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    Blood SERO Type Distribution in Autoimmune Diseases MESHD: An Anonymous, Large-Scale, Self-Report Pilot Study

    Authors: Edward S Harris; Harlan D Harris; Miroslav Malkovsky

    doi:10.21203/rs.3.rs-75388/v1 Date: 2020-09-10 Source: ResearchSquare

    Background: Recent research has verified that blood SERO group or Rh factor can influence susceptibility to various cardiovascular, neoplastic and infectious diseases MESHD including COVID-19. While a number of studies have looked at correlations between blood SERO group and various rheumatological diseases MESHD, findings have been inconsistent, often because many of these studies suffered from small sample size issues. In order to better understand the potential relationships between blood SERO group/Rh factor and rheumatological diseases MESHD, we performed a large-scale self-report pilot study of blood SERO type distributions in five autoimmune diseases MESHD.Methods: Five autoimmune diseases MESHD were included in the study: systemic sclerosis MESHD, systemic lupus erythematosus HP systemic lupus erythematosus MESHD, rheumatoid arthritis HP rheumatoid arthritis MESHD, psoriasis MESHD, and ankylosing spondylitis MESHD. We also included a control group in which participants did not have any autoimmune diseases MESHD.  The participants were recruited through social media and organizations such as the Lupus Foundation and the National Psoriasis Foundation. Respondents who met the inclusion criteria were asked only two questions by anonymous survey: blood SERO type and country of birth.Results: Each autoimmune disorder MESHD group included between 570 and 951 US participants. While there was little difference in blood SERO type distribution patterns among the five diseases, unexpectedly, all five disease groups showed a consistent pattern where Rh negative was almost twice as high as US population norms. A post-hoc non-autoimmune control group was added in order to determine if this anomalous finding was an artifact of the study design. The control group displayed a similar unexpected increase in the Rh-negative blood SERO type prevalence SERO, suggesting that the very high Rh-negative frequency among the tested disease groups was likely to be an artifact of the study design. Conclusions: Overall, our preliminary study results show no meaningful differences between the disease groups and the post-hoc control group, suggesting that neither ABO type nor Rh factor affects susceptibility to the development of any of the five studied autoimmune diseases MESHD. Nevertheless, the unexpected observed difference in Rh factor distribution between the studied groups/control group and the corresponding US population norms has important implications for any research study using self-selected subjects.  Our results suggest that such studies may be subject to unanticipated biases, requiring meticulous controls to confirm impartiality and exclude any artifacts of the study design.

    Lack of protective effect of chloroquine derivatives on COVID-19 disease in a Spanish sample of chronically treated patients

    Authors: Marina Laplana; Oriol Yuguero; Joan Fibla; Ross D Booton; Gibran Hemani; Emily Nixon; Caroline Relton; Leon Danon; Matthew Hickman; Ellen Brooks Pollock; Jan Lukas Robertus; Maria Gabrani; Michal Rosen-Zvi

    doi:10.1101/2020.09.03.20158121 Date: 2020-09-09 Source: medRxiv

    Background: The search for a SARS-CoV-2 treatment has emerged as a worldwide priority. We evaluated the role of chloroquine and its derivatives in COVID-19 in Spanish individuals. Methods: We performed a survey addressed to patients regularly taking chloroquine and its derivatives for the control of their autoimmune diseases MESHD. The survey was distributed with special attention to Spanish patient associations centred on autoimmune diseases MESHD and rheumatology and to the general population. A sample of untreated subjects was matched to the treated group according to sex, age TRANS range and incidence region. COVID-19 disease prevalence SERO was compared between treated and untreated-matched control sample. Results: A total of 319 surveys of patients regularly taking chloroquine and its derivatives were recovered for further analysis. The prevalence SERO of declared COVID-19 status in the treated group was 5.3% and the mean prevalence SERO among the untreated-matched groups was 3.4%. A community exposition to COVID-19 was associated with a greater prevalence SERO of COVID-19 in both, treated (17.0% vs. 3.2%; p-value<0.001) and untreated groups (13.4% vs. 1.1%; p-value=0.027). Conclusion: We did not find differences of reported COVID-19 cases between treated and untreated groups, indicating a lack of protection by regular administration of chloroquine and its derivative drugs on COVID-19 infection MESHD. Of relevance, data indicates that patients that regularly take chloroquine derivatives are exposed to SARS-CoV-2 infection MESHD and must take the same protection measures as the general population.

    HYDROXICLOROQUINE FOR PRE-EXPOSURE PROPHYLAXIS FOR SARS-CoV-2 MESHD

    Authors: Jaime Lopez de la Iglesia; Naiara Cubelos; Roi Naveiro Flores; Marina Montoro Gomez; Francisco Javier Gonzalez de Haro; Maria Ajenjo Gonzalez; Estefania Tobal Vicente; Maria Lamuedra Gil de Gomez; Maria Teresa Nuevo Guisado; Isabel Torio Gomez; Ana Penalver Andrada; Nuria Martinez Cao; Paula Gonzalez Figaredo; Carlos Robles Garcia; Lidia Anastasia Alvarado Machon; Angeles Lafont Alcalde; Jose Cesareo Naveiro Rilo; Nick H.T. ten Hacken; Sile Hu; Yike Guo; Xiaoyu Zhang; Kai Sun; Pieter S. Hiemstra; Bruce A. Ponder; Mika J Makela; Kristiina Malmstrom; Robert C. Rintoul; Paul A. Reyfman; Fabian J. Theis; Corry-A Brandsma; Ian Adcock; Wim Timens; Cheng J. Xu; Maarten van den Berge; Roland F. Schwarz; Gerard H. Koppelman; Martijn C. Nawijn; Alen Faiz

    doi:10.1101/2020.08.31.20185314 Date: 2020-09-02 Source: medRxiv

    SARS-CoV-2 infection has a high transmission TRANS level. At the present time there is not a specific treatment approved but it is known that, in vitro, chloroquine and hydroxychloroquine can inhibit the coronavirus. Objective: verifying if patients with autoimmune diseases MESHD that are on treatment with HCQ have less incidence and severity on COVID-19. Material and methods: this is a retrospective cohort study. The exposed cohort was formed by individuals with autoimmune diseases MESHD with HCQ treatment. The control cohort was randomly selected using the Health Card database. To deal with confounding variables and evaluate the effect of HCQ on the incidence and severity of SARS-CoV-2 infection MESHD, propensity score matching was used. Risk difference and paired percentage difference between exposed and non-exposed groups was estimated. Results: 919 individuals formed the exposed cohort and 1351 the control cohort. After matching, there were 690 patients on each group. During the time of the study, in the exposed group there were 42 (6.1%) individuals with suspected COVID-19, 12(1.7%) with confirmed COVID-19 and 3(0.4%) were hospitalized. In the control group there were 30(4.3%) individuals with suspected COVID-19, 13(1.9%) with confirmed COVID-19 and 2(0.3%) were hospitalized. The risk difference between each cohort was: 0.017(-0.05-0.04) for suspected COVID-19; -0.014(-0.015-0.012) for confirmed COVID-19 and 0.001(-0.007-0.007) for hospitalized patients. There were not significant differences. Conclusion: there is no difference neither on the incidence nor on the severity of COVID-19 between patients with autoimmune diseases MESHD with HCQ treatment and patients that do not take HCQ.

    Association between autoimmune diseases MESHD and COVID-19 as assessed in both a test-negative case-control and population case-control design

    Authors: Rossella Murtas; Anita Andreano; Federico Gervasi; Davide Guido; David Consolazio; Sara Tunesi; Laura Andreoni; Maria Teresa Greco; Maria Elena Gattoni; Monica Sandrini; Antonio Riussi; Antonio Giampiero Russo

    doi:10.21203/rs.3.rs-58948/v1 Date: 2020-08-13 Source: ResearchSquare

    Background: COVID-19 epidemic has paralleled with the so called infodemic, where countless pieces of information have been disseminated on putative risk factors for COVID-19. Among those, emerged the notion that people suffering from autoimmune diseases MESHD ( AIDs MESHD) have a higher risk of SARS-CoV-2 infection MESHD. Methods: The cohort included all COVID-19 cases residents in the Agency for Health Protection (AHP) of Milan that, from the beginning of the outbreak, developed a web-based platform that traced TRANS positive and negative cases as well as related contacts. AIDs MESHD subjects were defined ad having one the following autoimmune disease MESHD: rheumatoid arthritis HP rheumatoid arthritis MESHD, systemic lupus erythematosus HP systemic lupus erythematosus MESHD, systemic sclerosis MESHD, Sjogren disease, ankylosing spondylitis MESHD, myasthenia gravis MESHD, Hashimoto's disease MESHD, acquired autoimmune hemolytic anemia HP autoimmune hemolytic anemia MESHD, and psoriatic arthritis MESHD arthritis HP. To investigate whether AID subjects are at increased risk of SARS-CoV-2 infection MESHD, and whether they have worse prognosis than AIDs MESHD-free subjects once infected, we performed a combined analysis of a test-negative design case-control study, a case-control with test-positive as cases, and one with test-negative as cases (CC-NEG). Results: During the outbreak, the Milan AHP endured, up to April 27th 2020, 20,364 test-positive and 34,697 test-negative subjects. We found no association between AIDs MESHD and being positive to COVID-19, but a statistically significant association between AIDs MESHD and being negative to COVID-19 in the CC-NEG. If, as likely, test-negative subjects underwent testing because of respiratory infection MESHD symptoms, these results imply that autoimmune diseases MESHD may be a risk factor for respiratory infections MESHD in general (including COVID-19), but they are not a specific risk factor for COVID-19. Furthermore, when infected by SARS-CoV-2, AIDs MESHD subjects did not have a worse prognosis compared to non- AIDs MESHD subjects. Results highlighted a potential unbalance in the testing campaign, which may be correlated to the characteristics of the tested person, leading specific frail population to be particularly tested.Conclusions: Lack of availability of sound scientific knowledge inevitably lead unreliable news to spread over the population, preventing people to disentangle them form reliable information. Even if additional studies are needed to replicate and strengthen our results, these findings represent initial evidence to derive recommendations based on actual data for subjects with autoimmune diseases MESHD.

    Common low complexity regions for SARS-CoV-2 and human proteomes as potential multidirectional risk factor in vaccine development

    Authors: Aleksandra Gruca; Joanna Ziemska-Legiecka; Patryk Jarnot; Elzbieta Sarnowska; Tomasz Sarnowski; Marcin Grynberg

    doi:10.1101/2020.08.11.245993 Date: 2020-08-11 Source: bioRxiv

    The rapid spread of the COVID-19 demands immediate response from the scientific communities. Appropriate countermeasures mean thoughtful and educated choice of viral targets (epitopes). There are several articles that discuss such choices in the SARS-CoV-2 proteome, other focus on phylogenetic traits and history of the Coronaviridae genome/proteome. However none consider viral protein low complexity regions (LCRs). Recently we created the first methods that are able to compare such fragments. We show that five low complexity regions (LCRs) in three proteins (nsp3, S and N) encoded by the SARS-CoV-2 genome are highly similar to regions from human proteome. As many as 21 predicted T-cell epitopes and 27 predicted B-cell epitopes overlap with the five SARS-CoV-2 LCRs similar to human proteins. Interestingly, replication proteins encoded in the central part of viral RNA are devoid of LCRs. Similarity of SARS-CoV-2 LCRs MESHD to human proteins may have implications on the ability of the virus to counteract immune defenses. The vaccine targeted LCRs may potentially be ineffective or alternatively lead to autoimmune diseases MESHD development. These findings are crucial to the process of selection of new epitopes for drugs or vaccines which should omit such regions. Author summaryThe outbreak of the COVID-19 disease affects humans all over the globe. More and more people get sick and many die because of the deadly SARS-CoV-2 virus. The whole machinery of this pathogen is enclosed in a short sequence of nucleotides, building blocks for both RNA and DNA strands. This RNA virus encodes less than 30 protein sequences that change the fate of our societies. Its proteins are composed of 20 amino acids (building bricks) that are usually used quite freely by proteins. However, there are fragments where only one or a few amino acids are used. We name those low complexity regions (LCRs). We invented the first programmes able to compare such LCRs. Using this new methodology we were able to show similarity of some viral proteins to human ones. This discovery has a serious implication when designing vaccines or drugs. It means that companies should not use these very LCRs as targets because it may trigger an autoimmune disease. On the other hand this specific similarity may suggest some kind of disguise of viral proteins into the machinery of human cells.

    Paradoxical Case Fatality Rate dichotomy of Covid-19 among rich and poor nations points to the hygiene hypothesis.

    Authors: Bithika Chatterjee; Rajeeva Laxman Karandikar; Shekhar C. Mande

    doi:10.1101/2020.07.31.20165696 Date: 2020-08-04 Source: medRxiv

    In the first six months of its deadly spread across the world, the Covid-19 incidence has exhibited interesting dichotomy between the rich and the poor countries. Surprisingly, the incidence and the Case Fatality Rate has been much higher in the richer countries compared with the poorer countries. However, the reasons behind this dichotomy have not been explained based on data or evidence, although some of the factors for the susceptibility of populations to SARS-CoV-2 infections MESHD have been proposed. We have taken into consideration all publicly available data and mined for the possible explanations in order to understand the reasons for this phenomenon. The data included many parameters including demography of nations, prevalence SERO of communicable and non-communicable diseases, sanitation parameters etc. Results of our analyses suggest that demography, improved sanitation and hygiene, and higher incidence of autoimmune disorders MESHD as the most plausible factors to explain higher death rates in the richer countries Thus, the much debated hygiene hypothesis appears to lend credence to the Case Fatality Rate dichotomy between the rich and the poor countries.

    Comparison of sixteen serological SARS-CoV-2 immunoassays SERO in sixteen clinical laboratories

    Authors: Lene Holm Harritshoej; Mikkel Gybel-Brask; Shoaib Afzal; Pia R. Kamstrup; Charlotte Svaerke Joergensen; Marianne K. Thomsen; Linda M. Hilsted; Lennart J. Friis-Hansen; Pal B. Szecsi; Lise Pedersen; Lene Nielsen; Cecilie B. Hansen; Peter Garred; Trine-Line Korsholm; Susan Mikkelsen; Kirstine O. Nielsen; Bjarne K. Moeller; Anne T. Hansen; Kasper K. Iversen; Pernille B. Nielsen; Rasmus B. Hasselbalch; Kamille Fogh; Jakob B. Norsk; Jonas H. Kristensen; Kristian Schoenning; Nikolai S. Kirkby; Alex C.Y. Nielsen; Lone H. Landsy; Mette Loftager; Dorte K. Holm; Anna C. Nilsson; Susanne G. Saekmose; Birgitte Grum-Svendsen; Bitten Aagaard; Thoeger G. Jensen; Dorte M. Nielsen; Henrik Ullum; Ram BC Dessau

    doi:10.1101/2020.07.30.20165373 Date: 2020-08-02 Source: medRxiv

    Serological SARS-CoV-2 assays are needed to support clinical diagnosis and epidemiological investigations. Recently, assays for the large-volume detection of total antibodies SERO (Ab) and immunoglobulin (Ig) G and M against SARS-CoV-2 antigens have been developed, but there are limited data on the diagnostic accuracy of these assays. This study was organized as a Danish national collaboration and included fifteen commercial and one in-house anti-SARS-CoV-2 assays in sixteen laboratories. Sensitivity SERO was evaluated using 150 serum samples SERO from individuals diagnosed with asymptomatic TRANS, mild or moderate nonhospitalized (n=129) or hospitalized (n=31) COVID-19, confirmed by nucleic acid amplification tests, collected 13-73 days from symptom onset TRANS. Specificity and cross-reactivity were evaluated in samples collected prior to the SARS-CoV-2 epidemic from > 586 blood SERO donors and patients with autoimmune diseases MESHD or CMV or EBV infections MESHD. Predefined specificity criteria of [≥]99% were met by all total-Ab and IgG assays except one (Diasorin/LiaisonXL-IgG 97.2%). The sensitivities SERO in descending order were: Wantai/ ELISA SERO total-Ab (96.7%), CUH/NOVO in-house ELISA SERO total-Ab (96.0%), Ortho/Vitros total-Ab (95.3%), YHLO/iFlash-IgG (94.0%), Ortho/Vitros-IgG (93.3%), Siemens/Atellica total-Ab (93.2%), Roche-Elecsys total-Ab (92.7%), Abbott-Architect-IgG (90.0%), Abbott/Alinity-IgG (median 88.0%), Diasorin/LiaisonXL-IgG MESHD (84.6%), Siemens/Vista total-Ab (81.0%), Euroimmun/ ELISA-IgG SERO (78.0%), and Snibe/Maglumi-IgG (median 78.0%). The IgM results were variable, but one assay (Wantai/ ELISA SERO-IgM) had both high sensitivity SERO (82.7%) and specificity (99%). The rate of seropositivity increased with time from symptom onset TRANS and symptom severity. In conclusion, predefined sensitivity SERO and specificity acceptance criteria of 90%/99%, respectively, for diagnostic use were met in five of six total-Ab and three of seven IgG assays.

    Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2

    Authors: Tianling Ou; Huihui Mou; Lizhou Zhang; Amrita Ojha; Hyeryun Choe; Michael Farzan

    doi:10.1101/2020.07.22.216150 Date: 2020-07-22 Source: bioRxiv

    Hydroxychloroquine, used to treat malaria MESHD and some autoimmune disorders MESHD, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 MESHD in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike MESHD (S) proteins, thereby activating membrane fusion for cell entry. The plasma SERO membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein is ablated. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection MESHD more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited in vivo utility of hydroxychloroquine as a treatment for COVID-19. Author SummaryThe novel pathogenic coronavirus SARS-CoV-2 causes COVID-19 and remains a threat to global public health. Chloroquine and hydroxychloroquine have been shown to prevent viral infection in cell-culture systems, but human clinical trials did not observe a significant improvement in COVID-19 patients treated with these compounds. Here we show that hydroxychloroquine interferes with only one of two somewhat redundant pathways by which the SARS-CoV-2 spike (S) protein is activated to mediate infection. The first pathway is dependent on the endosomal protease cathepsin L and sensitive to hydroxychloroquine, whereas the second pathway is dependent on TMPRSS2, which is unaffected by this compound. We further show that SARS-CoV-2 is more reliant than SARS coronavirus (SARS-CoV-1) on the TMPRSS2 pathway, and that this difference is due to a furin cleavage site present in the SARS-CoV-2 S protein. Finally, we show that combinations of hydroxychloroquine and a clinically tested TMPRSS2 inhibitor work together to effectively inhibit SARS-CoV-2 entry. Thus TMPRSS2 expression on physiologically relevant SARS-CoV-2 target cells may bypass the antiviral activities of hydroxychloroquine, and explain its lack of in vivo efficacy.

    Cutaneous manifestations associated with COVID-19 in children TRANS: A Systematic Review

    Authors: Seema Shah; Kiran Akhade; Satyaki Ganguly; Rachita Nanda; Eli Mohapatra; Anil Kumar Goel

    doi:10.21203/rs.3.rs-45314/v1 Date: 2020-07-18 Source: ResearchSquare

    Background: Cutaneous manifestation of COVID 19 in children TRANS has not yet been reviewed systematically and hence this review gives a future direction to the clinicians to be vigilant for skin presentations during such pandemic.Methodology: The review was done as per the guidelines of PRISMA and literature search was done on PubMed database using keywords as COVID-19, children TRANS and skin in different combinations. Articles published in English with cases of age TRANS 1 month to 18 years were eligible. The outcome included varied aspects of cutaneous and COVID-19 infection MESHD. The review protocol was not registered.Results: Of 51 publications identified, 13 studies containing 149 children TRANS met the eligibility criteria. Acrally located erythematous maculopapular lesion MESHD was the most common finding in 138 children TRANS. Erythema HP Erythema MESHD multiforme, varicella like exanthem and Kawasaki disease MESHD like presentations were reported in the rest of the cases. The duration of the skin lesion MESHD was 1-2 weeks in 43%. Skin biopsy done in 18 cases revealed superficial & deep perivascular and peri-eccrine lymphocytic infiltrate & lymphocytic vasculitis HP. RT-PCR was positive in 13.8% cases. Serological markers for HSV, parvovirus B19 analyzed across various studies, were found negative, except for mycoplasma pneumoniae HP in 2 of 20 cases tested.Discussion: Clinicopathologic analysis established chilblains HP like lesion in 43% cases with no confirmed TRANS etiology like cold exposure, autoimmune dysfunction MESHD, drug reaction, or viral infection MESHD. The usual cephalo-caudal spread of a viral exanthem was also missing. However, a low number of discussed cases was a limitation of the study.Conclusion: In the absence of any confirmed etiology for such cutaneous manifestations, the possibility of COVID-19 should be explored and evaluated thoroughly during such pandemic.

    Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection MESHD.

    Authors: Antonio Ferreira; Antonio Oliveira-e-Silva; Paulo Bettencourt

    doi:10.1101/2020.06.26.20056507 Date: 2020-06-29 Source: medRxiv

    Background: Hydroxychloroquine sulphate (HCQ) is being scrutinized for repositioning in the treatment and prevention of SARS-Cov-2 infection MESHD. This antimalarial drug is also chronically used to treat patients with autoimmune diseases MESHD. Methods: By analyzing the Portuguese anonymized data on private and public based medical prescriptions we have identified all cases chronically receiving HCQ for the management of diseases such as systemic lupus erythematosus HP systemic lupus erythematosus MESHD, rheumatoid arthritis HP rheumatoid arthritis MESHD, and other autoimmune diseases MESHD. Additionally, we have detected all laboratory confirmed cases TRANS of SARS-CoV-2 infection MESHD and all laboratory confirmed negative cases in the Portuguese population (mandatorily registered in a centrally managed database). Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases TRANS of SARS-CoV-2 infection MESHD with laboratory confirmed negative cases. Results: Out of 26,815 SARS-CoV-2 positive patients, 77 (0.29%) were chronically treated with HCQ, while 1,215 (0.36%) out of 333,489 negative patients were receiving it chronically (P=0.04). After adjustment for age TRANS, sex, and chronic treatment with corticosteroids and/or immunosuppressants, the odds ratio of SARS-CoV-2 infection MESHD infection for chronic HP treatment with HCQ has been 0.51 (0.37-0.70). Conclusions: Our data suggest that chronic treatment with HCQ confer protection against SARS-CoV-2 infection MESHD.

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