid COVID-19 Call grant from King's College London. MG is supported by the European Research Council (ERC) Advanced Grant 787971 “CuRE” and by Programme Grant RG/19/11/34633 from the British Heart Foundation.

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27/10/2020 Articles
VITAMIN D STATUS IN HOSPITALIZED PATIENTS WITH SARS-CoV-2 INFECTION

OXFORD ACADEMY - JCEM (JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM)

Authors
José L. Hernández, Daniel Nan, Marta Fernandez-Ayala, Mayte García-Unzueta, Miguel A. Hernández-Hernández, Marcos López-Hoyos, Pedro Muñoz Cacho, José M. Olmos, Manuel Gutiérrez-Cuadra, Juan J. Ruiz-Cubillá, Javier Crespo, Víctor M. Martínez-Taboada

Abstract
Background
The role of vitamin D status in COVID-19 patients is a matter of debate.

Objectives
To assess serum 25-hydroxyvitamin D (25OHD) levels in hospitalized patients with COVID-19 and to analyze the possible influence of vitamin D status on disease severity.

Methods
Retrospective case-control study of 216 COVID-19 patients and 197 population-based controls. Serum 25OHD levels were measured in both groups. Besides, the association of serum 25OHD levels with COVID-19 severity (admission to the Intensive Care Unit, requirements for mechanical ventilation, or mortality) was also evaluated.

Results
Of the 216 patients, 19 were on vitamin D supplements and were analyzed separately. In COVID-19 patients, mean±SD 25OHD levels were 13.8±7.2 ng/ml, compared to 20.9±7.4 ng/ml in controls (p<0.0001). 25OHD values were lower in men than in women. Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (p<0.0001). 25OHD inversely correlate to serum ferritin (p=0.013) and D-dimer levels (p=0.027). Vitamin D-deficient COVID-19 patients had a greater prevalence of hypertension and cardiovascular diseases, raised serum ferritin and troponin levels, as well as a longer length of hospital stay than those with serum 25OHD levels ≥20 ng/ml. No causal relationship was found between vitamin D deficiency and COVID-19 severity as a combined endpoint or as its separate components.

Conclusions
25OHD levels are lower in hospitalized COVID-19 patients compared to population-based controls and these patients had a higher prevalence of deficiency. We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease.

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27/10/2020 Correspondence
RAAS Inhibitors and Risk of Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
NEJM GROUP

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20/10/2020 Articles
Cell‐mediated and humoral adaptive immune responses to SARS‐CoV‐2 are ...

Cell‐mediated and humoral adaptive immune responses to SARS‐CoV‐2 are lower in asymptomatic than symptomatic COVID‐19 patients

EUROPEAN JOURNAL OF IMMUNOLOGY

Authors
Alessio Mazzoni Laura Maggi Manuela Capone Michele Spinicci Lorenzo Salvati Maria Grazia Colao Anna Vanni Seble Tekle Kiros Jessica Mencarini Lorenzo Zammarchi Elisabetta Mantengoli Lorenzo Menicacci Eleonora Caldini Sergio Romagnani Francesco Liotta Alessandro Morettini Gian Maria Rossolini Alessandro Bartoloni Lorenzo Cosmi Francesco Annunziato

Abstract
The characterization of cell‐mediated and humoral adaptive immune responses to SARS‐CoV‐2 is fundamental to understand COVID‐19 progression and the development of immunological memory to the virus. In this study, we detected T‐cells reactive to SARS‐CoV‐2 proteins M, S, and N, as well as serum virus‐specific IgM, IgA, IgG, in nearly all SARS‐CoV‐2 infected individuals, but not in healthy donors. Virus‐reactive T cells exhibited signs of in vivo activation, as suggested by the surface expression of immune‐checkpoint molecules PD1 and TIGIT. Of note, we detected antigen‐specific adaptive immune response both in asymptomatic and symptomatic SARS‐CoV‐2 infected subjects. More importantly, symptomatic patients displayed a significantly higher magnitude of both cell‐mediated and humoral adaptive immune response to the virus, as compared to asymptomatic individuals. These findings suggest that an uncontrolled adaptive immune response contribute to the development of the life‐threatening inflammatory phase of the disease. Finally, this study might open the way to develop effective vaccination strategies.

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18/10/2020 Articles
Systematic review of EEG findings in 617 patients diagnosed with COVID...

Systematic review of EEG findings in 617 patients diagnosed with COVID-19

SEIZURE

Authors
Arun Raj Antony, Zulfi Haneef

Abstract
Objective
We performed a systematic review of the literature to synthesize the data on EEG findings in COVID-19. Frontal EEG patterns are reported to be a characteristic finding in COVID-19 encephalopathy. Although several reports of EEG abnormalities are available, there is lack of clarity about typical findings.
Methods
Research databases were queried with the terms “COVID” OR “coronavirus” OR “SARS” AND “EEG”. Available data was analyzed from 617 patients with EEG findings reported in 84 studies.
Results
The median age was 61.3 years (IQR 45−69, 33.3 % female). Common EEG indications were altered mental status (61.7 %), seizure-like events (31.2 %), and cardiac arrest (3.5 %). Abnormal EEG findings (n = 543, 88.0 %) were sub-classified into three groups: (1) Background abnormalities: diffuse slowing (n = 423, 68.6 %), focal slowing (n = 105, 17.0 %), and absent posterior dominant rhythm (n = 63, 10.2 %). (2) Periodic and rhythmic EEG patterns: generalized periodic discharges (n = 35, 5.7 %), lateralized/multifocal periodic discharges (n = 24, 3.9 %), generalized rhythmic activity (n = 32, 5.2 %). (3) Epileptiform changes: focal (n = 35, 5.7 %), generalized (n = 27, 4.4 %), seizures/status epilepticus (n = 34, 5.5 %). Frontal EEG patterns comprised of approximately a third of all findings. In studies that utilized continuous EEG, 96.8 % (n = 243) of the 251 patients were reported to have abnormalities compared to 85.0 % (n = 311) patients who did not undergo continuous EEG monitoring (χ2 = 22.8, p =< 0.001).
Significance
EEG abnormalities are common in COVID-19 related encephalopathy and correlates with disease severity, preexisting neurological conditions including epilepsy and prolonged EEG monitoring. Frontal findings are frequent and have been proposed as a biomarker for COVID-19 encephalopathy.

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16/10/2020 Reviews
Cytokine elevation in severe and critical COVID-19: a rapid systematic...

Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes

THE LANCET

Authors
Daniel E Leisman*, Lukas Ronner*, Rachel Pinotti, Matthew D Taylor, Pratik Sinha, Carolyn S Calfee, Alexandre V Hirayama, Fiore Mastroiani, Cameron J Turtle, Michael O Harhay, Matthieu Legrand, Clifford S Deutschman

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08/10/2020 Articles
Two distinct immunopathological profiles in autopsy lungs of COVID-19

NATURE

Authors
Ronny Nienhold, Yari Ciani, Viktor H. Koelzer, Alexandar Tzankov, Jasmin D. Haslbauer, Thomas Menter, Nathalie Schwab, Maurice Henkel, Angela Frank, Veronika Zsikla, Niels Willi, Werner Kempf, Thomas Hoyler, Mattia Barbareschi, Holger Moch, Markus Tolnay, Gieri Cathomas, Francesca Demichelis, Tobias Junt & Kirsten D. Mertz

Abstract
Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.

Introduction

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08/10/2020 Articles
Large-Scale Multi-omic Analysis of COVID-19 Severity

CELL SYSTEMS

Authors
Katherine A. Overmyer, Evgenia Shishkova, Ian J. Miller, Ron Stewart, Joshua J. Coon, Ariel Jaitovich

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07/10/2020 Articles
Targeting pivotal inflammatory pathways in COVID-19: A mechanistic rev...

Targeting pivotal inflammatory pathways in COVID-19: A mechanistic review

ELSEVIER

Authors
Akram Yarmohammadi, Mostafa Yarmohammadi, Sajad Fakhri, Haroon Khan

Abstract
As an emerging global health crisis, coronavirus disease 2019 (COVID-19) has been labeled a worldwide pandemic. Growing evidence is revealing further pathophysiological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Amongst these dysregulated pathways inflammation seems to play a more critical role toward COVID-19 complications. In the present study, precise inflammatory pathways triggered by SARS-CoV-2, along with potential therapeutic candidates have been discussed.

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25/09/2020 Articles
Viral presence and immunopathology in patients with lethal COVID-19: a...

Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study

THE LANCET

Authors
Bernadette Schurink, Eva Roos, Teodora Radonic, Ellis Barbe, Catherine S C Bouman, Hans H de Boer, Godelieve J de Bree, Esther B Bulle, Eleonora M Aronica, Sandrine Florquin, Judith Fronczek, Leo M A Heunks, Menno D de Jong, Lihui Guo, Romy du Long, Rene Lutter, Pam C G Molenaar, E Andra Neefjes-Borst, Hans W M Niessen, Carel J M van Noesel, Joris J T H Roelofs, Eric J Snijder, Eline C Soer, Joanne Verheij, Alexander P J Vlaar, Wim Vos, Nicole N van der Wel, Allard C van der Wal, Paul van der Valk, Marianna Bugian

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25/09/2020 Articles
Viral presence and immunopathology in patients with lethal COVID-19: a...

Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study

THE LANCET

Authors
Bernadette Schurink, Eva Roos, Teodora Radonic, Ellis Barbe, Catherine S C Bouman, Hans H de Boer, Godelieve J de Bree, Esther B Bulle, Eleonora M Aronica, Sandrine Florquin, Judith Fronczek, Leo M A Heunks, Menno D de Jong, Lihui Guo, Romy du Long, Rene Lutter, Pam C G Molenaar, E Andra Neefjes-Borst, Hans W M Niessen, Carel J M van Noesel, Joris J T H Roelofs, Eric J Snijder, Eline C Soer, Joanne Verheij, Alexander P J Vlaar, Wim Vos, Nicole N van der Wel, Allard C van der Wal, Paul van der Valk, Marianna Bugiani

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23/09/2020 Original Investigation
Association of Red Blood Cell Distribution Width With Mortality Risk i...

Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection

JAMA

Authors
Brody H. Foy, Jonathan C. T. Carlson, Erik Reinertsen, Raimon Padros I. Valls, Roger Pallares Lopez, Eric Palanques-Tost, Christopher Mow, M. Brandon Westover, Aaron D. Aguirre, John M. Higgins

Abstract
Importance Coronavirus disease 2019 (COVID-19) is an acute respiratory illness with a high rate of hospitalization and mortality. Biomarkers are urgently needed for patient risk stratification. Red blood cell distribution width (RDW), a component of complete blood counts that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases.

Objective To investigate whether an association between mortality risk and elevated RDW at hospital admission and during hospitalization exists in patients with COVID-19.

Design, Setting, and Participants This cohort study included adults diagnosed with SARS-CoV-2 infection and admitted to 1 of 4 hospitals in the Boston, Massachusetts area (Massachusetts General Hospital, Brigham and Women’s Hospital, North Shore Medical Center, and Newton-Wellesley Hospital) between March 4, 2020, and April 28, 2020.

Main Outcomes and Measures The main outcome was patient survival during hospitalization. Measures included RDW at admission and during hospitalization, with an elevated RDW defined as greater than 14.5%. Relative risk (RR) of mortality was estimated by dividing the mortality of those with an elevated RDW by the mortality of those without an elevated RDW. Mortality hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazards model.

Results A total of 1641 patients were included in the study (mean [SD] age, 62[18] years; 886 men [54%]; 740 White individuals [45%] and 497 Hispanic individuals [30%]; 276 nonsurvivors [17%]). Elevated RDW (>14.5%) was associated with an increased mortality risk in patients of all ages. The RR for the entire cohort was 2.73, with a mortality rate of 11% in patients with normal RDW (1173) and 31% in those with an elevated RDW (468). The RR in patients younger than 50 years was 5.25 (normal RDW, 1% [n = 341]; elevated RDW, 8% [n = 65]); 2.90 in the 50- to 59-year age group (normal RDW, 8% [n = 256]; elevated RDW, 24% [n = 63]); 3.96 in the 60- to 69-year age group (normal RDW, 8% [n = 226]; elevated RDW, 30% [104]); 1.45 in the 70- to 79-year age group (normal RDW, 23% [n = 182]; elevated RDW, 33% [n = 113]); and 1.59 in those ≥80 years (normal RDW, 29% [n = 168]; elevated RDW, 46% [n = 123]). RDW was associated with mortality risk in Cox proportional hazards models adjusted for age, D-dimer (dimerized plasmin fragment D) level, absolute lymphocyte count, and common comorbidities such as diabetes and hypertension (hazard ratio of 1.09 per 0.5% RDW increase and 2.01 for an RDW >14.5% vs ≤14.5%; P < .001). Patients whose RDW increased during hospitalization had higher mortality compared with those whose RDW did not change; for those with normal RDW, mortality increased from 6% to 24%, and for those with an elevated RDW at admission, mortality increased from 22% to 40%.

Conclusions and Relevance Elevated RDW at the time of hospital admission and an increase in RDW during hospitalization were associated with increased mortality risk for patients with COVID-19 who received treatment at 4 hospitals in a large academic medical center network.

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20/09/2020 New Result
Neuroinvasion of SARS-CoV-2 in human and mouse brain

BIORXIV

Authors
Eric Song, Ce Zhang, Benjamin Israelow, Alice Lu-Culligan, Alba Vieites Prado, Sophie Skriabine, Peiwen Lu, Orr-El Weizman, Feimei Liu, Yile Dai, Klara Szigeti-Buck, Yuki Yasumoto, Guilin Wang, Christopher Castaldi, Jaime Heltke, Evelyn Ng, John Wheeler, Mia Madel Alfajaro, Etienne Levavasseur, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Syed A. Jaffar Kazmi, Kai Zhang, Craig B Wilen, Tamas L. Horvath, Isabelle Plu, Stephane Haik, Jean-Leon Thomas, Angeliki Louvi, Shelli F. Farhadian, Anita Huttner, Danielle Seilhean, Nicolas Renier, ProfileKaya Bilguvar, Akiko Iwasaki

ABSTRACT
Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

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15/09/2020 Features
HOW COVID-19 CAN DAMAGE THE BRAIN

NATURE

Authors
Michael Marshall

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03/09/2020 Articles
COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads ...

COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm

NATURE

Authors
Wonhwa Lee, June Hong Ahn, Hee Ho Park, Hong Nam Kim, Hyelim Kim, Youngbum Yoo, Hyosoo Shin, Kyung Soo Hong, Jong Geol Jang, Chun Gwon Park, Eun Young Choi, Jong-Sup Bae, Young-Kyo Seo

ABSTRACT
Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients’ blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.

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31/08/2020 Correspondence
Haemoglobin oxygen affinity in patients with severe COVID‐19 infection...

Haemoglobin oxygen affinity in patients with severe COVID‐19 infection: Still unclear

WILEY ONLINE LIBRARY

Authors
Gurgen Harutyunyan Garnik Harutyunyan Gagik Mkhoyan Varsenik Harutyunyan Suren Soghomonyan

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27/08/2020 Articles
Pathophysiology of COVID-19-associated acute respiratory distress synd...

Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study

THE LANCET

Authors
Giacomo Grasselli, Tommaso Tonetti, Alessandro Protti, Thomas Langer, Massimo Girardis, Giacomo Bellani, John Laffey, Gianpaolo Carrafiello, Luca Carsana, Chiara Rizzuto, Alberto Zanella, Vittorio Scaravilli, Giacinto Pizzilli, Domenico Luca Grieco, Letizia Di Meglio, Gennaro de Pascale, Ezio Lanza, Francesco Monteduro, Maurizio Zompatori, Claudia Filippini, Franco Locatelli, Maurizio Cecconi, Roberto Fumagalli, Stefano Nava, Jean-Louis Vincent, Massimo Antonelli, Arthur S Slutsky, Antonio Pesenti, V Marco Ranieri

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02/08/2020 Articles
SARS-CoV-2 can infect the placenta and is not associated with specific...

SARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers

NATURE

Authors
Jonathon L. Hecht, Bradley Quade, Vikram Deshpande, Mari Mino-Kenudson, David T. Ting, Niyati Desai, Beata Dygulska, Taryn Heyman, Carolyn Salafia, Dejun Shen, Sara V. Bates, Drucilla J. Roberts



ABSTRACT
Congenital infection of SARS-CoV-2 appears to be exceptionally rare despite many cases of COVID-19 during pregnancy. Robust proof of placental infection requires demonstration of viral localization within placental tissue. Only two of the few cases of possible vertical transmission have demonstrated placental infection. None have shown placental expression of the ACE2 or TMPRSS2 protein, both required for viral infection. We examined 19 COVID-19 exposed placentas for histopathologic findings, and for expression of ACE2, and TMPRSS2 by immunohistochemistry. Direct placental SARS-CoV-2 expression was studied by two methods—nucleocapsid protein expression by immunohistochemistry, and RNA expression by in situ hybridization. ACE2 membranous expression in the syncytiotrophoblast (ST) of the chorionic villi is predominantly in a polarized pattern with expression highest on the stromal side of the ST. In addition, cytotrophoblast and extravillous trophoblast express ACE2. No ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells. TMPRSS2 expression was only present weakly in the villous endothelium and rarely in the ST. In 2 of 19 cases, SARS-CoV-2 RNA was present in the placenta focally in the ST and cytotrophoblast. There was no characteristic histopathology present in our cases including the two placental infections. We found that the placenta is capable of being infected but that this event is rare. We propose one explanation could be the polarized expression of ACE2 away from the maternal blood and pronounced paucity of TMPRSS2 expression in trophoblast.

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25/07/2020 Communication
Nox2 activation in Covid-19

ELSEVIER

Authors
Francesco Violi, Alessandra Oliva, Roberto Cangemi, Giancarlo Ceccarelli, Pasquale Pignatelli, Roberto Carnevale, Vittoria Cammisotto, Miriam Lichtner, Francesco Alessandri, Massimiliano De Angelis, Maria Claudia Miele, Gabriella D’Ettorre Franco Ruberto, Mario Venditti, Francesco Pugliese, Claudio Maria Mastroianni



ABSTRACT
Nox2 is responsible for artery dysfunction via production of reactive oxidant species. RNA viruses may activate Nox2, but it is unknown if this occurs in coronavirus 2019(Covid-19). Nox2 activation by soluble Nox2-derived peptide(sNox2-dp) was measured in patients hospitalized for Covid-19 (n = 182) and controls (n = 91). sNox2-dp values were higher in Covid-19 patients versus controls and in severe versus non severe Covid-19. Patients with thrombotic events(n = 35,19%) had higher sNox2-dp than thrombotic event-free ones. A logistic regression analysis showed that sNox2 and coronary heart disease predicted thrombotic events. Oxidative stress by Nox2 activation is associated severe disease and thrombotic events in Covid-19 patients.

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16/07/2020 Articles
Histopathology and ultrastructural findings of fatal COVID-19 infectio...

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series

THE LANCET

Authors
Benjamin T Bradley, Heather Maioli, Robert Johnston, Irfan Chaudhry, Susan L Fink, Haodong Xu, Behzad Najafian, Gail Deutsch, J Matthew Lacy, Timothy Williams, Nicole Yarid, Desiree A Marshall


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10/07/2020 Articles
Extrapulmonary manifestations of COVID-19

NATURE

Authors
Aakriti Gupta, Mahesh V. Madhavan, Kartik Sehgal, Nandini Nair, Shiwani Mahajan, Tejasav S. Sehrawat, Behnood Bikdeli, Neha Ahluwalia, John C. Ausiello, Elaine Y. Wan, Daniel E. Freedberg, Ajay J. Kirtane, Sahil A. Parikh, Mathew S. Maurer, Anna S. Nordvig, Domenico Accili, Joan M. Bathon, Sumit Mohan, Kenneth A. Bauer, Martin B. Leon, Harlan M. Krumholz, Nir Uriel, Mandeep R. Mehra, Mitchell S. V. Elkind, Gregg W. Stone, Allan Schwartz, David D. Ho, John P. Bilezikian, Donald W. Landry



ABSTRACT
The CAlthough COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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01/07/2020 Archivies
Adrenal Vascular Changes in COVID-19 Autopsies

COLLEGE OF AMERICAN PATHOLOGISTS

Authors
Alina C Iuga, Charles C Marboe, Mine M Yilmaz, Jay H Lefkowitch, Cosmin Gauran, Stephen M Lagana


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29/06/2020 Editorial
COVID-19 as a Vascular Disease: Lesson Learned from Imaging and Blood ...

COVID-19 as a Vascular Disease: Lesson Learned from Imaging and Blood Biomarkers

MDPI

Authors
PAOLO ZAMBONI



ABSTRACT
COVID-19, a disease initially thought to be prominently an interstitial pneumonia with varying degrees of severity, can be considered a vascular disease with regards to serious complications and causes of mortality. Quite recently, blood clots have emerged as the common factor unifying many of the symptoms initially attributed without an explanation to COVID-19. Cardiovascular biomarkers and particularly, D-dimer and troponin appear to be very powerful prognostic markers, signaling the need for earlier and more aggressive interventions and treatments in order to avoid and/or minimize arterial/venous thromboembolism and myocardial infarct. The ultrasound imaging patterns at both the lung and peripheral vascular level can also be very useful weapons that have the advantage of being able to monitor longitudinally the clinical picture, something that real-time PCR/nasopharyngeal swab is not able to do and that CT can only pursue with significant radiation exposure. A lesson learned in the early phase of the COVID-19 pandemic suggests quitting and starting again with targeted imaging and blood vascular biomarkers.

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24/06/2020
SARS-CoV-2-induced Acute Respiratory Distress Syndrome: Pulmonary Mech...

SARS-CoV-2-induced Acute Respiratory Distress Syndrome: Pulmonary Mechanics and Gas Exchange Abnormalities

ORCID

Authors
Enric Barbeta, Ana Motos, Antoni Torres, Adrian Ceccato, Miquel Ferrer, Catia Cilloniz, Leticia Bueno, Joan Ramon Badia, Pedro Castro, Carlos Ferrando, Rut Andrea, Manuel Castellà, Javier Fernández, Alex Soriano, Ricard Mellado, Rubén López-Aladid, Hua Yang, Minlan Yang, Laia Fernandez-Barat, Andrea Catalina Palomeque, Ivan Vollmer; José María Nicolás


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24/06/2020 Articles
ACE2 is on the X chromosome: could this explain COVID-19 gender differ...

ACE2 is on the X chromosome: could this explain COVID-19 gender differences?

EUROPEAN HEART JOURNAL

Authors
Esther Culebras, Félix Hernández


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22/06/2020 Articles
A systematic review of pathological findings in COVID-19: a pathophysi...

A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression

NATURE

Authors
Samuel B. Polak, Inge C. Van Gool, Danielle Cohen, Jan H. von der Thüsen, Judith van Paassen



ABSTRACT
Since the outbreak of the COVID-19 pandemic, much has been learned regarding its clinical course, prognostic inflammatory markers, disease complications, and mechanical ventilation strategy. Clinically, three stages have been identified based on viral infection, pulmonary involvement with inflammation, and fibrosis. Moreover, low and high elastance phenotypes can be distinguished in mechanically ventilated patients, based on lung mechanics, ventilation-to-perfusion ratio, and CT scans; these two phenotypes have presumed differences in their underlying pathophysiology. Although essential for therapeutic guidance, the pathophysiology of COVID-19 is poorly understood. Here, we systematically reviewed published case reports and case series in order to increase our understanding of COVID-19 pathophysiology by constructing a timeline and correlating histopathological findings with clinical stages of COVID-19. Using PRISMA-IPD guidelines, 42 articles reporting 198 individual cases were included in our analysis. In lung samples (n = 131 cases), we identified three main histological patterns: epithelial (n = 110, 85%), with reactive epithelial changes and DAD; vascular (n = 76, 59%) with microvascular damage, (micro)thrombi, and acute fibrinous and organizing pneumonia; and fibrotic (n = 28, 22%) with interstitial fibrosis. The epithelial and vascular patterns can present in all stages of symptomatic COVID-19, whereas the fibrotic pattern presents starting at ~3 weeks. Moreover, patients can present with more than one pattern, either simultaneously or consecutively. These findings are consistent with knowledge regarding clinical patterns of viral infection, development of hyperinflammation and hypercoagulability, and fibrosis. Close collaboration among medical staff is necessary in order to translate this knowledge and classification of pathophysiological mechanisms into clinical stages of disease in individual patients. Moreover, further research, including histopathological studies, is warranted in order to develop reliable, clinically relevant biomarkers by correlating these pathological findings with laboratory results and radiological findings, thus, increasing our understanding of COVID-19 and facilitating the move to precision medicine for treating patients.

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18/06/2020 Editorial
Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19

THE NEW ENGLISH JOURNAL OF MEDICINE

Authors
John A. Jarcho, Julie R. Ingelfinger, Mary Beth Hamel, Ralph B. D’Agostino, David P. Harrington


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16/06/2020 Articles
Human Leukocyte Antigen Susceptibility Map for Severe Acute Respirator...

Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

JOURNAL OF VIROLOGY

Authors
Austin Nguyen, Julianne K. David, Sean K. Maden, Mary A. Wood, Benjamin R. Weeder, Abhinav Nellore, Reid F. Thompson

ABSTRACT
Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.
IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

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16/06/2020 Viewpoint
Therapeutic blockade of granulocyte macrophage colony-stimulating fact...

Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities

THE LANCET

Authors
Puja Mehta, Joanna C Porter, Jessica J Manson, John D Isaacs, Peter J M Openshaw, Iain B McInnes, Charlotte Summers, Rachel C Chambers


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16/06/2020 Articles
The thromboembolism in COVID-19: the unsolved problem

EDIZIONE MINERVA MEDICA

Authors
Matteo CASALE, Giuseppe DATTILO, Egidio IMBALZANO, Marianna GIGLIOTTI DE FAZIO, Claudia MORABITO, Maurizio MAZZETTI, Paolo BUSACCA, Salvatore Santo SIGNORELLI, Natale Daniele BRUNETTI, michele CORREALE



ABSTRACT
INTRODUCTIONː The recent Sars-Cov-2 pandemic (COVID-19) has led to growing research to explain the poor clinical prognosis in some patients.
EVIDENCE ACQUISITIONː While early observational studies highlighted the role of the virus in lung failure, in a second moment thrombosis emerged as a possible explanation of the worse clinical course in some patients. Despite initial difficulties in management of such patients, the constant increase of literature in the field is to date clarifying some questions from clinicians. However, several other questions need answer.
EVIDENCE SYNTHESISː A novel disease (Covid-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was responsible for thousands of hospitalizations for severe acute respiratory syndrome, with several cases of thrombotic complications due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. Covid-19 and hospitalizations for Covid-19 may carry several potential risk factors for thrombosis. Severe coagulation abnormalities may occur in almost all of the severe and critical ill COVID-19 cases.
CONCLUSIONSː Despite a strong pathophysiological rationale, the evidences in literature are not enough to recommend an aggressive antithrombotic therapy in COVID- 19. However, it is our opinion that an early use, even at home at the beginning of the disease, could improve the clinical course.

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16/06/2020 Articles
The thromboembolism in COVID-19: the unsolved problem

EDIZIONE MINERVA MEDICA

Authors
Matteo CASALE, Giuseppe DATTILO, Egidio IMBALZANO, Marianna GIGLIOTTI DE FAZIO, Claudia MORABITO, Maurizio MAZZETTI, Paolo BUSACCA, Salvatore Santo SIGNORELLI, Natale Daniele BRUNETTI, michele CORREALE



ABSTRACT
INTRODUCTIONː The recent Sars-Cov-2 pandemic (COVID-19) has led to growing research to explain the poor clinical prognosis in some patients.
EVIDENCE ACQUISITIONː While early observational studies highlighted the role of the virus in lung failure, in a second moment thrombosis emerged as a possible explanation of the worse clinical course in some patients. Despite initial difficulties in management of such patients, the constant increase of literature in the field is to date clarifying some questions from clinicians. However, several other questions need answer.
EVIDENCE SYNTHESISː A novel disease (Covid-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was responsible for thousands of hospitalizations for severe acute respiratory syndrome, with several cases of thrombotic complications due to excessive inflammation, platelet activation, endothelial dysfunction, and stasis. Covid-19 and hospitalizations for Covid-19 may carry several potential risk factors for thrombosis. Severe coagulation abnormalities may occur in almost all of the severe and critical ill COVID-19 cases.
CONCLUSIONSː Despite a strong pathophysiological rationale, the evidences in literature are not enough to recommend an aggressive antithrombotic therapy in COVID- 19. However, it is our opinion that an early use, even at home at the beginning of the disease, could improve the clinical course.

Read More »

11/06/2020 PERSPECTIVE
Considering how biological sex impacts immune responses and COVID-19 o...

Considering how biological sex impacts immune responses and COVID-19 outcomes

NATURE

Authors
Eileen P. Scully, Jenna Haverfield, Rebecca L. Ursin, Cara Tannenbaum, Sabra L. Klein



ABSTRACT
A male bias in mortality has emerged in the COVID-19 pandemic, which is consistent with the pathogenesis of other viral infections. Biological sex differences may manifest themselves in susceptibility to infection, early pathogenesis, innate viral control, adaptive immune responses or the balance of inflammation and tissue repair in the resolution of infection. We discuss available sex-disaggregated epidemiological data from the COVID-19 pandemic, introduce sex-differential features of immunity and highlight potential sex differences underlying COVID-19 severity. We propose that sex differences in immunopathogenesis will inform mechanisms of COVID-19, identify points for therapeutic intervention and improve vaccine design and increase vaccine efficacy.

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08/06/2020 Articles
Pulmonary post-mortem findings in a series of COVID-19 cases from nort...

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study

THE LANCET

Authors
Luca Carsana, Aurelio Sonzogni, Ahmed Nasr, Roberta Simona Rossi, Alessandro Pellegrinelli, Pietro Zerbi, Roberto Rech, Riccardo Colombo, Spinello Antinori, Mario Corbellino, Massimo Galli, Emanuele Catena, Antonella Tosoni, Andrea Gianatti, Manuela Nebuloni


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01/06/2020 Editorial
COVID-19 coagulopathy: an evolving story

The Lancet

Authors
The Lancet Haematology

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29/05/2020 Images
Magnetic Resonance Imaging Alteration of the Brain in a Patient With C...

Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia

JAMA

Authors
Letterio S. Politi, Ettore Salsano, Marco Grimaldi

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28/05/2020 Report
COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrati...

COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review

CLINICS AND PRACTICE

Authors
Attilio Cavezzi, Emidio Troiani, Salvatore Corrao



ABSTRACT
Coronavirus disease-19 (COVID-19) has been regarded as an infective-inflammatory disease, which affects mainly lungs. More recently, a multi-organ involvement has been highlighted, with different pathways of injury. A hemoglobinopathy, hypoxia and cell iron overload might have a possible additional role. Scientific literature has pointed out two potential pathophysiological mechanisms: i) severe acute respiratory syndrome-coronavirus-2 (SARS-CoV- 2) interaction with hemoglobin molecule, through CD147, CD26 and other receptors located on erythrocyte and/or blood cell precursors; ii) hepcidin-mimetic action of a viral spike protein, inducing ferroportin blockage. In this translational medicine-based narrative review, the following pathologic metabolic pathways, deriving from hemoglobin denaturation and iron metabolism dysregulation, are highlighted: i) decrease of functioning hemoglobin quote; ii) iron overload in cell/tissue (hyperferritinemia); iii) release of free toxic circulating heme; iv) hypoxemia and systemic hypoxia; v) reduction of nitric oxide; vi) coagulation activation; vii) ferroptosis with oxidative stress and lipoperoxidation; viii) mitochondrial degeneration and apoptosis. A few clinical syndromes may follow, such as pulmonary edema based on arterial vasoconstriction and altered alveolo-capillary barrier, sideroblastic-like anemia, endotheliitis, vasospastic acrosyndrome, and arterio- venous thromboembolism. We speculated that in COVID-19, beyond the classical pulmonary immune-inflammation view, the occurrence of an oxygen-deprived blood disease, with iron metabolism dysregulation, should be taken in consideration. A more comprehensive diagnostic/therapeutic approach to COVID-19 is proposed, including potential adjuvant interventions aimed at improving hemoglobin dysfunction, iron over-deposit and generalized hypoxic state.

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27/05/2020 Articles
SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in t...

SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

SCIENCE DIRECT

Authors
Yixuan J. Hou, Kenichi Okuda, Caitlin E. Edwards, David R. Martinez, Takanori Asakura, Kenneth H. Dinnon, III, Takafumi Kato, Rhianna E. Lee, Boyd L. Yount, Teresa M. Mascenik, Gang Chen, Kenneth N. Olivier, Andrew Ghio, Longping V. Tse, Sarah R. Leist, Lisa E. Gralinski, Alexandra Schäfer, Hong Dang, Rodney Gilmore, Satoko Nakano, Ling Sun, M. Leslie Fulcher, Alessandra Livraghi-Butrico, Nathan I. Nicely, Mark Cameron, Cheryl Cameron, David J. Kelvin, Aravinda de Silva, David M. Margolis, Alena Markmann, Luther Bartelt, Ross Zumwalt, Fernando J. Martinez, Steven P. Salvatore, Alain Borczuk, Purushothama R. Tata, Vishwaraj Sontake, Adam Kimple, Ilona

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22/05/2020 Articles
Microvascular COVID-19 lung vessels obstructive thromboinflammatory sy...

Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS)...

Publmed.gov

Authors
Fabio Ciceri, Luigi Beretta, Anna Mara Scandroglio, Sergio Colombo, Giovanni Landoni, Annalisa Ruggeri, Jacopo Peccatori, Armando D&rsquo;Angelo, Francesco De Cobelli, Patrizia Rovere-Querini, Moreno Tresoldi, Lorenzo Dagna and Alberto Zangrillo

ABSTRACT

We suggest the use of MicroCLOTS (microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome) as a new name for severe pulmonary coronavirus disease 2019 (COVID-19). We hypothesise that, in predisposed individuals, alveolar viral damage is followed by an inflammatory reaction and by microvascular pulmonary thrombosis. This progressive endothelial thromboinflammatory syndrome may also involve the microvascular bed of the brain and other vital organs, leading to multiple organ failure and death. Future steps in the understanding of the disease and in the identification of treatments may benefit from this definition and hypothesised sequence of events.

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21/05/2020 Letter
Postmortem Examination of Patients With COVID-19

JAMA

Authors
Tina Schaller, Klaus Hirschb&uuml;hl, Katrin Burkhardt

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16/05/2020 Articles
Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expr...

Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV- 2 Receptor ACE2 in the Respiratory Tract

DEVELOPMENTAL CELL

Authors
Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Anand Vasudevan, Kristen M. John, Jason M. Sheltzer

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15/05/2020 Articles
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

CELL

Authors
Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Jean K. Lim, Randy A. Albrecht, Benjamin R. tenOever

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14/05/2020 Articles
Complement Activation In Patients With Covid-19: A Novel Therapeutic T...

Complement Activation In Patients With Covid-19: A Novel Therapeutic Target

CELL

Authors
Massimo Cugno, Pier Luigi Meroni, Roberta Gualtierotti, Samantha Griffini, Elena Grovetti, Adriana Torri, Mauro Panigada, Stefano Aliberti, Francesco Blasi, Francesco Tedesco, Flora Peyvandi

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13/05/2020 Correspondence
Multiorgan and Renal Tropism of SARS-CoV-2

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Victor G. Puelles, Marc Lütgehetmann, Maja T. Lindenmeyer, Jan P. Sperhake, Milagros N. Wong, Lena Allweiss, Silvia Chilla, Axel Heinemann, Nicola Wanner, Shuya Liu, Fabian Braun, Shun Lu, Susanne Pfefferle, Ann S. Schröder, Carolin Edler M.D.,Oliver Gross, M.D.Markus Glatzel, Dominic Wichmann, Thorsten Wiech, Stefan Kluge, Klaus Pueschel, Martin Aepfelbacher, Tobias B. Huber

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11/05/2020 Articles
COVID‐19 and comorbidities: A role for dipeptidyl peptidase 4 (DPP4) i...

COVID‐19 and comorbidities: A role for dipeptidyl peptidase 4 (DPP4) in disease severity?

WILEY ONLINE LIBRARY

Authors
Margaret F. Bassendine Simon H. Bridge Geoffrey W. McCaughan Mark D. Gorrell

ABSTRACT
The coronavirus disease 2019 (COVID‐19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), similar to SARS‐CoV and Middle East respiratory syndrome (MERS‐CoV), which cause acute respiratory distress syndrome and case fatalities. COVID‐19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS‐CoV binds to the metalloprotease angiotensin‐converting enzyme 2 (ACE2), MERS‐CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS‐CoV‐2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane‐bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID‐19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID‐19 disease severity, which creates interest regarding the use of gliptins in management of COVID‐19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS‐CoV‐2.

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11/05/2020 Review
Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an...

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an...

JOURNAL OF CLINICAL MEDICINE

Authors
Celestino Sardu, Jessica Gambardella, Marco Bruno Morelli, Xujun Wang , Raffaele Marfella and Gaetano Santulli

ABSTRACT

The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations.

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08/05/2020 Review
Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an ...

Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an Old Concern...

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Authors
Andrea Picchianti Diamanti,Maria Manuela Rosado,Claudio Pioli,Giorgio Sesti, Bruno Laganà

ABSTRACT

On 7 January 2020, researchers isolated and sequenced in China from patients with seve re pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CR, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient’s clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk.

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07/05/2020 Correspondence
Prevention of the cytokine storm in COVID-19

The Lancet

Authors
David J M Wright

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07/05/2020 Comment
Assessment of SARS-CoV-2 replication in the context of other respirato...

Assessment of SARS-CoV-2 replication in the context of other respiratory viruses

The Lancet

Authors
Jessica A Belser

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06/05/2020 Progress
Pathological inflammation in patients with COVID-19: a key role for mo...

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

NATURE REVIEWS

Authors
Miriam Merad, Jerome C. Martin

ABSTRACT

The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathological roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.

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06/05/2020 Short Communication
The role of vitamin D in the prevention of coronavirus disease 2019...

SPRINGER LINK

Authors
Petre Cristian Ilie, Simina Stefanescu, Lee Smith

ABSTRACT WHO declared SARS-CoV-2 a global pandemic. The present aim was to propose an hypothesis that there is a potential association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19. The mean levels of vitamin D for 20 European countries and morbidity and mortality caused by COVID-19 were acquired. Negative correlations between mean levels of vitamin D (average 56 mmol/L, STDEV 10.61) in each country and the number of COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed. Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.

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05/05/2020 Review
COVID-19, SARS and MERS: A neurological perspective

Journal of Clinical Neuroscience

Authors
Koy Chong, Ng Kee Kwonga, Puja, R.Mehtab, GarimaShukla, Arpan R.Mehta

ABSTRACT

Central to COVID-19 pathophysiology is an acute respiratory infection primarily manifesting as pneumonia. Two months into the COVID-19 outbreak, however, a retrospective study in China involving more than 200 participants revealed a neurological component to COVID-19 in a subset of patients. The observed symptoms, the cause of which remains unclear, included impaired consciousness, skeletal muscle injury and acute cerebrovascular disease, and appeared more frequently in severe disease. Since then, findings from several studies have hinted at various possible neurological outcomes in COVID-19 patients. Here, we review the historical association between neurological complications and highly pathological coronaviruses including SARS-CoV, MERS-CoV and SARS-CoV-2. We draw from evidence derived from past coronavirus outbreaks, noting the similarities and differences between SARS and MERS, and the current COVID-19 pandemic. We end by briefly discussing possible mechanisms by which the coronavirus impacts on the human nervous system, as well as neurology-specific considerations that arise from the repercussions of COVID-19.

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05/05/2020 Correspondence
Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Co...

Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors
Louise Bowles, Sean Platton, Nada Yartey, Minal Dave, Kurtis Lee, Daniel P. Hart, Vickie MacDonald, M.B., B.Chir., Laura Green, Suthesh Sivapalaratnam, K. John Pasi,Peter MacCallum

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04/05/2020 Articles
Post-mortem examination of COVID19 patients reveals diffuse alveolar d...

Post-mortem examination of COVID19 patients reveals diffuse alveolar damage with...

WILEY ONLINE LIBRARY

Authors
T. Menter, J.D. Haslbauer, R. Nienhold, S. Savic, H. Hopfer, N. Deigendesch, S. Frank, D. Turek, N. Willi, H. Pargger, S. Bassetti, J.D. Leuppi, G. Cathomas, M. Tolnay, K.D. Mertz, A. Tzankov

ABSTRACT Aims Coronavirus disease 2019 (COVID‐19) caused by SARS‐CoV‐2 has rapidly evolved into a sweeping pandemic. While its major manifestation is in the respiratory tract, the general extent of organ involvement as well as microscopic changes in the lungs remain insufficiently characterised. Autopsies are essential to elucidate COVID‐19‐associated organ alterations.

Methods This study reports autopsy findings of 21 COVID‐19 patients hospitalised at the University Hospital Basel and at the Cantonal Hospital Baselland, Switzerland. An in‐corpore technique was performed to ensure optimal staff safety.

Results The primary cause of death was respiratory failure with exudative diffuse alveolar damage with massive capillary congestion often accompanied by microthrombi despite anticoagulation. Ten cases showed superimposed bronchopneumonia. Further findings included pulmonary embolisms (n=4), alveolar haemorrhage (n=3) and vasculitis (n=1). Pathologies in other organ systems were predominantly attributable to shock; three patients showed signs of generalised thrombotic microangiopathy. Six patients were diagnosed with senile cardiac amyloidosis upon autopsy. Most patients suffered from one or more comorbidities (hypertension, obesity, cardiovascular diseases, diabetes mellitus). Additionally, there was an overall predominance of males and individuals with blood group A (81% and 65%, respectively). All relevant histological slides are linked as open‐source scans in supplementary files.

Conclusions This study provides an overview of post‐mortem findings in COVID‐19 cases, implying that hypertensive, elderly, obese, male individuals with severe cardiovascular comorbidities as well as those with blood group A may have a lower threshold of tolerance for COVID‐19. This provides a pathophysiological explanation for higher mortality rates amongst these patients.

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28/04/2020 Research Highlight
COVID-19: towards understanding of pathogenesis

CELL RESEARCH

Authors
Wei Cao, Taisheng Li

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23/04/2020 Brief Report
Association of Renin-Angiotensin System Inhibitors With Severity or Ri...

Association of Renin-Angiotensin System Inhibitors With Severity or Risk...

JAMA

Authors
Juyi Li, Xiufang Wang, Jian Chen, Hongmei Zhang, Aiping Deng

ABSTRACT Importance Data are lacking whether patients with hypertension who are taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have increased severity or risk of mortality during hospitalization for coronavirus disease 2019 (COVID-19).

Objective To investigate the association between ACEIs/ARBs and severity of illness and mortality in patients with hypertension hospitalized for COVID-19 infection.

Design, Setting, and Participants Retrospective, single-center case series of the 1178 hospitalized patients with COVID-19 infections at the Central Hospital of Wuhan, China, from January 15 to March 15, 2020.

Main Outcomes and Measures COVID-19 was confirmed by real-time reverse transcription–polymerase chain reaction and epidemiologic, clinical, radiologic, laboratory, and drug therapy data were analyzed in all patients. The percentage of patients with hypertension taking ACEIs/ARBs was compared between those with severe vs nonsevere illness and between survivors vs nonsurvivors.

Results Of the 1178 patients with COVID-19, the median age was 55.5 years (interquartile range, 38-67 years) and 545 (46.3%) were men. The overall in-hospital mortality was 11.0%. There were 362 patients with hypertension (30.7% of the total group; median age, 66.0 years [interquartile range, 59-73 years]; 189 [52.2%] were men), of whom 115 (31.8%) were taking ACEI/ARBs. The in-hospital mortality in the patients with hypertension was 21.3%. The percentage of patients with hypertension taking ACEIs/ARBs did not differ between those with severe and nonsevere infections (32.9% vs 30.7%; P = .65) nor did it differ between nonsurvivors and survivors (27.3% vs 33.0%; P = .34). Similar findings were observed when data were analyzed for patients taking ACEIs and those taking ARBs.

Conclusions and Relevance This study provides clinical data on the association between ACEIs/ARBs and outcomes in patients with hypertension hospitalized with COVID-19 infections, suggesting that ACEIs/ARBs are not associated with the severity or mortality of COVID-19 in such patients. These data support current guidelines and societal recommendations for treating hypertension during the COVID-19 pandemic

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23/04/2020 Opinion
COVID-19 Infection and Circulating ACE2 Levels: Protective Role in Wom...

COVID-19 Infection and Circulating ACE2 Levels: Protective Role in Women and Children

FRONTIERS IN PEDIATRICS

Authors
Elena Ciaglia, Carmine Vecchion, Annibale Alessandro Puca

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23/04/2020 Brief Communication
SARS-CoV-2 entry factors are highly expressed in nasal epithelial cell...

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together...

NATURE MEDICINE

Authors
Waradon Sungnak, Ni Huang, Christophe Bécavin, Marijn Berg, Rachel Queen, Monika Litvinukova, Carlos Talavera-López, Henrike Maatz, Daniel Reichart, Fotios Sampaziotis, Kaylee B. Worlock, Masahiro Yoshida, Josephine L. Barnes, HCA Lung

ABSTRACT

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.

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20/04/2020 Correspondence
Endothelial cell infection and endotheliitis in COVID-19

The Lancet

Authors
Zsuzsanna Varga, Andreas J Flammer, Peter Steiger, Martina Haberecker, Rea Andermatt, Annelies S Zinkernagel, Mandeep R Mehra, Reto A Schuepbach, Frank Ruschitzka, Holger Moch

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17/04/2020 Report
Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman pri...

Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Science

Authors
Barry Rockx,Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Bas B. Oude Munnink, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, Peter van Run, Lonneke Leijten, Reina Sikkema, Ernst Verschoor, Babs Verstrepen, Willy Bogers, Jan Langermans, Christian Drosten, Martje Fentener van Vlissingen, Ron Fouchier, Rik de Swart, Marion Koopmans, Bart L. Haagmans

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17/04/2020 Summary
SARS-CoV-2 and viral sepsis: observations and hypotheses

The Lancet

Authors
Hui Li, Liang Liu, Dingyu Zhang, Jiuyang Xu, Huaping Dai, Nan Tang, Xiao Su, Bin Cao

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12/04/2020 Articles
Estimation of airborne viral emission: Quanta emission rate of SARS-Co...

Estimation of airborne viral emission: Quanta emission rate of SARS-CoV-2 for infection risk assessment

MEDRXIV

Authors
Giorgio Buonanno, Luca Stabile, Lidia Morawska

ABSTRACT

Airborne transmission is a pathway of contagion that is still not sufficiently investigated despite the evidence in the scientific literature of the role it can play in the context of an epidemic. While the medical research area dedicates efforts to find cures and remedies to counteract the effects of a virus, the engineering area is involved in providing risk assessments in indoor environments by simulating the airborne transmission of the virus during an epidemic. To this end, virus air emission data are needed. Unfortunately, this information is usually available only after the outbreak, based on specific reverse engineering cases. In this work, a novel approach to estimate the viral load emitted by a contagious subject on the basis of the viral load in the mouth, the type of respiratory activity (e.g. breathing, speaking), respiratory physiological parameters (e.g. inhalation rate), and activity level (e.g. resting, standing, light exercise) is proposed. The estimates of the proposed approach are in good agreement with values of viral loads of well-known diseases from the literature. The quanta emission rates of an asymptomatic SARS-CoV-2 infected subject, with a viral load in the mouth of 108 copies mL-1, were 10.5 quanta h-1 and 320 quanta h-1 for breathing and speaking respiratory activities, respectively, at rest. In the case of light activity, the values would increase to 33.9 quanta h-1 and 1.03×103 quanta h-1, respectively. The findings in terms of quanta emission rates were then adopted in infection risk models to demonstrate its application by evaluating the number of people infected by an asymptomatic SARS-CoV-2 subject in Italian indoor microenvironments before and after the introduction of virus containment measures. The results obtained from the simulations clearly highlight that a key role is played by proper ventilation in containment of the virus in indoor environments.

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09/04/2020 Articles
Coagulation disorders in coronavirus infected patients: COVID-19, SARS...

Coagulation disorders in coronavirus infected patients: COVID-19, SARS- CoV-1, MERS-CoV and lessons from the past

ELSEVIER

Authors
Dimitrios Giannis , Ioannis A.Ziogas, Panagiota Gianni



ABSTRACT
Coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus strain disease, has recently emerged in China and rapidly spread worldwide. This novel strain is highly transmittable and severe disease has been reported in up to 16% of hospitalized cases. More than 600,000 cases have been confirmed and the number of deaths is constantly increasing. COVID-19 hospitalized patients, especially those suffering from severe respiratory or systemic manifestations, fall under the spectrum of the acutely ill medical population, which is at increased venous thromboembolism risk. Thrombotic complications seem to emerge as an important issue in patients infected with COVID-19. Preliminary reports on COVID-19 patients’ clinical and laboratory findings include thrombocytopenia, elevated D-dimer, prolonged prothrombin time, and disseminated intravascular coagulation. As the pandemic is spreading and the whole picture is yet unknown, we highlight the importance of coagulation disorders in COVID-19 infected patients and review relevant data of previous coronavirus epidemics caused by the severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV).

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06/04/2020 Review
Dysregulation of lung myeloid cells in COVID-19

Springer

Authors
B&eacute;reng&egrave;re Salom&eacute;, Assaf Magen

Read More »

06/04/2020 Review
Fighting COVID-19 exhausts T cells

Springer

Authors
Chang Moon

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03/04/2020 Viewpoint
The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Dis...

The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Disease..

JAMA

Authors
Majd AlGhatrif, Oscar Cingolani, Edward G. Lakatta

Read More »

27/03/2020 Report
A highly conserved cryptic epitope in the receptor-binding domains of ...

A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV

Science

Authors
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson

Abstract

The outbreak of COVID-19 caused by SARS-CoV-2 virus has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein to 3.1 Å. CR3022 targets a highly conserved epitope, distal from the receptor-binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBD on the trimeric S protein are in the “up” conformation and slightly rotated. Overall, this study provides molecular insights into antibody recognition of SARS-CoV-2.

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27/03/2020 Articles
Structural basis for the recognition of the SARS-CoV-2 by full-length ...

Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2

Science

Authors
Renhong Yan, Yuanyuan Zhang, Yaning Li, Lu Xia, Yingying Guo, Qiang Zhou

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for SARS coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious epidemic COVID-19. Here we present cryo-EM structures of full-length human ACE2, in the presence of a neutral amino acid transporter B0AT1, with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 Å, with a local resolution of 3.5 Å at the ACE2-RBD interface. The ACE2- B0AT1 complex is assembled as a dimer of heterodimers, with the Collectrin-like domain (CLD) of ACE2 mediating homo-dimerization. The RBD is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. These findings provide important insights to the molecular basis for coronavirus recognition and infection.

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18/03/2020 PERSPECTIVE
SARS-CoV-2, the Virus that Causes COVID-19: Cytometry and the New Chal...

SARS-CoV-2, the Virus that Causes COVID-19: Cytometry and the New Challenge for Global Health

Wiley Online Library

Authors
Andrea Cossarizza, Sara De Biasi,Giovanni Guaraldi, Massimo Girardis, Cristina Mussini

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01/03/2020 Articles
Molecular immune pathogenesis and diagnosis of COVID-19

ELSEVIER Journal of Pharmaceutical Analysis

Authors
Xiaowei Li, Manman Geng, Yizhao Peng, Liesu Meng, Shemin Lu

Coronavirus disease 2019 (COVID-19) is a kind of viral pneumonia with an unusual outbreak in Wuhan, China, in December 2019, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). The emergence of SARS-CoV-2 has been marked as the third introduction of a highly pathogenic coronavirus into the human population after the severe acute respiratory syndrome coronavirus (SARS- CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) in the twenty-first century. In this minireview, we provide a brief introduction of the general features of SARS-CoV-2 and discuss current knowledge of molecular immune pathogenesis, diagnosis and treatment of COVID-19 on the base of the present understanding of SARS-CoV and MERS-CoV infections, which may be helpful in offering novel insights and potential therapeutic targets for combating the SARS-CoV-2 infection. © 2020 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license"

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27/02/2020 Review
The neuroinvasive potential of SARS‐CoV2 may play a role in the respir...

The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients

Wiley Online Library

Authors
Yan‐Chao Li, Wan‐Zhu Bai, Tsutomu Hashikawa

Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS‐CoV and SARS‐CoV2, it remains to make clear whether the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.

cell susceptibility, coronavirus, dissemination, nervous system

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