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NATURE
Authors Georgia Colleluori, Laura Graciotti, Mauro Pesaresi, Angelica Di Vincenzo, Jessica Perugini, Eleonora Di Mercurio, Sara Caucci, Patrizia Bagnarelli, Cristina M. Zingaretti, Enzo Nisoli, Stefano Menzo, Adriano Tagliabracci, Annie Ladoux, Christian Dani, Antonio Giordano, Saverio Cinti
Abstract Background Preliminary data suggested that fat embolism could explain the importance of visceral obesity as a critical determinant of coronavirus disease-2019 (COVID-19). Methods We performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissue (VAT), lungs and livers of 19 subjects with COVID-19 (COVID-19+), and 23 people without COVID-19 (controls). Human adipocytes (hMADS) infected with SARS-CoV-2 were also studied. Results Although there were no between-group differences in body-mass-index and adipocytes size, a higher prevalence of CD68+ macrophages among COVID-19+ VAT was detected (p = 0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV-2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution by ORO. Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19+ (p < 0.001). Notably, signs of fat embolism were more prevalent among people with obesity (p = 0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication exacerbated by SARS-CoV-2 infection. Importantly, all infected subjects’ lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control patient with non-COVID-19-related pneumonia. Importantly, transition aspects between embolic fat and hyaline membranes were also observed. Conclusions This study confirms the lung fat embolism in COVID-19+ patients and describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in people with COVID-19 and obesity.
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Authors Rachel A. Reyna, Megumi Kishimoto-Urata, Shinji Urata, Tomoko Makishima, Slobodan Paessler, Junki Maruyama
Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for a pandemic affecting billions of people worldwide. Apart from the extreme global economic impact, the pandemic will likely have a lasting impact through long-term sequelae not yet fully understood. Fully understanding the mechanisms driving the various symptoms and sequelae of SARS-CoV-2 infection will allow for the eventual development of therapeutics to prevent or treat such life-altering symptoms. In this study, we developed a behavioral test of anosmia in SARS-CoV-2-infected hamsters. We find a moderately strong correlation between the level of anosmia and the score of histological damage within the olfactory epithelium. We also find a moderately strong correlation between the level of anosmia and the thickness of the olfactory epithelium, previously demonstrated to be severely damaged upon infection. Thus, this food-searching behavioral test can act as a simple and effective screening method in a hamster model for various therapeutics for SARS-CoV-2-related anosmia.
MEDRXIV
Authors Josalyn L. Cho, Raul Villacreses, Prashant Nagpal, Junfeng Guo, Alejandro A. Pezzulo, Andrew L. Thurman, Nabeel Y. Hamzeh, Robert J. Blount, Spyridon Fortis, Eric A. Hoffman, Joseph Zabner, Alejandro P. Comellas
Abstract Background The sequelae of SARS-CoV-2 infection on pulmonary structure and function remain incompletely characterized. Methods Adults with confirmed COVID-19 who remained symptomatic more than thirty days following diagnosis were enrolled and classified as ambulatory, hospitalized or requiring the intensive care unit (ICU) based on the highest level of care received during acute infection. Symptoms, pulmonary function tests and chest computed tomography (CT) findings were compared across groups and to healthy controls. CT images were quantitatively analyzed using supervised machine-learning to measure regional ground glass opacities (GGO) and image-matching to measure regional air trapping. Comparisons were performed using univariate analyses and multivariate linear regression. Results Of the 100 patients enrolled, 67 were in the ambulatory group. All groups commonly reported cough and dyspnea. Pulmonary function testing revealed restrictive physiology in the hospitalized and ICU groups but was normal in the ambulatory group. Among hospitalized and ICU patients, the mean percent of total lung classified as GGO was 13.2% and 28.7%, respectively, and was higher than in ambulatory patients (3.7%, P<0.001). The mean percentage of total lung affected by air trapping was 25.4%, 34.5% and 27.2% in the ambulatory, hospitalized and ICU groups and 7.3% in healthy controls (P<0.001). Air trapping measured by quantitative CT correlated with the residual volume to total lung capacity ratio (RV/TLC; ρ=0.6, P<0.001). Conclusions Air trapping is present in patients with post-acute sequelae of COVID-19 and is independent of initial infection severity, suggesting obstruction at the level of the small airways. The long-term consequences are not known.
HTTPS://PUBMED.NCBI.NLM.NIH.GOV/34047654/
Authors Debby van Riel, Carmen W E Embregts, Gregorius J Sips, Johannes P C van den Akker, Henrik Endeman, Els van Nood, Mathijs Raadsen, Lisa Bauer, Jeroen van Kampen, Richard Molenkamp, Marion Koopmans, David van de Vijver, Corine H GeurtsvanKessel
Abstract COVID-19 is associated with a wide range of extrarespiratory complications, of which the pathogenesis is currently not fully understood. However, both systemic spread and systemic inflammatory responses are thought to contribute to the systemic pathogenesis. In this study, we determined the temporal kinetics of viral RNA in serum (RNAemia) and the associated inflammatory cytokines and chemokines during the course of COVID-19 in hospitalized patients. We show that RNAemia can be detected in 90% of the patients who develop critical disease, compared to 50% of the patients who develop moderate or severe disease. Furthermore, RNAemia lasts longer in patients who develop critical disease. Elevated levels of interleukin-10 (IL-10) and MCP-1-but not IL-6-are associated with viral load in serum, whereas higher levels of IL-6 in serum were associated with the development of critical disease. In conclusion, RNAemia is common in hospitalized patients, with the highest frequency and duration in patients who develop critical disease. The fact that several cytokines or chemokines are directly associated with the presence of viral RNA in the circulation suggests that the development of RNAemia is an important factor in the systemic pathogenesis of COVID-19. IMPORTANCE Severe COVID-19 can be considered a systemic disease as many extrarespiratory complications occur. However, the systemic pathogenesis is poorly understood. Here, we show that the presence of viral RNA in the blood (RNAemia) occurs more frequently in patients who develop critical disease, compared to patients with moderate or severe disease. In addition, RNAemia is associated with increased levels of inflammatory cytokines and chemokines, like MCP-1 and IL-10, in serum during the course of disease. This suggests that extrarespiratory spread of SARS-CoV-2 contributes to systemic inflammatory responses, which are an important factor in the systemic pathogenesis of COVID-19.
Authors Mariana G. Ferrarini, Avantika Lal, Rita Rebollo, Andreas J. Gruber, Andrea Guarracino, Itziar Martinez Gonzalez, Taylor Floyd, Daniel Siqueira de Oliveira, Justin Shanklin, Ethan Beausoleil, Taneli Pusa, Brett E. Pickett & Vanessa Aguiar-Pulido
Abstract The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a worldwide pandemic (COVID-19) after emerging in Wuhan, China. Here we analyzed public host and viral RNA sequencing data to better understand how SARS-CoV-2 interacts with human respiratory cells. We identified genes, isoforms and transposable element families that are specifically altered in SARS-CoV-2-infected respiratory cells. Well-known immunoregulatory genes including CSF2, IL32, IL-6 and SERPINA3 were differentially expressed, while immunoregulatory transposable element families were upregulated. We predicted conserved interactions between the SARS-CoV-2 genome and human RNA-binding proteins such as the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and eukaryotic initiation factor 4 (eIF4b). We also identified a viral sequence variant with a statistically significant skew associated with age of infection, that may contribute to intracellular host–pathogen interactions. These findings can help identify host mechanisms that can be targeted by prophylactics and/or therapeutics to reduce the severity of COVID-19.
JOURNAL OF HEPATOLOGY
Authors Matthew J. McConnell, Nao Kawaguchi, Reiichiro Kondo, John Hwa, Mario Strazzabosco, Yasuko Iwakiri
ABSTRACT Background and Aims COVID-19 is associated with liver injury and elevated IL-6. We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. Methods Coagulopathy, endotheliopathy, and ALT were retrospectively analyzed in a subset (n=68), followed by a larger cohort(n=3,780) of COVID-19 patients. Liver histology from 43 COVID-19 patients was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. Results Factor VIII, fibrinogen, D-dimer, vWF activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in COVID-19 patients with liver injury (elevated ALT). IL-6 positively correlated with vWF antigen(P=0.02), factor VIII activity(P=0.02), and D-dimer(P<0.0001). On liver histology, COVID-19 patients with elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet(P<0.0001) and vWF(P<0.01) staining, and IL-6 levels positively correlated with vWF staining(P<0.01). IL-6 trans-signaling leads to increased expression of procoagulant (Factor VIII, vWF) and proinflammatory factors, increased cell surface vWF(P<0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble gp130 (IL-6 trans-signaling inhibitor), JAK inhibitor Ruxolitinib, and STAT1/3 siRNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. Conclusion COVID-19 is associated with coagulopathy and endotheliopathy in the liver endothelium driven by IL-6 trans-signaling, a possible mechanism of liver injury.
THE LANCET
Authors David Saadoun, Matheus Vieira, Mathieu Vautier, Xenofon Baraliakos, Ioana Andreica, José A P da Silva, Marlene Sousa, Mariana Luis, Nikita Khmelinskii, José María Alvaro Gracía, Isabel Castrejon, Juan Carlos Nieto Gonzalez, Carlo Alberto Scirè, Ettore Silvagni, Alessandra Bortoluzzi, Henry Penn, Shahir Hamdulay, Pedro M Machado, Bruno Fautrel, Patrice Cacoub, Matthieu Resche-Rigon, Laure Gossec
Authors Ming Zhao, Yu Yu, Li-Ming Sun, Jia-Qing Xing, Tingting Li, Yunkai Zhu, Miao Wang, Yin Yu, Wen Xue, Tian Xia, Hong Cai, Qiu-Ying Han, Xiaoyao Yin, Wei-Hua Li, Ai-Ling Li, Jiuwei Cui, Zhenghong Yuan, Rong Zhang, Tao Zhou, Xue-Min Zhang, Tao Li
Abstract Lack of detailed knowledge of SARS-CoV-2 infection has been hampering the development of treatments for coronavirus disease 2019 (COVID-19). Here, we report that RNA triggers the liquid–liquid phase separation (LLPS) of the SARS-CoV-2 nucleocapsid protein, N. By analyzing all 29 proteins of SARS-CoV-2, we find that only N is predicted as an LLPS protein. We further confirm the LLPS of N during SARS-CoV-2 infection. Among the 100,849 genome variants of SARS-CoV-2 in the GISAID database, we identify that ~37% (36,941) of the genomes contain a specific trio-nucleotide polymorphism (GGG-to-AAC) in the coding sequence of N, which leads to the amino acid substitutions, R203K/G204R. Interestingly, NR203K/G204R exhibits a higher propensity to undergo LLPS and a greater effect on IFN inhibition. By screening the chemicals known to interfere with N-RNA binding in other viruses, we find that (-)-gallocatechin gallate (GCG), a polyphenol from green tea, disrupts the LLPS of N and inhibits SARS-CoV-2 replication. Thus, our study reveals that targeting N-RNA condensation with GCG could be a potential treatment for COVID-19.
AHA JOURNALS
Authors Yuyang Lei, Jiao Zhang, Cara R. Schiavon, Ming He, Lili Chen, Hui Shen, Yichi Zhang, Qian Yin, Yoshitake Cho, Leonardo Andrade, Gerald S. Shadel, Mark Hepokoski, Ting Lei, Hongliang Wang, Jin Zhang, Jason X.-J. Yuan, Atul Malhotra, Uri Manor, Shengpeng Wang, Zu-Yi Yuan, John Y-J. Shyy
Authors André F. Rendeiro, Hiranmayi Ravichandran, Yaron Bram, Vasuretha Chandar, Junbum Kim, Cem Meydan, Jiwoon Park, Jonathan Foox, Tyler Hether, Sarah Warren, Youngmi Kim, Jason Reeves, Steven Salvatore, Christopher E. Mason, Eric C. Swanson, Alain C. Borczuk, Olivier Elemento, Robert E. Schwartz
Abstract Recent studies have provided insights into the pathology and immune response to coronavirus disease 2019 (COVID-19)1–8. However, thorough interrogation of the interplay between infected cells and the immune system at sites of infection is lacking. We use high parameter imaging mass cytometry9 targeting the expression of 36 proteins, to investigate at single cell resolution, the cellular composition and spatial architecture of human acute lung injury including SARS-CoV-2. This spatially resolved, single-cell data unravels the disordered structure of the infected and injured lung alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyper-inflammatory cell state associated with lung damage. By leveraging the temporal range of COVID-19 severe fatal disease in relation to the time of symptom onset, we observe increased macrophage extravasation, mesenchymal cells, and fibroblasts abundance concomitant with increased proximity between these cell types as the disease progresses, possibly as an attempt to repair the damaged lung tissue. This spatially resolved single-cell data allowed us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. This spatial single-cell landscape enabled the pathophysiological characterization of the human lung from its macroscopic presentation to the single-cell, providing an important basis for the understanding of COVID-19, and lung pathology in general.
JAMA
Authors Maura Boldrini, Peter D. Canoll, Robyn S. Klein
SCIENCE
Authors Juan A. Perez-Bermejo, Serah Kang, Sarah J. Rockwood, Camille R. Simoneau, David A. Joy, Ana C. Silva, Gokul N. Ramadoss, Will R. Flanigan, Parinaz Fozouni, Huihui Li, Pei-Yi Chen, Ken Nakamura, Jeffrey D. Whitman, Paul J. Hanson, Bruce M. McManus, Melanie Ott, Bruce R. Conklin, Todd C. McDevitt
Abstract Although coronavirus disease 2019 (COVID-19) causes cardiac dysfunction in up to 25% of patients, its pathogenesis remains unclear. Exposure of human induced pluripotent stem cell (iPSC)-derived heart cells to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed productive infection and robust transcriptomic and morphological signatures of damage, particularly in cardiomyocytes. Transcriptomic disruption of structural genes corroborates adverse morphologic features, which included a distinct pattern of myofibrillar fragmentation and nuclear disruption. Human autopsy specimens from patients with COVID-19 reflected similar alterations, particularly sarcomeric fragmentation. These striking cytopathic features in cardiomyocytes provide insights into SARS-CoV-2-induced cardiac damage, offer a platform for discovery of potential therapeutics, and raise concerns about the long-term consequences of COVID-19 in asymptomatic as well as severe cases.
ELSEVIER
Authors Yuguo Li, Hua Qian, Jian Hang, Xuguang Chen, Pan Cheng, Hong Ling, Shengqi Wang, Peng Liang, Jiansen Li, Shenglan Xiao, Jianjian Wei, Li Liu, Benjamin J. Cowling, Min Kang
Abstract Although airborne transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been recognized, the condition of ventilation for its occurrence is still being debated. We analyzed a coronavirus disease 2019 (COVID-19) outbreak involving three families in a restaurant in Guangzhou, China, assessed the possibility of airborne transmission, and characterized the associated environmental conditions. We collected epidemiological data, obtained a full video recording and seating records from the restaurant, and measured the dispersion of a warm tracer gas as a surrogate for exhaled droplets from the index case. Computer simulations were performed to simulate the spread of fine exhaled droplets. We compared the in-room location of subsequently infected cases and spread of the simulated virus-laden aerosol tracer. The ventilation rate was measured using the tracer gas concentration decay method. This outbreak involved ten infected persons in three families (A, B, C). All ten persons ate lunch at three neighboring tables at the same restaurant on January 24, 2020. None of the restaurant staff or the 68 patrons at the other 15 tables became infected. During this occasion, the measured ventilation rate was 0.9 L/s per person. No close contact or fomite contact was identified, aside from back-to-back sitting in some cases. Analysis of the airflow dynamics indicates that the infection distribution is consistent with a spread pattern representative of long-range transmission of exhaled virus-laden aerosols. Airborne transmission of the SARS-CoV-2 virus is possible in crowded space with a ventilation rate of 1 L/s per person.
THE BMJ
Authors Amy H Attaway, Rachel G Scheraga, Adarsh Bhimraj, Michelle Biehl, Umur Hatipoğli
Abstract Severe covid-19 pneumonia has posed critical challenges for the research and medical communities. Older age, male sex, and comorbidities increase the risk for severe disease. For people hospitalized with covid-19, 15-30% will go on to develop covid-19 associated acute respiratory distress syndrome (CARDS). Autopsy studies of patients who died of severe SARS CoV-2 infection reveal presence of diffuse alveolar damage consistent with ARDS but with a higher thrombus burden in pulmonary capillaries. When used appropriately, high flow nasal cannula (HFNC) may allow CARDS patients to avoid intubation, and does not increase risk for disease transmission. During invasive mechanical ventilation, low tidal volume ventilation and positive end expiratory pressure (PEEP) titration to optimize oxygenation are recommended. Dexamethasone treatment improves mortality for the treatment of severe and critical covid-19, while remdesivir may have modest benefit in time to recovery in patients with severe disease but shows no statistically significant benefit in mortality or other clinical outcomes. Covid-19 survivors, especially patients with ARDS, are at high risk for long term physical and mental impairments, and an interdisciplinary approach is essential for critical illness recovery.
Authors Simon Schroeder, Fabian Pott, Daniela Niemeyer, Talitha Veith, Anja Richter, Doreen Muth, Christine Goffinet, Marcel A Müller, Christian Drosten
Authors Sirui Zhou, Guillaume Butler-Laporte, Tomoko Nakanishi, David R. Morrison, Jonathan Afilalo, Marc Afilalo, Laetitia Laurent, Maik Pietzner, Nicola Kerrison, Kaiqiong Zhao, Elsa Brunet-Ratnasingham, Danielle Henry, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Meriem Bouab, Louis Petitjean, Charlotte Guzman, Xiaoqing Xue, Chris Tselios, Branka Vulesevic, Olumide Adeleye, Tala Abdullah, Noor Almamlouk, Yiheng Chen, Michaël Chassé, Madeleine Durand, Clare Paterson, Johan Normark, Robert Frithiof, Miklós Lipcsey, Michael Hultström, Celia M. T. Greenwood, Hugo Zeberg, Claudia Langenberg, Elin Thysell, Michael Pollak, Vincent Mooser, Vincenzo Forgetta, Daniel E. Kaufmann, J. Brent Richards
Abstract To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.
FRONTIERS IN IMMUNOLOGY
Authors Maxim Shkurnikov, Stepan Nersisyan, Tatjana Jankevic, Alexei Galatenko, Ivan Gordeev, Valery Vechorko, Alexander Tonevitsky
Authors Janis A. Müller, Rüdiger Groß, Carina Conzelmann, Jana Krüger, Uta Merle, Johannes Steinhart, Tatjana Weil, Lennart Koepke, Caterina Prelli Bozzo, Clarissa Read, Giorgio Fois, Tim Eiseler, Julia Gehrmann, Joanne van Vuuren, Isabel M. Wessbecher, Manfred Frick, Ivan G. Costa, Markus Breunig, Beate Grüner, Lynn Peters, Michael Schuster, Stefan Liebau, Thomas Seufferlein, Steffen Stenger, Albrecht Stenzinger, Patrick E. MacDonald, Frank Kirchhoff, Konstantin M. J. Sparrer, Paul Walther, Heiko Lickert, Thomas F. E. Barth, Martin Wagner, Jan Münch, Sandra Heller, Alexander Kleger
Abstract Infection-related diabetes can arise as a result of virus-associated β-cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), impairs glucose homoeostasis, but experimental evidence that SARS-CoV-2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.
MDPI
Authors Eric Dumonteil, Dahlene Fusco, Arnaud Drouin, Claudia Herrera
first_pagesettings Open AccessArticle Genomic Signatures of SARS-CoV-2 Associated with Patient Mortality by Eric Dumonteil 1,*OrcID,Dahlene Fusco 1,2,Arnaud Drouin 2,3OrcID andClaudia Herrera 1OrcID 1 Department of Tropical Medicine, Vector-Borne and Infectious Disease Research Center, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA 2 Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA 3 Department of Pathology, School of Medicine, Tulane University, New Orleans, LA 70112, USA * Author to whom correspondence should be addressed. Academic Editors: Luis Martinez-Sobrido and Fernando Almazan Toral Viruses 2021, 13(2), 227; https://doi.org/10.3390/v13020227 Received: 1 December 2020 / Revised: 12 January 2021 / Accepted: 27 January 2021 / Published: 2 February 2021 (This article belongs to the Collection Coronaviruses) Download PDF Browse Figures Review Reports Citation Export Abstract Infections with SARS-CoV-2 can progress toward multiple clinical outcomes, and the identification of factors associated with disease severity would represent a major advance to guide care and improve prognosis. We tested for associations between SARS-CoV-2 genomic variants from an international cohort of 2508 patients and mortality rates. Findings were validated in a second cohort. Phylogenetic analysis of SARS-CoV-2 genome sequences revealed four well-resolved clades which had significantly different mortality rates, even after adjusting for patient demographic and geographic characteristics. We further identified ten single-nucleotide polymorphisms (SNPs) in the SARS-CoV-2 genome that were associated with patient mortality. Three SNPs remained associated with mortality in a generalized linear model (GLM) that also included patient age, sex, geographic region, and month of sample collection. Multiple SNPs were confirmed in the validation cohort. These SNPs represent targets to assess the mechanisms underlying COVID-19 disease severity and warrant straightforward validation in functional studies.
Authors Leonard H Calabrese, Kevin Winthrop, Vibeke Strand, Jinoos Yazdany, Jolan E Walter
Authors Luke Y C Chen, Tien T T Quach
Authors Chengliang Yang, Kenneth R Chapman, Aaron Wong, Mingyao Liu
Authors Luke Y C Chen Ryan L Hoiland Sophie Stukas Cheryl L Wellington Mypinder S Sekhon
Authors Michael Marshall
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.
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.
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.
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.
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.
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
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
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.
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.
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.
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.
METABOLISM CLINICAL AND EXPERIMENTAL
Authors Guillaume Favre, Kevin Legueult, Christian Pradier, Charles Raffaelli, Carole Ichai, Antonio Iannelli, Alban Redheuil, Olivier Lucidarme, Vincent Esnaulta
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.
To show that visceral fat accumulation better predicts severity of COVID-19 outcome compared to either SCF amounts or BMI.
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.
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).
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.
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.
CELL METABOLISM
Authors Bo Yu, Chenze Li, Yang Sun, Dao Wen Wang
Authors Gregory Piazza, David A. Morrow
Authors Francis Collins
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
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
Authors Flora Marzia Liotti, Giulia Menchinelli, Simona Marchetti, Brunella Posteraro, Francesco Landi, Maurizio Sanguinetti, Paola Cattani
Authors NIH (NATIONAL INSTITUTES OF HEALTH)
Authors Yu Zuo, Shanea K. Estes, Ramadan A. Ali, Alex A. Gandhi, Srilakshmi Yalavarthi, Hui Shi, Gautam Sule, Kelsey Gockman, Jacqueline A. Madison, Melanie Zuo, Vinita Yadav, Jintao Wang, Wrenn Woodard, Sean P. Lezak, Njira L. Lugogo, Stephanie A. Smith, James H. Morrissey, Yogendra Kanthi, Jason S. Knight
Abstract Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19. Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti–β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.
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.
BIORXIV
Authors Adam L. Bailey, Oleksandr Dmytrenko, Lina Greenberg, Andrea L. Bredemeyer, Pan Ma, Jing Liu, Vinay Penna, Lulu Lai, Emma S. Winkler, Sanja Sviben, Erin Brooks, Ajith P. Nair, Kent A. Heck, Aniket S. Rali, Leo Simpson, Mehrdad Saririan, Dan Hobohm, W. Tom Stump, James A. Fitzpatrick, Xuping Xie, Pei-Yong Shi, J. Travis Hinson, Weng-Tein Gi, Constanze Schmidt, Florian Leuschner, Chieh-Yu Lin, Michael S. Diamond, Michael J. Greenberg, Kory J. Lavine
Abstract Epidemiological studies of the COVID-19 pandemic have revealed evidence of cardiac involvement and documented that myocardial injury and myocarditis are predictors of poor outcomes. Nonetheless, little is understood regarding SARS-CoV-2 tropism within the heart and whether cardiac complications result directly from myocardial infection. Here, we develop a human engineered heart tissue model and demonstrate that SARS-CoV-2 selectively infects cardiomyocytes. Viral infection is dependent on expression of angiotensin-I converting enzyme 2 (ACE2) and endosomal cysteine proteases, suggesting an endosomal mechanism of cell entry. After infection with SARS-CoV-2, engineered tissues display typical features of myocarditis, including cardiomyocyte cell death, impaired cardiac contractility, and innate immune cell activation. Consistent with these findings, autopsy tissue obtained from individuals with COVID-19 myocarditis demonstrated cardiomyocyte infection, cell death, and macrophage-predominate immune cell infiltrate. These findings establish human cardiomyocyte tropism for SARS-CoV-2 and provide an experimental platform for interrogating and mitigating cardiac complications of COVID-19.
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.
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.
THE NEW ENGLAND JOURNAL OF MEDICINE
Authors NEJM GROUP
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.
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.
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
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
CELL SYSTEMS
Authors Katherine A. Overmyer, Evgenia Shishkova, Ian J. Miller, Ron Stewart, Joshua J. Coon, Ariel Jaitovich
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.
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
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
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.
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.
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.
WILEY ONLINE LIBRARY
Authors Gurgen Harutyunyan Garnik Harutyunyan Gagik Mkhoyan Varsenik Harutyunyan Suren Soghomonyan
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
EUROPEAN JOURNAL OF HEPATOLOGY
Authors Luan, Junwen; Ren, Yongwen; Gao, Shan; Zhang, Leiliang
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.
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.
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
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.
COLLEGE OF AMERICAN PATHOLOGISTS
Authors Alina C Iuga, Charles C Marboe, Mine M Yilmaz, Jay H Lefkowitch, Cosmin Gauran, Stephen M Lagana
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.
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
EUROPEAN HEART JOURNAL
Authors Esther Culebras, Félix Hernández
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.
THE NEW ENGLISH JOURNAL OF MEDICINE
Authors John A. Jarcho, Julie R. Ingelfinger, Mary Beth Hamel, Ralph B. D’Agostino, David P. Harrington
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.
Authors Puja Mehta, Joanna C Porter, Jessica J Manson, John D Isaacs, Peter J M Openshaw, Iain B McInnes, Charlotte Summers, Rachel C Chambers
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.
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.
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
The Lancet
Authors The Lancet Haematology
Authors Letterio S. Politi, Ettore Salsano, Marco Grimaldi
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.
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
Publmed.gov
Authors Fabio Ciceri, Luigi Beretta, Anna Mara Scandroglio, Sergio Colombo, Giovanni Landoni, Annalisa Ruggeri, Jacopo Peccatori, Armando D’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.
Authors Tina Schaller, Klaus Hirschbühl, Katrin Burkhardt
DEVELOPMENTAL CELL
Authors Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Anand Vasudevan, Kristen M. John, Jason M. Sheltzer
Authors Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Jean K. Lim, Randy A. Albrecht, Benjamin R. tenOever
Authors Massimo Cugno, Pier Luigi Meroni, Roberta Gualtierotti, Samantha Griffini, Elena Grovetti, Adriana Torri, Mauro Panigada, Stefano Aliberti, Francesco Blasi, Francesco Tedesco, Flora Peyvandi
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
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.
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.
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.
Authors David J M Wright
Authors Jessica A Belser
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.
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.
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
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.
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.
CELL RESEARCH
Authors Wei Cao, Taisheng Li
FRONTIERS IN PEDIATRICS
Authors Elena Ciaglia, Carmine Vecchion, Annibale Alessandro Puca
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
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.
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
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
Authors Hui Li, Liang Liu, Dingyu Zhang, Jiuyang Xu, Huaping Dai, Nan Tang, Xiao Su, Bin Cao
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.
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).
Springer
Authors Bérengère Salomé, Assaf Magen
Authors Chang Moon
Authors Majd AlGhatrif, Oscar Cingolani, Edward G. Lakatta
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.
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.
Wiley Online Library
Authors Andrea Cossarizza, Sara De Biasi,Giovanni Guaraldi, Massimo Girardis, Cristina Mussini
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"
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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