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Overview

MeSH Disease

Human Phenotype

Transmission

Seroprevalence
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    Impaired cellular immunity to SARS-CoV-2 in severe COVID-19 patients

    Authors: Ling Ni; Meng-Li Cheng; Hui Zhao; Yu Feng; Jingyuan Liu; Fang Ye; Qing Ye; Gengzhen Zhu; Xiaoli Li; Pengzhi Wang; Jing Shao; Yong-qiang Deng; Peng Wei; Fang Chen; Cheng-feng Qin; Guoqing Wang; Fan Li; Hui Zeng; Chen Dong

    doi:10.1101/2020.08.10.20171371 Date: 2020-08-12 Source: medRxiv

    The World Health Organization has declared SARS-CoV-2 virus outbreak a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, the basis of which remains largely unclear. Currently, though convalescent individuals have been shown with both cellular and humoral immune responses, there is very limited understanding on the immune responses, especially adaptive immune responses, in patients with severe COVID-19. Here, we examined 10 blood SERO samples from COVID-19 patients with acute respiratory distress HP syndrome MESHD (ARDS). The majority of them (70%) mounted SARS-CoV-2-specific humoral immunity with production of neutralizing antibodies SERO. However, compared to healthy controls, the percentages and absolute numbers of both NK cells and CD8+ T cells were significantly reduced, accompanied with decreased IFNg expression in CD4+ T cells in peripheral blood SERO from severe patients. Most notably, we failed in detecting SARS-CoV-2-specific IFNg production by peripheral blood SERO lymphocytes from these patients. Our work thus indicates that COVID-19 patients with severe symptoms are associated with defective cellular immunity, which not only provides insights on understanding the pathogenesis of COVID-19, but also has implications in developing an effective vaccine to SARS-CoV-2.

    Dissemination and co-circulation of SARS-CoV2 subclades exhibiting enhanced transmission TRANS associated with increased mortality in Western Europe and the United States

    Authors: Yuan Hu; Lee W Riley

    doi:10.1101/2020.07.13.20152959 Date: 2020-07-15 Source: medRxiv

    Mechanisms underlying the acute respiratory distress HP syndrome MESHD (ARDS)-like clinical manifestations leading to deaths MESHD in patients who develop COVID-19 remain uncharacterized. While multiple factors could influence these clinical outcomes, we explored if differences in transmissibility TRANS and pathogenicity of SARS-CoV2 variants could contribute to these terminal clinical consequences of COVID-19. We analyzed 34,412 SARS-CoV2 sequences deposited in the Global Initiative for Sharing All Influenza Data (GISAID) SARS-CoV2 sequence database to determine if regional differences in circulating strain variants correlated with increased mortality in Europe, the United States, and California. We found two subclades descending from the Wuhan HU-1 strain that rapidly became dominant in Western Europe and the United States. These variants contained nonsynonymous nucleotide mutations in the Orf1ab segment encoding RNA-dependent RNA polymerase (C14408T), the spike protein gene (A23403G), and Orf1a (G25563T), which resulted in non-conservative amino acid substitutions P323L, D614G, and Q57H, respectively. In Western Europe, the A23403G-C14408T subclade dominated, while in the US, the A23403G-C14408T-G25563T mutant became the dominant strain in New York and parts of California. The high cumulative frequencies of both subclades showed inconsistent but significant association with high cumulative CFRs in some of the regions. When the frequencies of the subclades were analyzed by their 7-day moving averages across each epidemic, we found co-circulation of both subclades to temporally correlate with peak mortality periods. We postulate that in areas with high numbers of these co-circulating subclades, a person may get serially infected. The second infection MESHD may trigger a hyperinflammatory response similar to the antibody SERO-dependent enhancement (ADE) response, which could explain the ARDS-like manifestations observed in people with co-morbidity, who may not mount sufficient levels of neutralizing antibodies SERO against the first infection MESHD. Further studies are necessary but the implication of such a mechanism will need to be considered for all current COVID-19 vaccine designs.

    Antibody SERO responses to SARS-CoV2 are distinct in children TRANS with MIS-C compared to adults TRANS with COVID-19

    Authors: Stuart P Weisberg; Thomas Connors; Yun Zhu; Matthew Baldwin; Wen-Hsuan Lin; Sandeep Wontakal; Peter A Szabo; Steven B Wells; Pranay Dogra; Joshua I Gray; Emma Idzikowski; Francesca Bovier; Julia Davis-Porada; Rei Matsumoto; Maya Meimei Li Poon; Michael P Chait; Cyrille Mathieu; Branka Horvat; Didier Decimo; Zachary C Bitan; Francesca La Carpia; Stephen A Ferrara; Emily Mace; Joshua Milner; Anne Moscona; Eldad A Hod; Matteo Porotto; Donna L Farber

    doi:10.1101/2020.07.12.20151068 Date: 2020-07-14 Source: medRxiv

    Clinical manifestations of COVID-19 caused by the novel coronavirus SARS-CoV-2 are associated with age TRANS. While children TRANS are largely spared from severe respiratory disease MESHD, they can present with a SARS-CoV-2-associated multisystem inflammatory syndrome MESHD (MIS-C) similar to Kawasaki's disease MESHD. Here, we show distinct antibody SERO (Ab) responses in children TRANS with MIS-C compared to adults TRANS with severe COVID-19 causing acute respiratory distress HP syndrome MESHD (ARDS), and those who recovered from mild disease MESHD. There was a reduced breadth and specificity of anti- SARS-CoV-2-specific antibodies SERO in MIS-C patients compared to the COVID patient groups; MIS-C predominantly generated IgG Abs specific for the Spike (S) protein but not for the nucleocapsid (N) protein, while both COVID-19 cohorts had anti-S IgG, IgM and IgA Abs, as well as anti-N IgG Abs. Moreover, MIS-C patients had reduced neutralizing activity compared to COVID-19 cohorts, indicating a reduced protective serological response. These results suggest a distinct infection MESHD course and immune response in children TRANS and adults TRANS who develop severe disease MESHD, with implications for optimizing treatments based on symptom and age TRANS.

    Placental SARS-CoV-2 in a patient with mild COVID-19 disease MESHD

    Authors: Albert L. Hsu; Minhui Guan; Eric Johannesen; Amanda J. Stephens; Nabila Khaleel; Nikki Kagan; Breanna C. Tuhlei; Xiu-Feng Wan

    doi:10.1101/2020.07.11.20149344 Date: 2020-07-14 Source: medRxiv

    Background: The full impact of COVID-19 on pregnancy remains uncharacterized. Current literature suggests minimal maternal, fetal, and neonatal morbidity and mortality,1 and COVID-19 manifestations appear similar between pregnant and non-pregnant women.2 We present a case of placental SARS-CoV-2 virus in a woman with an uncomplicated pregnancy and mild COVID-19 disease MESHD. Methods: A pregnant woman was evaluated at University of Missouri Women and Childrens Hospital. Institutional review board approval was obtained; information was obtained from medical records. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect SARS-CoV-2. A gynecological pathologist examined the placenta and performed histolopathology. Sections were formalin-fixed and paraffin-embedded; slides were cut and subjected to hematoxylin-and-eosin or immunohistochemistry (IHC) staining. IHC was performed with specific monoclonal antibodies SERO to detect SARS-CoV-2 antigen or to identify trophoblasts. Findings: A 29 year-old multigravida presented at 40-4/7 weeks for labor induction. With myalgias MESHD myalgias HP two days prior, she tested positive for SARS-CoV-2. Her parents TRANS were in self-isolation for COVID-19 positivity; husband was asymptomatic TRANS and tested negative for COVID-19, but exposed to a workplace (meatpacking facility) outbreak. Prenatal course was uncomplicated, with no gestational hypertension MESHD hypertension HP. She was afebrile and asymptomatic TRANS with normal vital signs throughout hospitalization. Her myalgias MESHD myalgias HP improved prior to admission. A liveborn male TRANS infant was delivered vaginally. Newborn course was uneventful; he was appropriate for gestational age TRANS, physical was unremarkable, and he was discharged home at 36 hours. COVID-19 RT-PCR test was negative at 24 hours. At one-week follow-up, newborn was breastfeeding well, with no fevers MESHD fevers HP or respiratory distress HP. Overall placental histology is consistent with acute uterine hypoxia MESHD (subchorionic laminar necrosis MESHD) superimposed on chronic uterine hypoxia MESHD (extra-villous trophoblasts and focal chronic villitis). IHC using SARS-CoV-2 nucleocapsid-specific monoclonal antibody SERO demonstrated SARS-CoV-2 antigens throughout the placenta in chorionic villi endothelial cells, and rarely in CK7-expressing trophoblasts. Negative control placenta (November 2019 delivery) and ferret nasal turbinate tissues (not shown) were negative for SARS-CoV-2. Interpretation: In this report, SARS-CoV-2 was found in the placenta, but newborn was COVID-19 negative. Our case shows maternal vascular malperfusion, with no features of fetal vascular malperfusion. To our knowledge, this is the first report of placental COVID-19 despite mild COVID-19 disease MESHD in pregnancy (with no symptoms of COVID-19 aside from myalgias MESHD myalgias HP); specifically, this patient had no fever MESHD fever HP, cough MESHD cough HP, or shortness of breath, but only myalgias MESHD myalgias HP and sick contacts. Despite her having mild COVID-19 disease MESHD in pregnancy, we demonstrate placental vasculopathy and presence of SARS-CoV-2 virus across the placenta. Evidence of placental COVID-19 raises concern for possible placental vasculopathy (potentially leading to fetal growth restriction, pre-eclampsia MESHD eclampsia HP, and other pregnancy complications MESHD) as well as for potential vertical transmission TRANS -- especially for pregnant women who may be exposed to COVID-19 in early pregnancy. Further studies are urgently needed, to determine whether women with mild, pre-symptomatic, or asymptomatic TRANS COVID-19 may have SARS-CoV-2 virus that can cross the placenta, cause fetal vascular malperfusion, and possibly affect the fetus. This raises important public health and public policy questions of whether future pregnancy guidance should include stricter pandemic precautions, such as screening for a wider array of COVID-19 symptoms, increased antenatal surveillance, and possibly routine COVID-19 testing on a regular basis throughout pregnancy.

    SARS-CoV-2 assays to detect functional antibody SERO responses that block ACE2 recognition in vaccinated animals and infected patients

    Authors: Daniel W Kulp; Susanne Walker; Neethu Chokkalingam; Emma L Reuschel; Mansi Purwar; Ziyang Xu; Ebony Y Gary; Kevin Y. Kim; Katherine Schultheis; Jewell Walters; Stephanie Ramos; Trevor R.F. Smith; Kate Broderick; Pablo Tebas; Ami Patel; David B Weiner

    doi:10.1101/2020.06.17.158527 Date: 2020-06-20 Source: bioRxiv

    SARS-CoV-2 ( Severe Acute Respiratory Syndrome MESHD Coronavirus 2) has caused a global pandemic of COVID-19 resulting in cases of mild to severe respiratory distress HP and significant mortality. The global outbreak of this novel coronavirus has now infected >8 million people worldwide with >2 million cases in the US (June 17th, 2020). There is an urgent need for vaccines and therapeutics to combat the spread of this coronavirus. Similarly, the development of diagnostic and research tools to determine infection MESHD and vaccine efficacy are critically needed. Molecular assays have been developed to determine viral genetic material present in patients. Serological assays SERO have been developed to determine humoral responses to the spike protein or receptor binding domain (RBD). Detection of functional antibodies SERO can be accomplished through neutralization of live SARS-CoV2 virus, but requires significant expertise, an infectible stable cell line, a specialized BioSafety Level 3 (BSL-3) facility. As large numbers of people return from quarantine, it is critical to have rapid diagnostics that can be widely adopted and employed to assess functional antibody SERO levels in the returning workforce. This type of surrogate neutralization diagnostic can also be used to assess humoral immune responses induced in patients from the large number of vaccine and immunotherapy trials currently on-going. Here we describe a rapid serological diagnostic assay for determining antibody SERO receptor blocking and demonstrate the broad utility of the assay by measuring the antibody SERO functionality of sera from small animals and non-human primates immunized with an experimental SARS-CoV-2 vaccine and using sera from infected patients.

    Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma SERO. A proof of concept single arm multicenter interventional trial

    Authors: Cesare Perotti; Fausto Baldanti; Raffaele Bruno; Claudia Delfante; Elena Seminari; Salvatore Casari; Elena Percivalle; Claudia Glingani; Valeria Musella; Mirko Belliato; Martina Garuti; Federica Meloni; Marilena Frigato; Antonio Di Sabatino; Catherine Klersy; Giuseppe De Donno; Massimo Franchini

    doi:10.1101/2020.05.26.20113373 Date: 2020-05-29 Source: medRxiv

    BACKGROUND Hyperimmune plasma SERO from Covid-19 convalescent is a potential treatment for severe Covid-19. METHODS We conducted a multicenter one arm proof of concept interventional study. Patients with Covid-19 disease MESHD with moderate-to-severe Acute Respiratory Distress HP Syndrome MESHD, elevated C-reactive Protein and need for mechanical ventilation and/or CPAP were enrolled. One to three 250-300 ml unit of hyperimmune plasma SERO ( neutralizing antibodies SERO titer [≥]1:160) were administered. Primary outcome was 7-days hospital mortality. Secondary outcomes were PaO2/FiO2, laboratory and radiologic changes, as well as weaning from mechanical ventilation and safety. RESULTS The study observed 46 patients from March, 25 to April, 21 2020. Patients were aged TRANS 63, 61% male TRANS, 30 on CPAP and 7 intubated. PaO2/FiO2 was 128 (SD 47). Symptoms and ARDS duration were 14 (SD 7) and 6 days (SD 3). Three patients (6.5%) died within 7 days. The upper one-sided 90%CI was 13.9%, allowing to reject the null hypothesis of a 15% mortality. PaO2/FiO2 increased by 112 units (95%CI 82 to142) in survivors, the chest radiogram severity decreased in 23% (95%CI 5% to 42%); CRP, Ferritin and LDH decreased by 60, 36 and 20% respectively. Weaning from CPAP was obtained in 26/30 patients and 3/7 were extubated. Five serious adverse events occurred in 4 patients (2 likely, 2 possible treatment related). CONCLUSIONS Hyperimmune plasma SERO in Covid-19 shows promising benefits, to be confirmed in a randomized controlled trial. This proof of concept study could open to future developments including hyperimmune plasma SERO banking, development of standardized pharmaceutical products and monoclonal antibodies SERO.

    Systemic and mucosal antibody SERO secretion specific to SARS-CoV-2 during mild versus severe COVID-19

    Authors: Carlo Cervia; Jakob Nilsson; Yves Zurbuchen; Alan Valaperti; Jens Schreiner; Aline Wolfensberger; Miro E. Raeber; Sarah Adamo; Marc Emmenegger; Sara Hasler; Philipp P. Bosshard; Elena De Cecco; Esther Baechli; Alain Rudiger; Melina Stuessi-Helbling; Lars C. Huber; Annelies S. Zinkernagel; Dominik J. Schaer; Adriano Aguzzi; Ulrike Held; Elsbeth Probst-Mueller; Silvana K. Rampini; Onur Boyman

    doi:10.1101/2020.05.21.108308 Date: 2020-05-23 Source: bioRxiv

    BackgroundInfection with the severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) causes an acute illness termed coronavirus disease MESHD 2019 (COVID-19). Humoral immune responses likely play an important role in containing SARS-CoV-2, however, the determinants of SARS-CoV-2-specific antibody SERO responses are unclear. MethodsUsing immunoassays SERO specific for the SARS-CoV-2 spike protein, we determined SARS-CoV-2-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) in sera and mucosal fluids of two cohorts, including patients with quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR)-confirmed SARS-CoV-2 infection MESHD (n = 56; median age TRANS 61 years) with mild versus severe COVID-19, and SARS-CoV-2-exposed healthcare workers (n = 109; median age TRANS 36 years) with or without symptoms and tested negative or positive by RT-qPCR. FindingsOn average, SARS-CoV-2-specific serum SERO IgA titers in mild COVID-19 cases became positive eight days after symptom onset TRANS and were often transient, whereas serum SERO IgG levels remained negative or reached positive values 9-10 days after symptom onset TRANS. Conversely, patients with severe COVID-19 showed a highly significant increase of SARS-CoV-2-specific serum SERO IgA and IgG titers as a function of duration since symptom onset TRANS, independent of patient age TRANS and comorbidities. Very high levels of SARS-CoV-2-specific serum SERO IgA correlated with severe acute respiratory distress HP syndrome MESHD (ARDS). Interestingly, some of the SARS-CoV-2-exposed healthcare workers with negative SARS-CoV-2-specific IgA and IgG serum SERO titers had detectable SARS-CoV-2-specific IgA antibodies SERO in their nasal fluids and tears. Moreover, SARS-CoV-2-specific IgA levels in nasal fluids of these healthcare workers were inversely correlated with patient age TRANS. InterpretationThese data show that systemic IgA and IgG production against SARS-CoV-2 develops mainly in severe COVID-19, with very high IgA levels seen in patients with severe ARDS, whereas mild disease MESHD may be associated with transient serum SERO titers of SARS-CoV-2-specific antibodies SERO but stimulate mucosal SARS-CoV-2-specific IgA secretion. The findings suggest four grades of antibody SERO responses dependent on COVID-19 severity.

    Identification of immune checkpoints in COVID-19

    Authors: Julien Carvelli; Olivier Demaria; Frédéric Vély; Luciana Batista; Nassima Chouaki Benmansour; Joanna Fares; Sabrina Carpentier; Marie-Laure Thibult; Ariane Morel; Pascale André; Agnès Represa; Christelle Piperoglou; the Explore COVID-19 IPH group; the Explore COVID-19 Medical group; Pierre Yves Cordier; Erwan Le Dault; Christophe Guervilly; Pierre Simeone; Marc Gainnier; Yannis Morel; Mikael Ebbo; Nicolas Schleinitz; Eric Vivier

    doi:10.21203/rs.3.rs-27340/v1 Date: 2020-05-07 Source: ResearchSquare

    Coronavirus disease MESHD 2019 (COVID-19) is a new pandemic acute respiratory disease MESHD caused by infection MESHD infection with severe HP with severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2)11-3. We provide here a longitudinal analysis of immune responses, including immune cell phenotyping and assessments of the soluble factors present in the blood SERO and broncho-alveolar lavage fluid (BALF) of patients at various stages of COVID-19 severity: paucisymptomatic, pneumonia MESHD pneumonia HP and acute respiratory distress HP syndrome MESHD (ARDS). While we confirm a lymphopenia MESHD lymphopenia HP associated with COVID-19 severity4-7, we report an increase in expression of the NKG2A and PD-1 inhibitory receptors on T and natural killer (NK) cells, as well as an increase in CD39 expression on NK cells, suggesting that therapeutic blocking antibodies SERO targeting these molecules already used for cancer immunotherapy8 could be repurposed as first line of defense to promote SARS-CoV-2 clearance. In addition, the C5a anaphylatoxin and its receptor C5aR1 (CD88) play a key role in the initiation and maintenance of inflammatory responses, by recruiting neutrophils and monocytes to the lungs9,10. We report an increase in soluble C5a levels proportional to COVID-19 severity and high levels of C5aR1 expression in blood SERO and BALF myeloid cells, indicating a potential role of the C5a-C5aR1 axis in the pathophysiology of ARDS. Avdoralimab is a clinical-stage anti-C5aR1 therapeutic monoclonal antibody SERO (mAb) that prevents C5a-mediated myeloid cell recruitment and activation. We propose the use of this antibody SERO to limit myeloid cell infiltration in the lung and to prevent the excessive lung inflammation MESHD associated with ARDS in COVID-19 patients. 

    Immune alterations during SARS-CoV-2-related acute respiratory distress HP syndrome MESHD

    Authors: Lila Bouadma; Aurelie Wiedemann; Juliette Patrier; Mathieu Surenaud; Paul-Henri Wicky; Emile Foucat; Jean-Luc Diehl; Boris P Hejblum; Fabrice Sinnah; Etienne de Montmollin; Christine Lacabaratz; Rodolphe Thiebaut; Jean-Francois Timsit; Yves Levy

    doi:10.1101/2020.05.01.20087239 Date: 2020-05-07 Source: medRxiv

    We report a longitudinal analysis of the immune response associated with a fatal case of COVID-19. This patient exhibited a rapid evolution towards multiorgan failure. SARS-CoV-2 was detected in multiple nasopharyngeal, blood SERO, and pleural samples, despite antiviral and immunomodulator treatment. Clinical evolution in the blood SERO was marked by an increase (2-3 fold) in differentiated effector T cells expressing exhaustion (PD-1) and senescence (CD57) markers, an expansion of antibody SERO-secreting cells, a 15-fold increase in {gamma}{delta} T-cell and proliferating NK-cell populations, and the total disappearance of monocytes, suggesting lung trafficking. In the serum SERO, waves of a proinflammatory cytokine storm, Th1 and Th2 activation, and markers of T-cell exhaustion, apoptosis, cell cytotoxicity, and endothelial activation were observed until the fatal outcome. This case underscores the need for well-designed studies to investigate complementary approaches to control viral replication, the source of the hyperinflammatory status, and immunomodulation to target the pathophysiological response.

    Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma SERO Viral Load in Critical COVID-19

    Authors: Bruce K Patterson; Harish Seethamraju; Kush Dhody; Michael J Corley; Kazemm Kazempour; Jay P Lalezari; Alina PS Pang; Christopher Sugai; Edgar B Francisco; Amruta Pise; Hallison Rodrigues; Matthew Ryou; Helen L Wu; Gabriela M Webb; Byung S Park; Scott Kelly; Nadar Pourhassan; Alena Lelic; Lama Kdouh; Monica Herrera; Eric Hall; Enver Aklin; Lishomwa Ndhlovu; Jonah B Sacha

    doi:10.1101/2020.05.02.20084673 Date: 2020-05-05 Source: medRxiv

    Severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease MESHD 2019 (COVID-19), is now pandemic with nearly three million cases reported to date. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease MESHD with pneumonia MESHD pneumonia HP and acute respiratory distress HP syndrome MESHD (ARDS) requiring mechanical ventilation. Emerging results indicate a dysregulated immune response characterized by runaway inflammation MESHD, including cytokine release syndrome MESHD (CRS), as the major driver of pathology in severe COVID-19. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation MESHD in severe disease MESHD caused by SARS-CoV-2 infection MESHD are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma SERO IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma SERO viremia MESHD viremia HP. Following compassionate care treatment with the CCR5 blocking antibody SERO leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma SERO IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma SERO viremia MESHD viremia HP. Consistent with reduction of plasma SERO IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation MESHD, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma SERO viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19.

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MeSH Disease
Human Phenotype
Transmission
Seroprevalence


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