Role of antibodies, inflammatory markers, and echocardiographic findings in post-acute cardiopulmonary symptoms after SARS-CoV-2 infection (preprint)

ABSTRACT BACKGROUND Shortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. METHODS In a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after PCR-confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. RESULTS We enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex (OR 2.55, 95%CI 1.13-5.74) and hospitalization during acute infection (OR 3.25, 95%CI 1.08-9.82) were associated with symptoms. IgG antibody to SARS-CoV-2 receptor binding domain (OR 1.38 per doubling, 95%CI 1.38-1.84) and high-sensitivity C-reactive protein (OR 1.31 per doubling, 95%CI 1.00-1.71) were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with pericardial effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters (including left ventricular ejection fraction and strain, right ventricular strain, pulmonary artery pressure) or high-sensitivity troponin, NT-pro-BNP, interleukin-10, interferon-gamma, or tumor necrosis factor-alpha. CONCLUSIONS Among adults in the post-acute phase of SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted. FUNDING This work was supported by the UCSF Division of Cardiology at Zuckerberg San Francisco General, and the National Institutes of Health/National Heart Lung Blood Institute and National Institute of Allergy and Infectious Diseases. MSD is supported by NIH 5K12HL143961. MJP is supported on NIH T32 AI60530-12. JDK is supported by NIH K23AI135037. TJH is supported by NIH/NIAID 3R01A1141003-03S1. PYH is supported by NIH/NAID 2K24AI112393-06. This publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1TR001872. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. GRAPHICAL ABSTRACT

Enhanced Diagnosis of the COVID-19 Behaviour Using the Rough Set Theory and Genetic Algorithms (preprint)

The outbreak of the coronavirus 2019 (COVID-19) has created an excellent challenge for the care system worldwide. One in every of the foremost vital points of this challenge is that the management of COVID-19 patients needing acute and/or vital metastasis care. The main objective of applying data mining to Covid-19 dataset is essential to propel learning by empowering data-oriented decision making to improve existing clinical practices and learning materials. Current data mining techniques offer patient data analysis for achieving an automated diagnosis of the diseases as an example; however, the results are not very accurate nor reliable, especially with a dynamic virus as the COVID-19. In this paper, we are proposing a multi-stage diagnostic ( MSD-Covid19 ) model to enhance the diagnosis of the COVID-19, and to provide a sustainable automated system to improve the healthcare systems and patient outcomes. The first stage includes a selection of a classification model with no reduction attributes. Tested classification algorithms include Deep learning, Multilayer Perceptron, KNN, Bayesian Auto Regression, Logistic Model Trees (LMT), Hoeffding tree (VFDT), and Fuzzy Unordered Rule Induction Algorithm. In the second stage, a rough set reduction algorithm based on genetic algorithms is employed, and finally, an optimization of the classification is conducted using the reduced attributes. The proposed model is evaluated on a global COVID-19 dataset. Experimental results demonstrate that the proposed MSD-Covid19 has a great contribution to increase the diagnostic accuracy of the COVID-19 disease behaviour.

Development and Validation of SCOPE Score: A Clinical Score to Predict Progression to Severe Respiratory Failure in Hospitalized Patients With COVID-19 Pneumonia (preprint)

Most patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but several develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from C-reactive protein, D-dimer, interleukin-6, and ferritin circulating concentrations at hospitalization during the SAVE-MORE study, offers comparable predictive accuracy for progression to SRF or death within 14 days as suPAR ≥6 ng/ml (area under receiver operator characteristic curve, 0.81 for both). SCOPE score was validated against an independent dataset from the SAVE study. The SCOPE score is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.Funding: The study was funded in part by the Hellenic Institute for the Study of Sepsis and by Swedish Orphan Biovitrum. The Hellenic Institute for the Study of Sepsis is the Sponsor of the SAVE and SAVE-MORE studies.Declaration of Interests:E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, AxisShield, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and XBiotech Inc.; and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis). G. Poulakou has received independent educational grants from Pfizer, MSD, Angelini, and Biorad. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. L. Dagna had received consultation honoraria from SOBI. M. Bassetti has received funds for research grants and/or advisor/consultant and/or speaker/chairman from Angelini, Astellas, Bayer, Biomerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi and Nabriva. P. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. G. N. Dalekos is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, Sobi, received research grants from Abbvie, Gilead and has served as PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. M. G. Netea is supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. Hes is a scientific founder of TTxD and he has received independent educational grants from TTxD, GSK, Ono Pharma and ViiV HealthCare. The other authors do not have any competing interest to declare.Ethics Approval Statement: The SAVE protocol was approved by the National Ethics Committee of Greece (approval 38/20) and National Organization for Medicines approval (ISO 28/20). The SAVE-MORE protocol was approved by the National Ethics Committee of Greece (approval 161/20) and by the Ethics Committee of the National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, in Rome (1 February 2021).Trial Registration: The SAVE study was prospectively registered prior to enrolling the first patient (EudraCT number 2020-001466-11; ClinicalTrials.gov identifier NCT04357366). The SAVE-MORE study was prospectively registered (EudraCT no. 2020-005828-11; ClinicalTrials.gov identifier NCT04680949). Written informed consent was provided by all patients prior to enrollment.

Quantitative serology for SARS-CoV-2 using self-collected saliva and finger-stick blood (preprint)

Convenient and widespread serology testing may alter the trajectory of the COVID-19 pandemic. This study seeks to leverage high-throughput, multiplexed serologic assays, which have been adopted as benchmarks for vaccine efficacy, to support large-scale surveys of SARS-CoV-2 immunity using finger-stick blood and/or saliva. Specifically, we optimized MSD’s serology assays, which were analytically validated for serum, to test self-collected finger-stick blood and saliva samples. We show that these assays can be used with FDA-registered specimen collection devices to obtain quantitative measurements for self-collected samples. Antibody levels were measured using an electrochemiluminescent (ECL) multiplex immunoassay, which has been used to measure humoral responses to several COVID-19 vaccines, including those funded by the U.S. Government’s Operation Warp Speed. First, we show that salivary antibodies are stable without refrigeration or preservatives for at least five days. Using matched samples, we show that testing of saliva and finger-stick blood equivalently identified individuals with humoral responses to CoV-2 antigens. Moreover, we piloted a simple saliva collection kit that can be used to safely send samples through the mail. This work demonstrates that robust methods for self-collection of finger-stick blood and saliva, in combination with quantitative, automated immunoassays, provide the technical capabilities needed to support large-scale serology testing.

Aspergillus Tracheobronchitis in COVID-19 ARDS Patients – A Cohort Study (preprint)

Background: Coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome patients are at risk for fungal infections, especially aspergillosis and mucormycosis. COVID-19-associated pulmonary aspergillosis (CAPA) is differentiated in a pulmonary form and Aspergillus tracheobronchitis (ATB). During the first wave of the pandemic, bronchoscopy for diagnosing Aspergillus superinfections was rarely performed in COVID-19 patients, so that detailed on data on ATB in CAPA patients is scarce. We analyzed prevalence and mortality of tracheobronchitis in patients with CAPA.Methods: We conducted a retrospective, single-centre study at the 14-bed intensive care unit (ICU) of the Department I of Internal Medicine of the University Hospital of Cologne, Germany from March 2020 to February 2021. CAPA patients were identified by twice weekly analysis of tracheal aspirates for Aspergillus growth, Aspergillus DNA (PCR) and galactomannan combined with serum galactomannan testing. In case of positive results, bronchoscopy with the examination of trachea and lower airways and bronchoalveolar lavage followed.Findings: A total of 69 COVID-19 patients were admitted to the ICU, with 17 patients developing probable CAPA. All CAPA patients received bronchoscopy resulting in a clinical diagnosis of tracheobronchitis in 8 patients with signs of tracheal lesions, pseudomembranes or vulnerable bloody trachea. Seven bronchoalveolar lavages revealed culture and eight PCR positivity for Aspergillus fumigatus. In 7 of 8 tracheobronchitis patients, bronchoalveolar lavage samples tested positive for galactomannan antigen optical density index of >0.5. The overall mortality of CAPA patients was 52.9% and the overall mortality of ATB patients was 75%.Interpretation: Our data indicate a substantial prevalence of tracheobronchitis in this single-center cohort of CAPA patients. To facilitate early diagnosis bronchoscopic tracheal examination is crucial as computed tomography lacks diagnostic accuracy to enable timely initiation of therapy.Funding Information: This work was in part supported by the German Registry of COVID-19 Autopsies (www.DeRegCOVID.ukaachen.de), funded by the Federal Ministry of Health (ZMVI1-2520COR201), and the project DEFEAT PANDEMICs, funded by the Federal Ministry of Education and Research (01KX2021).Declaration of Interests: PK reports grants or contracts from German Federal Ministry of Research and Education and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. SvS none. JGB reports scientific grants and travel expenses from Kite/Gilead outside the submitted work. FF has a clinician scientist position supported by the deans office, medical faculty, University of Cologne. JSG none. FP none. BB reports honoraria, travel expenses and advisory role from/for Astellas, Celgene, Johnson & Johnson, Kite/Gilead, MSD, Novartis, Pfizer, Takeda and financing of scientific research by Astellas, Celgene, Kite/Gilead, MSD and Takeda outside the submitted work. DAE received honoraria from Sanofi and TAKEDA outside the submitted work. ASV reports travel grants from Gilead Sciences outside the submitted work. OK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead and Pfizer and receipt of equipment, materials, drugs, medical writing, gifts or other services by Pfizer, MSD, Basilea, Gilead, Virotech and Wako Fujifilm outside the submitted work. PB none. MK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead, MSD and Pfizer outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al 344 Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley outside the submitted work.Ethics Approval Statement: Patients with CAPA were included in the FungiScope® global registry for emerging invasive fungal infections (https://www.clinicaltrials.gov; National Clinical Trials identifier NCT01731353), which was approved by the local ethics committee of the University of Cologne, Cologne, Germany (identifier 05-102).

Rationally Designed Immunogens Enable Immune Focusing Following SARS-CoV-2 Spike Imprinting (preprint)

Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit spread of related viruses with pandemic potential. Here, we leveraged rational immunogen design to focus humoral responses on conserved epitopes. Using glycan engineering and epitope scaffolding, we directed murine serum antibody responses to conserved receptor binding motif (RBM) and domain (RBD) epitopes in the context of SARS-CoV-2 spike imprinting. Whereas all engineered immunogens elicited a robust SARS-CoV-2-neutralizing serum response, the RBM-focusing immunogens exhibited increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV; structural characterization of representative antibodies defined a conserved epitope. Furthermore, the RBM-focused sera conferred protection against SARS-CoV-2 challenge. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses without compromising SARS-CoV-2 protection. Broadly, these engineering strategies are adaptable to other viral glycoproteins for targeting conserved epitopes.Funding: We acknowledge funding from NIH R01s AI146779 (AGS), AI124378, AI137057 and AI153098 (DL), R01 AI157155 (MSD) and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant (AGS); training grants: NIGMS T32 GM007753 (BMH, TMC); T32 AI007245 (JF); F31 Al138368 (MS); F30 AI160908 (BMH). ABB is supported by the National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the MGH Transformative Scholars Program as well as funding from the Charles H. Hood Foundation (ABB). This independent research was supported by the Gilead Sciences Research Scholars Program in HIV (ABB). JBC is supported by a Helen Hay Whitney Foundation postdoctoral fellowship.Declaration of Interests: BMH, TMC, and AGS have filed a provisional patent for the described immunogens. MSD is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, and Emergent BioSolutions.Ethics Approval Statement: All experiments were conducted with institutional IACUC approval (MGH protocol 2014N000252). Animal studies were carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocols were approved by the Institutional Animal Care and Use Committee at the Washington University School of Medicine (assurance number A3381–01).

Neutrophil Extracellular Traps, Local IL-8 Expression, and Cytotoxic T-Lymphocyte Absence in the Lungs of Fatal COVID-19: A Retrospective Histopathology Cohort Study (preprint)

Background: Excessive inflammation is pathogenic in pneumonitis associated to severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defence mechanism against bacteria but have also been shown to mediate tissue damage in a number of diseases. Methods: In this retrospective cohort study, sixteen immediate post-mortem lung biopsies were methodologically analysed as exploratory and validation cohorts. NETs were quantitatively analysed by multiplexed immunofluorescence and correlated with local levels of IL-8 mRNA expression and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by RT-PCR and immunohistochemistry.Findings: NETs were found in the lung interstitium and surrounding the bronchiolar epithelium with interindividual and spatial heterogeneity. NET density did not correlate with SARS-CoV-2 tissue viral load. NETs were associated with local IL-8 mRNA levels. NETs were also detected in pulmonary thrombi and in only one out of eight liver tissues in spatial fashion. NET focal presence negatively correlated with CD8+ T-cell infiltration in the lungs. Interpretation: Abundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, showing no correlation with viral loads. The strong association between NETs and IL-8 focal expression points to this chemokine as the potential causative factor. The function of cytotoxic T-lymphocytes in the immune responses against SARS-CoV-2 may be interfered by the presence of NETs.Funding Information: This study was supported by Banco Bilbao Vizcaya (BBVA) Foundation, “Ayudas a Equipos de Investigación Científica SARS-CoV-2 y COVID-19”. Declaration of Interests: I.M. reports receiving commercial research grants from BMS, Bioncotech, Alligator, Pfizer, Leadartis and Roche; has received speakers bureau honoraria from MSD; and is a consultant or advisory board member for BMS, Roche, Genmab, F-Star, Bioncotech, Bayer, Numab, Pieris, Alligator, and Merck Serono. C.E.A reports research grants from AstraZeneca. All other authors declare no competing interests.Ethics Approval Statement: This study was approved by the ethics committee of the University of Navarra, Spain (Approval 2020.192). Tissue collections were obtained with consent from a first-degree relative, following a protocol approved by the ethics committee of the University of Navarra (Protocol 2020.192p).

Comparison of Contraceptive Sales Before and After the SARS-CoV-2 Pandemic in Brazil (preprint)

Background: The SARS-CoV-2 (COVID-19) pandemic has put the health care system under severe strain. Sexual and reproductive health services, including contraception provision, were one of the most disrupted. Our objective was to assess the impact of the COVID-19 pandemic on the sales of modern contraceptive methods in Brazil.Methods: We analysed monthly data of short-acting, long-acting reversible contraceptives (LARCs; implants and intrauterine devices [IUD]), and COVID-19 related deaths. We categorised the sales in: i) emergency contraceptive (EC), ii) oral contraceptives, rings and patches, iii) injectable contraceptives, iv) LARC methods, including copper-IUD, and v) LARC methods, except Cu-IUDs.Findings: Contraceptives sales had a non-significant increase in the year 2020 compared to the year 2019, and the annual average ranged from 12·8 to 13·0 million units/month. We observed an increase in the sales of injectable contraceptives for the February-May/2020 and EC pills for the June-July/2020 and a non-significant variation for pills, patches and rings. The hormonal-IUD/ENG-implant had three patterns: a decrease in sales between February-April, which coincides with the closure of family planning services; an increment of sales since April, which coincide with the first COVID-19 related deaths and an important increment of sales since July/2020.Interpretation: The COVID-19 pandemic has disrupted the Brazilian healthcare system and due to the fact that many family planning clinics were closed, the sales of most of the modern contraceptives fall over the year 2020; however, the increment of sales of the LNG-IUD/ENG-implant at private sector indicated the inequity in access of contraception.Funding Information: This study received partial financial support from the Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP; award number 2015/20504‐9) and from the Brazilian National Research Council (CNPq; grant number 573747/2008‐3). Moreover, CMC and AM received funding from SRH, part of the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the World Health Organisation (WHO), to complete their Post-graduate studies. This article represents the views of the named authors only and does not represent the views of the mentioned organisations.Declaration of Interests: LB received honoraria as lecturer from Bayer Healthcare and MSD. The other authors declared no conflict of interest.

Increased Risk of Severe COVID-19 in Hospitalized Patients With SARS-CoV-2 Variant of Concern Alpha Infection in France: A Multicentre Matched Cohort Study With Retrospective Data Collection (preprint)

Background: The impact of the variant of concern (VOC) Alpha on the severity of COVID-19 is debated and has to be analyzed in different epidemiological situations. We report our analysis in France.Methods: We conducted an exposed/unexposed cohort study with retrospective data collection, comparing patients infected by VOC Alpha to patients infected by historical lineages. Participants were matched on age (+/- 2.5 years), sex and region of hospitalization. The primary endpoint was the proportion of hospitalized participants with severe COVID-19, defined as a WHO-scale >5 or by the need of a non-rebreather mask, occurring up to day 29 after admission. We used a logistic regression model stratified on each matched pair and accounting for factors known to be associated with the severity of the disease (age, BMI and comorbidities) to compare the 2 groups. Findings: We included 650 pairs of patients hospitalized between Jan 1, 2021, and Feb 28, 2021, in 47 hospitals. Median age was 70 years and 61.3% of participants were male. The proportion of participants with comorbidities was high in both groups (85.0% vs 90%, p=0.004). Infection by VOC Alpha was associated with a higher risk of severe COVID-19 (41.7% vs 38.5% - aOR=1.33 95% CI [1.03-1.72]). The rate of mortality was 24.0% vs 19.0% (aHR 1.21 95% CI [0.93-1.58]).Interpretation: Infection by the VOC Alpha was associated with a higher risk of severe COVID-19 during the third COVID-19 epidemic wave in France.Clinical Trial Registration Details: Registered on ClinicalTrials.gov (NCT04863547). Funding Information: The study was funded by the ANRS Maladies Infectieuses Emergentes.Declaration of Interests: DC reports HIV grants from Janssen (2017-2018, 2019-2020), personal fees from Janssen (2018) and Gilead (2018, 2020) for lectures on HIV outside the submitted work. CC reports personal fees from Janssen (2018), MSD (2019), Gilead (2018-2020), Theratechnologies (2020) and ViiV Healthcare (2018-2020). HC reports personal fees from MSD (2020) and ViiV Healthcare (2020) for lectures on HIV. GMB reports support for attending meetings and personal fees from BMS, MSD, Janssen, Sanofi, Pfizer and Gilead for lectures outside the submitted work. JP reports support for attending meetings and personal fees from Gilead, Pfizer and Eumedica Gilead for lectures. DD reports personal fees from Gilead, ViiV Healthcare and Janssen for participation on an advisory Board. Other authors declare that they have no competing interest.Ethics Approval Statement: The study was approved by the SPILF Ethics Committee.

Immunogenicity of SARS-CoV-2 mRNA Vaccines in Patients with Cancer: Findings from an International Collaborative Cohort Study (preprint)

Patients with cancer experience higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, compared to the general population. SARS-CoV-2 mRNA vaccines have shown to be highly effective in clinical trials; however, few data are available on the efficacy of SARS-CoV-2 vaccines in patients with cancer. Using a prospective cohort study design, we assessed the seroconversion rates and anti-SARS-CoV-2 S antibody titers following the 1st and 2nd dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer at centers in U.S. and Europe from January 2021 to April 2021. Among 131 patients included in the immunogenicity analysis, most (94%) developed antibody levels; however, 6% showed no seroconversion after completing the mRNA vaccination series. No differences in seroconversion rates were observed between BNT162b2 and mRNA-1273 vaccine groups. Patients with solid tumors (98%) were much more likely to seroconvert and develop higher antibody titers than those with hematological malignancy (77%). Although seroconversion rates were consistently high in patients receiving different types of anti-cancer therapy except anti-CD-20 antibody; the antibody titers were much lower in patients who received cytotoxic chemotherapy, immunotherapy, or monoclonal antibody compared to those on clinical surveillance or receiving endocrine therapy within six months prior to vaccination. None of the patients on anti-CD-20 antibody therapy developed an antibody response, even after receiving 2 doses of the vaccines. After correlating with cell-mediated immunity in a subset of patients at high-risk for antibody non-response, we propose exploring the addition of a second booster, or convalescent plasma therapy, or postpone vaccination until after completion of their specific anti-cancer treatment. Although encouraging results, we suggest high-risk vaccinated patients with cancer to continue taking safety precautions until their immune response is confirmed at 4 weeks after 2nd dose of mRNA vaccines. We also highly encourage all eligible individuals in the general population to get vaccinated to ensure the protection of the most vulnerable groups, such as those with cancer.Funding: This project has been funded in whole or in part with federal funds from National Cancer Institute grant P30 CA054174 (Mays Cancer Center at University of Texas Health San Antonio MD Anderson); and grant MRSG-16-152-01-CCE the American Cancer Society and Hope Foundation for Cancer Research. A ‘Research & Development Program’ grant from Geneva University Hospitals awarded to Natacha Bordry funded part of this study.Declaration of Interest: Dr. Addeo reported receiving personal fees for attending advisory from Bristol‐Myers Squibb, AstraZeneca, Roche, Pfizer, Merck Sharp and Dohme,Astella, Eli Lilly and Boehringer‐Ingelheim. He has received fees for speaking bureau for Eli Lilly, AstraZeneca, MSD for work performed outside of the current study. Dr. P. Shah reported receiving grant from the Biomedical Advanced Research and Development Authority outside of this work. Dr Labidi-Galy reported receiving personal fees for attending advisory from AstraZeneca. Proferssor Mach is a founder and minority shareholder of MaxiVAX SA, a private biotech company based in Geneva Switzerland, working on personalized cancer immunotherapy and infectious disease vaccines; with no impact on the current manuscript. Dr. Taylor reported funding from NIAID/NIH and the COVID-19 Prevention Network which conducts COVID-19 vaccine trials. Dr. Patel reported receiving grant support from the National Institutes of Health, Cancer Prevention Research Institute of Texas, ThriveWell Foundation and the Bill and Ella Owens Medical Foundation outside of this work Dr. Wang reported receiving grants from 80/20 Foundation, National Institute of Health, and Nancy Smith Hurd Foundation. Dr. Mesa reported receiving research support from Celgene, Incyte, Abbvie, Samus, Genotech, Promedior, and CTI; and consulting fees from Novartis, Sierra Onc, LaJolla, and Pharma. Dr. D. Shah reported receiving grants from American Cancer Society and Hope Foundation for Cancer Research during the conduct of the study. Dr. D. Shah reported receiving grant from the Biomedical Advanced Research and Development Authority outside of this work. No other disclosures were reported. All other coauthors reported no conflict of interests.Ethical Approval: This study was approved by institutional review boards at each institution.

Remdesivir for the Treatment of Hospitalised Patients with COVID-19 (DisCoVeRy): A Randomised, Controlled, Open-Label Trial (preprint)

Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in patients with COVID-19 requiring oxygen and/or ventilator support.Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial in adults hospitalised with COVID-19 (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care alone or in combination with intravenous remdesivir (200 mg on day 1, then 100 mg once-daily for 9 days or until discharge). Treatment assignation was performed via web-based randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 832 participants were included for the evaluation of remdesivir (control, n=418; remdesivir, n=414). There was no difference in the clinical status neither at day 15 between treatment groups (OR for remdesivir, 0.98, 95% CI, 0.77 to 1.25, P=0.85) nor at day 29. The proportion of deaths at day 28 was not significantly different between control (8.9%) and remdesivir (8.2%) treatment groups (OR for remdesivir, 0.93 95%CI 0.57 to 1.52, P=0.77). There was also no difference on SARS-CoV-2 viral kinetics (effect of remdesivir on viral load slope, -0.004 log10 cp/10,000 cells/day, 95% CI, -0.03 to 0.02, P=0.75). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups.Interpretation: The use of remdesivir for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15 or day 29, nor with a reduction in mortality, nor with a reduction in SARS-CoV-2 RNA.Trial Registration: DisCoVeRy, NCT04315948; EudraCT2020-000936-23Funding: European Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE)Declaration of Interests: Dr. Costagliola reports grants and personal fees from Janssen, personal fees from Gilead, outside the submitted work. Dr. Mentré reports grants from INSERM Reacting (French Government), grants from Ministry of Health (French Government), grants from European Commission, during the conduct of the study; grants from Sanofi, grants from Roche, outside the submitted work. Dr. Hites reports grants from The Belgian Center for Knowledge (KCE), grants from Fonds Erasme-COVID-ULB, during the conduct of the study; personal fees from Gilead, outside the submitted work. Dr. Mootien reports non-financial support from GILEAD, outside the submitted work. Dr. Gaborit reports non-financial support from Gilead, non- financial support from MSD, outside the submitted work. Dr. Botelho-Nevers reports other from Pfizer, other from Janssen, outside the submitted work. Dr. Lacombe reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Dr. Wallet reports personal fees and non-financial support from Jazz pharmaceuticals, personal fees and non-financial support from Novartis, personal fees and nonPage financial support from Kite-Gilead, outside the submitted work. Dr. Kimmoun reports personal fees from Aguettan, personal fees from Aspen, outside the submitted work. Dr. Thiery reports personal fees from AMGEN, outside the submitted work. Dr. Burdet reports personal fees from Da Volterra, personal fees from Mylan Pharmaceuticals, outside the submitted work. Dr. Poissy reports personal fees from Gilead for lectures, outside the submitted work. Dr. Goehringer reports personal fees from Gilead Sciences, non-financial support from Gilead Sciences, grants from Biomerieux, non-financial support from Pfizer, outside the submitted work. Dr. Peytavin reports personal fees from Gilead Sciences, personal fees from Merck France, personal fees from ViiV Healthcare, personal fees from TheraTechnologies, outside the submitted work. Dr. Danion reports personal fees from Gilead, outside the submitted work. Dr. Raffi reports personal fees from Gilead, personal fees from Janssen, personal fees from MSD, personal fees from Abbvie, personal fees from ViiV Healthcare, personal fees from Theratechnologies, personal fees from Pfizer, outside the submitted work. Dr. Gallien reports personal fees from Gilead, personal fees from Pfizer, personal fees from ViiV, personal fees from MSD, outside the submitted work; and has received consulting fee from Gilead in August 2020 to check the registration file of remdesivir for the French administration. Dr. Nseir reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomérieux, personal fees from BioRad, outside the submitted work. Dr. Lefèvre reports personal fees from Mylan, personal fees from Gilead, outside the submitted work. Dr. Guedj reports personal fees from Roche, outside the submitted work. Other authors have nothing to disclose.Ethics Approval Statement: The trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744), and is sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France); it was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all included participants (or their legal representatives if unable to consent). The present analysis is based on the protocol v11.0 of December 12th, 2020.

The Emergence of COVID-19 Associated Mucormycosis: Analysis of Cases From 18 Countries (preprint)

Coronavirus disease 2019 (COVID-19)–associated mucormycosis (CAM) has recently been increasingly reported, particularly among patients with uncontrolled diabetes. Patients with diabetes and hyperglycemia often display an inflammatory state that may be potentiated by the activation of antiviral immunity to SARS-CoV-2, and thus may favor secondary infections. We analyze 80 published and unpublished cases of CAM, with a predominance (42/80) of cases from India. Uncontrolled diabetes mellitus as well as systemic corticosteroid treatment represented major comorbid predisposing factors and rhino-orbital cerebral mucormycosis was the most frequent presentation of disease. Mortality was high at 49%, driven particularly by those with pulmonary or disseminated mucormycosis and those with cerebral involvement. Furthermore, a significant proportion of surviving patients suffered life-changing morbidities (loss of vision in 46% of survivors). Our review indicates that CAM may be a relevant complication of severe COVID-19, particularly in those with uncontrolled diabetes. Funding: Martin Hoenigl received funding from Astellas for two investigator initiated studies (ISR005824 and ISR005838), and was supported by the National Institutes of Health, Grant UL1TR001442. Agostinho Carvalho was supported by the Fundação para a Ciência e a Tecnologia (FCT) (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003.Declaration of Interest: MH received research funding from Gilead, Pfizer, Astellas, Scynexis and NIH. JPG received speaker and expert advice fees from Pfizer and Gilead. NK has received research grants or honoraria as a speaker or advisor from Astellas, Gilead, MSD, and Pfizer, outside the submitted work. KL received consultancy fees from SMB Laboratoires Brussels, MSD and Gilead, travel support from Pfizer, speaker fees from FUJIFILM WAKO, Pfizer and Gilead, a service fee from Thermo fisher Scientific. OAC is supported by the German Federal Ministry of Research and Education, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388 and has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra Therapeutics, Al-Jazeera Pharmaceuticals, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead, Grupo Biotoscana, Immunic, IQVIA, Janssen, Matinas, Medicines Company, MedPace, Melinta Therapeutics, Menarini, Merck/MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi. PLW performed diagnostic evaluations and received meeting sponsorship from Bruker, Dynamiker, and Launch Diagnostics; Speakers fees, expert advice fees and meeting sponsorship from Gilead; and speaker and expert advice fees 489 from F2G and speaker fees MSD and Pfizer. Is a founding member of the European Aspergillus PCR Initiative. ACh received funding support from educational grant of Pfizer, MSD Pharmaceutical Ltd, and Gilead. All other authors no conflicts.Ethical Approval: MISSING

The Role of Chest CT in Deciphering Interstitial Lung Involvement: Systemic Sclerosis Versus COVID-19 (preprint)

Background: In clinical practice, the striking similarities observed at computed tomography (CT) between the diseases make it difficult to distinguish a COVID-19 pneumonia from a progression of interstitial lung disease (ILD) secondary to Systemic sclerosis (SSc). The aim of the present study was to identify the main CT features that may help distinguishing SSc-ILD from COVID-19 pneumonia. Methods: This multicentric study included 22 international readers divided in the radiologist group (RAD) and non-radiologist group (nRAD). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study.Findings: Fibrosis inside focal ground glass opacities (GGO) in the upper lobes; fibrosis in the lower lobe GGO; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONS in the lower lobes (p <0.0001) and signs of fibrosis in GGO in the lower lobes (p <0.0001) remained independently associated with COVID-19 pneumonia or SSc-ILD, respectively. A predictive score weas created which resulted positively associated with the COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity).Interpretation: The CT differential diagnosis between COVID-19 pneumonia and SSc-ILD is possible through the combination our score and the radiologic expertise. If an overlap of both diseases is suspected, the presence of consolidation in the lower lobes may suggest a COVID-19 pneumonia while the presence of fibrosis inside GGO may indicate a SSc-ILD.Funding: No Funding were received for this study.Declaration of Interests: SC reports personal fees from NOVARTIS-SANOFI-LILLY-CELTHER-PFIZER-JANSSEN; MK reports grants and personal fees from Boehringer-Ingelheim, personal fees from Corbus, grants and personal fees from Chugai, grants and personal fees from Ono Pharmeceuticals, personal fees from Tanabe-Mitsubishi, personal fees from Astellas, personal fees from Gilead, personal fees from Mochida; ST reports personal fees from Boehringer Ingelheim, personal fees from Roche, outside the submitted work; GS reports personal fees from Boehringer Ingelheim; CB reports personal fees from Actelion, personal fees from Eli Lilly, grants from European Scleroderma Trial and Research (EUSTAR) group, grants from New Horizon Fellowship, grants from Foundation for Research in Rheumatology (FOREUM), grants from Fondazione Italiana per la Ricerca sull'Artrite (FIRA); CV reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from F. Hoffmann-La Roche Ltd.; FL reports lectures fee from Roche and from Boehringer- Ingelheim; CPD reports grants and personal fees from GSK, personal fees from Boerhinger Ingelheim, grants from Servier, grants and personal fees from Inventiva, grants and personal fees from Arxx Therapeutics, personal fees from Corbus, personal fees from Sanofi, personal fees from Roche; FL reports grants and personal fees from GSK, personal fees from Boehringer Ingelheim, personal fees from Orion Pharma, personal fees from AstraZeneca, grants from MSD, personal fees from HIKMA, personal fees from Trudell International, grants and personal fees from Chiesi Farmaceutici, personal fees from Novartis Pharma; MH reports personal fees from Speaking fees from Actelion, Eli lilly and Pfizer; D K reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from Boehringer Ingelhem, personal fees from CSL Behring, grants and personal fees from Horizon, grants from Pfizer, personal fees from Corbus, grants and personal fees from BMS, outside the submitted work; and Dr Khanna is the Chief Medical officer of Eicos Sciences Inc and has stock options. All the mentioned authors declared previous feed outside the submitted work. All other authors declare no competing interests.Ethics Approval Statement: This retrospective, observational, multicentric, international study was approved by the Institutional Ethics Committee of Florence Careggi hospital (protocol number 17104_oss).

Comparative Evaluation of Rapid Salivary RT-LAMP Assay for Screening of SARS-CoV-2 Infection (preprint)

Background: Response to the COVID-19 outbreak calls for rapid and accurate diagnostic tests to control the pandemic outbreak. We aimed to evaluate saliva specimen as well as rapid RT-LAMP test for diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Methods: This monocentric study screened outpatients that were either symptomatic or contact-cases of a COVID-19 confirmed case.Nasopharyngeal-swabs (NPS) and saliva were collected simultaneously and tested by RT-qPCR. Saliva samples were also analyzed using an extraction-free rapid RT-LAMP test (EasyCOV®). Infected participants were those with a positive (Ct value <35) NP and/or salivary RT-qPCR (Composite Reference Test, CRTest).Findings: Between the 1st September and the 7th of October 2020, samples of 443 adults were collected and analyzed. The mean age was 32·2 years, 59·4% declared mild symptoms at the time of sampling and 40·6% were asymptomatic. Positivity rate of NP and/or salivary RT-qPCR was 16·0% (71/443) and the concordance between these two methods was 87·3%. Sensitivity and specificity of RT-LAMP compared to CRTest were 85·9% (95% CI 77·8%-94·0%) and 99·5% (98·7%-100%), respectively. RT-LAMP accuracy was 91·0% and 98·2% compared to NP and salivary RT-qPCR, respectively. All 52 participants with a salivary RT-qPCR Ct value <31 were positive by RT-LAMP. Performances of RT-LAMP for symptomatic and asymptomatic participants were similar.Interpretation: We demonstrated that self-collected saliva and a rapid RT-LAMP-based field test are reliable alternatives for SARS-CoV-2 detection. Their use could complement, simplify and accelerate COVID-19 diagnostics.Clinical Trial Registration: NCT04337424Funding Statement: SkillCell, CNRS, Region OccitanieDeclaration of Interests: Dr. J Reynes reports personal fees from Gilead company, personal feesfrom ViiV Healthcare company, personal fees from MSD Company, personalfees from Pfizer Company, personal fees from TheratechnologiesCompany, outside the submitted work.Dr. F Molina reports grants from SkillCell ; personal fees fromSkillCell, outside the submitted work. In addition, Dr. Molina has apatent Patent # EP20166524 pending.Dr. J Espeut, Dr. J Baptiste and Dr. F Santos Schneider reportspersonal fees from SkillCell, outside the submitted workThe other authors declared no competing interest.Ethics Approval Statement: The study was approved by a French ethic committee (CPP-lle de France XI) on April 03, 2020 and a substantial modification was approved on May 11, 2020.

Analyzing Host-Viral Interactome of SARS-CoV-2 for Identifying Vulnerable Host Proteins during COVID-19 Pathogenesis (preprint)

The development of therapeutic targets for COVID-19 treatment is based on the understanding of the molecular mechanism of pathogenesis. The identification of genes and proteins involved in the infection mechanism is the key to shed out light into the complex molecular mechanisms. The combined effort of many laboratories distributed throughout the world has produced the accumulation of both protein and genetic interactions. In this work we integrate these available results and we obtain an host protein-protein interaction network composed by 1432 human proteins. We calculate network centrality measures to identify key proteins. Then we perform functional enrichment of central proteins. We observed that the identified proteins are mostly associated with several crucial pathways, including cellular process, signalling transduction, neurodegenerative disease. Finally, we focused on proteins involved in causing disease in the human respiratory tract. We conclude that COVID19 is a complex disease, and we highlighted many potential therapeutic targets including RBX1, HSPA5, ITCH, RAB7A, RAB5A, RAB8A, PSMC5, CAPZB, CANX, IGF2R, HSPA1A, which are central and also associated with multiple diseases

Severe COVID-19 in People with Type 1 and Type 2 Diabetes in Sweden: A Nationwide Retrospective Case-Control Study (preprint)

Introduction: Whether infection with SARS-CoV-2 leads to excess risk of requiring hospitalization or intensive care in persons with diabetes has not been reported, nor have risk factors in diabetes associated with increased risk for these outcomes.Methods: We included 44,639 and 411,976 adult patients with type 1 and type 2 diabetes alive on Jan 1, 2020, and compared them to controls matched for age, sex, and county of residence (n=204,919 and 1,948,900). Standardized rates of hospitalizations, admissions to intensive care and death were estimated and hazard ratios were calculated using Cox regression analyses.Findings: There were 10,486 hospitalizations and 1,416 admissions into intensive care. A total of 1,175 patients with diabetes and 1,820 matched controls died from COVID-19, of these 53·2% had been hospitalized and 10·7% had been in intensive care. Patients with type 2 diabetes, compared to controls, displayed a hazard ratio (HR) of 2·22, 95%CI 2·13-2·32) of being hospitalized, which decreased to HR 1·40, 95%CI 1·34-1·47) after adjustment for sociodemographic factors, pharmacological treatment and comorbidities, had higher risk for admission to intensive care (HR 2·49, 95%CI 2·22-2·79, decreasing to 1·42, 95%CI 1·25-1·62 after adjustment, and increased risk for death (HR 2·19, 95%CI 2·03-2·36, adjusted 1·50, 95%CI 1·39-1·63). HR for hospitalization for type 1 diabetes was 2·10, 95%CI 1·72-2·57), decreasing to 1·25, 95%CI 0·3097-1·62) after adjustment· Patients with diabetes type 1 were twice as likely to require intensive care for COVID-19, however, not after adjustment (HR 1·49, 95%CI 0·75-2·92), and more likely to die (HR 2·90, 95% CI 1·6554-5·47), but not independently of other factors (HR 1·38, 95% CI 0·64-2·99). Among people with diabetes, elevated glycated hemoglobin levels were associated with higher risk for most outcomes.Interpretation: In this nationwide study, type 2 diabetes was independently associated with increased risk of hospitalization, admission to intensive care and death for COVID-19, whereas type 1 diabetes was not independently associated with excess risk for any outcome.Funding Statement: This work was supported by grants from: the Swedish state under an agreement concerning research and education of doctors [ALFGBG-717211]; the Swedish Heart and Lung Foundation [2018- 0366]; the Swedish Research Council [2013-05187, VRREG 2019-00193, 2020-05792]Declaration of Interests: Professor Eliasson reports personal fees (expert panels, lectures) from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Mundipharma, Navamedic, NovoNordisk, RLS Global, grants and personal fees from Sanofi, all outside the submitted work. NN declare that they have no conflict of interest. MG reports personal fees (scientific advisory boards, lectures) from Gilead Sciences, GSK/ViiV, MSD, Biogen, Amgen, Novocure, Novo Nordic and research grants from Gilead Sciences, all outside the submitted work. All other authors have nothing to disclose. Ethics Approval Statement: The Swedish Ethical Review Authority approved the study.

Persistence of Sera Neutralizing Activity Six Month after Hospitalization for COVID-19 (preprint)

Background: SARS-CoV-2 induces a humoral response with seroconversion occurring within the first weeks after COVID-19 disease. Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution overtime after COVID-19 is however unknown.Methods: In this monocentric prospective study, sera of 107 patients hospitalized with COVID-19 were collected at 3 months and 6 months post-infection. We performed quantitative neutralization experiments on top of high-throughput serological assays evaluating anti-Spike (S) and anti-Nucleocapsid (NP) IgG.Findings: Levels of sero-neutralization decreased significantly over study time, as well as IgG rates. After 6 months, 2.8% of the patients had a negative serological status for both anti-S and anti-NP IgG. However, all sera had a persistent and effective neutralizing effect on SARS-CoV-2 neutralizing assays. IgG levels correlated with sero-neutralization and this correlation was stronger for anti-S than for anti-NP antibodies. The level of sero-neutralization quantified at 6 months correlated with markers of initial severity, notably admission in intensive care units and the need for mechanical invasive ventilation.Interpretation: Decrease of IgG rates and serological assays becoming negative did not imply loss of neutralizing capacity in our patients. Those results are encouraging and in favor of sustained humoral response for at least 6 months in patients previously hospitalized for COVID-19, which will have to be considered in global deployment of vaccination strategy.Trial Registration: The French Covid cohort (NCT04262921)Funding Statement: The French COVID cohort is funding by the REACTing (REsearch & ACtion emergING infectious diseases) consortium and by a grant of the French Ministry of Health (PHRC n°20-0424).Outside the submitted work, JSH is supported by AP-HP, INSERM, the French National Research Agency (NADHeart ANR-17-CE17-0015-02, PACIFIC ANR-18-CE14-0032-01, CORRECT_LMNA ANR-19-CE17-0013-02), the ERA-Net-CVD (ANR-16-ECVD-0011-03, Clarify project), Fédération Française de Cardiologie, the Fondation pour la Recherche Médicale, and by a grant from the Leducq Foundation (18CVD05), and is coordinating a French PIA Project (2018-PSPC-07, PACIFIC-preserved, BPIFrance) and a University Research Federation against heart failure (FHU2019, PREVENT_Heart Failure). JG reports personal fees from ViiV Healthcare, Gilead Science, Janssen Cilag, and research grants from Gilead Sciences, MSD and ViiV Healthcare, outside the submitted work.Declaration of Interests: Authors have nothing to disclose. There are no relationships with industry.Ethics Approval Statement: The French Covid cohort (NCT04262921) is a prospective multi-center observational cohort sponsored by Inserm which was authorized by the French Ethics Committee CPP Ile-de-France VI (ID RCB:2020-A00256-33).

Senior-COVID-Rea Multicentre Observational Cohort Study: Development of a Geriatric Prediction Model of Day 30 Mortality in Patients Over 60 in ICU (preprint)

Background: Current SARS-COV2 pandemic induces tensions on the health systems and ethical dilemmas. A triage tool is needed to define older patients with individual advantage to be considered for intensive care unit (ICU) transfer.Methods: This multicentre observational cohort study included patients over 60 admitted into 7 ICUs between 7th March and 7th May 2020. The primary objective was to evaluate age impact on 30-day mortality, to construct a multivariate prognostic model. This analysis explores the prediction value of geriatric parameters 1 month before ICU admission. This trial is registered with ClinicalTrials.gov, number NCT04422340.Findings: Among 290 screened patients, 231 were included in the cohort. In univariate analysis, factors associated with decreased day-30 survival were: age>75 (OR 4·82 [95%CI: 2·56-9·06]), three or more CIRS-G grade ≥2 comorbidities (OR 2·49 [95%CI: 1·36-4·56]), impaired ADL (Activities of Daily Living), (OR 4·86 [95%CI: 2·44-9·72]), impaired IADL8 (Instrumental ADL, 8 variables, OR 6·33 [95%CI: 3·31-12·10], p<0·001), frailty according Fried score (OR 4·33 [95%CI: 2·03-9·24] or the Clinical Frailty Score≥5 (OR 3·79 [95%CI: 1·76-8·15), six months fall history (OR 3·46 [95%CI: 1·58-7·63]). The final multivariate model included age>75 (OR 4·64 [95%CI: 2·36-9·39], p<0.001) and impaired IADL8 (OR 5·69 [95%CI: 2·90-11·47], p<0.001)). Considered as continuous variables, the model led to an AUC of 0.78 [95% CI: 0.72, 0.85].Interpretation: Age and IADL8 provide independent prognostic factors for day-30 mortality in patients over 60 admitted in ICU for severe COVID-19 infection. Our triage model proposes 3 classes of day-30 mortality risks: 8-14% for patients younger than 80 with no impairment in IADL, 30-40% for patients either younger than 70 with at least one impairment in IADL8 or older than 80 with no impairment in IADL and 67-88% for patients over 80 with at least one impairment in IADL.Trial Registration: ClinicalTrials platform on June 9, 2020 (NCT04422340).Funding Statement: Hospices Civils de LyonDeclaration of Interests: All the authors declare grants from Hospices Civils de Lyon, during the conduct of the study, no other competing interests with the considered topic. CF reports outside of the present work consulting/advisory roles for GSK, Leo Pharma, Pfizer, MSD Oncology, Teva, AstraZeneca, Baxter, Eisai, Janssen, and Novartis; research funding from Chugai Pharma, Pfizer, Pierre Fabre, and Astellas Pharma; and travel/accommodation/expenses from Janssen Oncology, Pierre Fabre, and Leo Pharma.Ethics Approval Statement: The study protocol (V1.0 of April 7, 2020) was approved by a COVID-19-dedicated Ethics Committee of the Hospices Civils de Lyon on May 12, 2020.