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    Hydroxychloroquine for prevention of COVID-19 mortality: a population-based cohort study

    Authors: Christopher T Rentsch; Nicholas J DeVito; Brian MacKenna; Caroline E Morton; Krishnan Bhaskaran; Jeremy P Brown; Anna Schultze; William J Hulme; Richard Croker; Alex J Walker; Elizabeth J Williamson; Chris Bates; Seb Bacon; Amir Mehrkar; Helen J Curtis; David Evans; Kevin Wing; Peter Inglesby; Rohini Mathur; Henry Drysdale; Angel YS Wong; Helen I McDonald; Jonathan Cockburn; Harriet Forbes; John Parry; Frank Hester; Sam Harper; Liam Smeeth; Ian J Douglas; William G Dixon; Stephen JW Evans; Laurie Tomlinson; Ben Goldacre; Sacha Gnjatic; Noam Harpaz; Silvio Danese; Adeeb Rahman; Nikhil A Kumta; Alessio Aghemo; Francesca Petralia; Harm van Bakel; Adolfo Garcia-Sastre; Saurabh Mehandru

    doi:10.1101/2020.09.04.20187781 Date: 2020-09-09 Source: medRxiv

    Background. Hydroxychloroquine has been shown to inhibit severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) in vitro, but early clinical studies found no benefit treating patients with coronavirus disease MESHD 2019 (COVID-19). We set out to evaluate the effectiveness of hydroxychloroquine for prevention, as opposed to treatment, of COVID-19 mortality. Methods. We pre-specified and conducted an observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, representing 40% of the general population in England. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use prior to the COVID-19 outbreak in England and risk of COVID-19 mortality among people with rheumatoid arthritis HP rheumatoid arthritis MESHD ( RA MESHD) or systemic lupus erythematosus HP systemic lupus erythematosus MESHD ( SLE MESHD). Model adjustment was informed by a directed acyclic graph. Findings. Of 194,637 patients with RA MESHD or SLE MESHD, 30,569 (15.7%) received [≥]2 prescriptions of hydroxychloroquine in the six months prior to 1 March 2020. Between 1 March 2020 and 13 July 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0.23% (95% CI 0.18-0.29) among users and 0.22% (95% CI 0.20-0.25) among non-users; an absolute difference of 0.008% (95% CI -0.051-0.066). After accounting for age TRANS, sex, ethnicity, use of other immunuosuppressives, and geographic region, no association with COVID-19 mortality was observed (HR 1.03, 95% CI 0.80-1.33). We found no evidence of interactions with age TRANS or other immunosuppressives. Quantitative bias analyses indicated observed associations were robust to missing information regarding additional biologic treatments for rheumatological disease MESHD. We observed similar associations with the negative control outcome of non-COVID-19 mortality. Interpretation. We found no evidence of a difference in COVID-19 mortality among patients who received hydroxychloroquine for treatment of rheumatological disease MESHD prior to the COVID-19 outbreak in England.

    Severe COVID-19 is associated with elevated serum SERO IgA and antiphospholipid IgA- antibodies SERO

    Authors: Omar Hasan Ali; David Bomze; Lorenz Risch; Silvio D Brugger; Matthias Paprotny; Myriam Weber; Sarah Thiel; Lukas Kern; Werner C Albrich; Philipp Kohler; Christian R Kahlert; Pietro Vernazza; Philipp K Buehler; Reto A Schuepbach; Alejandro Gomez-Mejia; Alexandra M Popa; Andreas Bergthaler; Josef M Penninger; Lukas Flatz

    doi:10.1101/2020.07.21.20159244 Date: 2020-07-24 Source: medRxiv

    Background: While the pathogenesis of coronavirus disease MESHD 2019 (COVID-19) is becoming increasingly clear, there is little data on IgA response, the first line of bronchial immune defense. Objective: To determine, whether COVID-19 is associated with a vigorous total IgA response and whether IgA autoantibodies are associated with complications of severe illness. Since thrombotic MESHD events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome MESHD ( APS MESHD), our approach focused on antiphospholipid antibodies SERO (aPL). Materials and methods: In this retrospective cohort study we compared clinical data and aPL from 64 patients with COVID-19 from three independent centers (two in Switzerland, one in Liechtenstein). Samples were collected from April 9, 2020 to May 1, 2020. Total IgA and aPL were measured with FDA-approved commercially available clinical diagnostic kits. Results: Clinical records of the 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID, n=26 [41%]), a discovery cohort with severe illness (sdCOVD, n=14 [22%]) and a confirmation cohort with severe illness (scCOVID, n=24 [38%]). Severe illness MESHD was significantly associated with increased total IgA (sdCOVID, P=0.01; scCOVID, P<0.001). Total IgG levels were similar in both cohorts. Among aPL, both cohorts with severe illness significantly correlated with elevated anti-Cardiolipin IgA (sdCOVID and scCOVID, P<0.001), anti-Cardiolipin IgM (sdCOVID, P=0.003; scCOVID, P<0.001), and anti-Beta2 Glycoprotein-1 IgA (sdCOVID and scCOVID, P<0.001). Systemic lupus erythematosus HP Systemic lupus erythematosus MESHD was excluded from all patients as a potential confounder of APS MESHD. Conclusions: Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response triggered in the bronchial mucosa induces systemic autoimmunity MESHD autoimmunity HP.

    Clot Waveform of APTT Has Abnormal Patterns in Subjects with COVID-19

    Authors: Takuya Shimura; Makoto Kurano; Yoshiaki Kanno; Mahoko Ikeda; Koh Okamoto; Daisuke Jubishi; Sohei Harada; Shu Okugawa; Kyoji Moriya; Yutaka Yatomi

    doi:10.21203/rs.3.rs-43405/v1 Date: 2020-07-15 Source: ResearchSquare

    In Coronavirus disease MESHD 2019 (COVID-19) subjects, recent evidence suggests the presence of unique coagulation abnormalities HP coagulation abnormalities MESHD. In this study, we performed clot waveform analyses to investigate whether specific modulations are observed in COVID-19 subjects. We analyzed the second derivative of the absorbance in routine APTT tests performed using an ACL-TOP system. We observed high frequencies of abnormal patterns in APTT second-derivative curves that could be classified into an early shoulder type, a late shoulder type, or a biphasic type, high maximum first-derivative and second-derivative peak levels, and a low minimum second-derivative peak level in COVID-19 subjects. These modulations were not observed in subjects with disseminated intravascular coagulation HP intravascular coagulation MESHD. These abnormal patterns are also observed in patients with lupus anticoagulant HP lupus anticoagulant MESHD, hemophilia MESHD, or factor IX deficiency MESHD. The plasma SERO fibrinogen levels might also be involved in the abnormal APTT waveforms, especially the high maximum first-derivative and second-derivative peak levels. The abnormal patterns in the APTT second-derivative curves appear with highest frequency at around 2 weeks after the onset of COVID-19 and were not associated with the severity of COVID-19. These results suggest the possible presence of a specific abnormal coagulopathy MESHD in COVID-19.

    Prevalence SERO, specificity, and clinical association of anti-phospholipid antibodies SERO in COVID-19 patients: are the antibodies SERO really guilty?

    Authors: Maria Orietta Borghi; Asmaa Beltagy; Emirena Garrafa; Daniele Curreli; Germana Cecchini; Caterina Bodio; Claudia Grossi; Simonetta Blengino; Angela Tincani; Franco Franceschini; Laura Andreoli; Maria Grazia Lazzaroni; Silvia Piantoni; Stefania Masneri; Francesca Crisafulli; Dulio Brugnoni; Maria Lorenza Muiesan; Massimo Salvetti; Gianfranco Parati; Erminio Torresani; Michael Mahler; Francesca Heilbron; Francesca Pregnolato; Martino Pengo; Francesco Tedesco; Nicola Pozzi; Pier Luigi Meroni

    doi:10.1101/2020.06.17.20134114 Date: 2020-06-19 Source: medRxiv

    Background. Critically ill MESHD patients with coronavirus disease MESHD 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy MESHD which leads to organ failure MESHD and death MESHD. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies SERO (aPL) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant HP lupus anticoagulant MESHD) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-{beta}2GPI) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies SERO was not investigated systematically. Epitope specificity of anti-{beta}2GPI antibodies SERO was not reported. Objective. To evaluate the prevalence SERO and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-{beta}2GPI antibodies SERO. Methods. ELISA SERO and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic MESHD events. Results. Anti-{beta}2GPI IgG/IgA/IgM were the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM were detected in 5.7/6.6% by ELISA SERO. Comparable values were found by chemiluminescence. aPS MESHD/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA SERO. No association between thrombosis MESHD and aPL was found. Reactivity against domain 1 and 4-5 of {beta}2GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-{beta}2GPI nor with thrombosis MESHD. Conclusions. aPL show a low prevalence SERO in COVID-19 patients and are not associated with major thrombotic MESHD events. aPL in COVID-19 patients are mainly directed against {beta}2GPI but display an epitope specificity different from antibodies SERO in antiphospholipid syndrome.

    Cell entry of SARS-CoV-2 conferred by angiotensin-converting enzyme 2 (ACE2) of different species

    Authors: Yan-Dong Tang; Yuming Li; Jing Sun; Hongliang Zhang; Tong-yun Wang; Ming-Xia Sun; Yue-Lin Yang; Xiaoliang Hu; Jincun Zhao; Xuehui Cai

    doi:10.1101/2020.06.15.153916 Date: 2020-06-16 Source: bioRxiv

    The outbreak of the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) poses a huge threat to many countries around the world. However, where is it origin and which animals are sensitive to cross-species transmission TRANS is unclear. The interaction of virus and cell receptor is a key determinant of host range for the novel coronavirus. Angiotensin-converting enzyme 2 (ACE2) is demonstrated as the primary entry receptor for SARS-CoV-2. In this study, we evaluated the SARS-CoV-2 entry mediated by ACE2 of 11 different species of animals, and discovered that ACE2 of Rhinolophus sinicus (Chinese horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris MESHD (dog), Sus scrofa (pig), Capra hircus (goat) and especially Manis javanica (Malayan pangolin) were able to render SARS-CoV-2 entry in non-susceptible cells. This is the first report that ACE2 of Pangolin could mediate SARS-CoV-2 entry which increases the presume that SARS-CoV-2 may have a pangolin origin. However, none of the ACE2 proteins from Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (chicken), Notechis scutatus (mainland tiger snake), Mus musculus (house mouse) rendered SARS-CoV-2 entry. Specifically, a natural isoform of Macaca mulatta (Rhesus monkey) ACE2 with a mutation of Y217N was resistance to infection, which rises the possible impact of this type of ACE2 during monkey studies of SARS-CoV-2. Overall, these results clarify that SARS-CoV-2 could engage receptors of multiple species of animals and it is a perplexed work to track SARS-CoV-2 origin and its intermediate hosts. IMPORTANCEIn this study, we illustrated that SARS-CoV-2 is able to engage receptors of multiple species of animals. This indicated that it may be a perplexed work to track SARS-CoV-2 origin and discover its intermediate hosts. This feature of virus is considered to potentiate its diverse cross-species transmissibility TRANS. Of note, here is the first report that ACE2 of Pangolin could mediate SARS-CoV-2 entry which increases the possibility that SARS-CoV-2 may have a pangolin origin. And we also demonstrated that not all species of bat were sensitive to SARS-CoV-2 infection. At last, it is also important to detect the expression ratio of the Y217N ACE2 to the prototype in Rhesus monkeys to be recruited for studies on SARS-CoV-2 infection.

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