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Published Data

Data available from Swedish public agencies and large data produces

Data available from research groups in Sweden

The list below is curated manually and as such may not be exhaustive. If you would like to see your dataset here or correct information about your dataset, please get in touch with us. Projects sharing data where at least one author has an affiliation with a Swedish research institute are included. At this point, projects which share data openly or which explicitly promise to share data on request are included in this section. In the near future, only projects that either share data openly or have at least a metadata-only record with a clear data access procedure will be included.

Last updated: 2021-09-09

Project Last updated Available data
Roxhed N, Bendes A, Dale M, Mattsson C, Hanke L, [...], Schwenk JM
Nat Commun 12 (1)
10.1038/s41467-021-23893-4
2021-12-00
Högelin KA, Ruffin N, Pin E, Månberg A, Hober S, [...], Al Nimer F
iScience 103078
10.1016/j.isci.2021.103078
B-cell depleting therapies (BCDTs) are widely used as immunomodulating agents for autoimmune diseases such as multiple sclerosis. Their possible impact on development of immunity to SARS-CoV-2 has raised concerns with the COVID-19 pandemic. We here evaluated the frequency of COVID-19-like symptoms and determined immunological responses in participants of an observational trial comprising several multiple sclerosis disease modulatory drugs, (COMBAT-MS; NCT03193866) and in eleven patients after vaccination, with a focus on BCDT. Almost all seropositive and 17.9% of seronegative patients on BCDT, enriched for a history of COVID-19-like symptoms, developed anti-SARS-CoV-2 T-cell memory and T-cells displayed functional similarity to controls producing IFN-γ and TNF. Following vaccination, vaccine-specific humoral memory was impaired, while all patients developed a specific T-cell response. These results indicate that BCDTs do not abrogate SARS-CoV-2 cellular memory and provide a possible explanation as to why the majority of patients on BCDTs recover from COVID-19.
2021-09-02
Yin Y, Su W, Zhang J, Huang W, Li X, [...], Wang H
ACS Nano
10.1021/acsnano.1c03252
The successful control of coronavirus disease 2019 (COVID-19) pandemic is not only relying on the development of vaccines, but also depending on the storage, transportation, and administration of vaccines. Ideally, nucleic acid vaccine should be directly delivered to proper immune cells or tissue (such as lymph nodes). However, current developed vaccines are normally treated through intramuscular injection, where immune cells do not normally reside. Meanwhile, current nucleic acid vaccines must be stored in a frozen state that may hinder their application in developing countries. Here, we report a separable microneedle (SMN) patch to deliver polymer encapsulated spike (or nucleocapsid) protein encoding DNA vaccines and immune adjuvant for efficient immunization. Compared with intramuscular injection, SMN patch can deliver nanovaccines into intradermal for inducing potent and durable adaptive immunity. IFN-γ+CD4/8+ and IL-2+CD4/8+ T cells or virus specific IgG are significantly increased after vaccination. Moreover, in vivo results show the SMN patches can be stored at room temperature for at least 30 days without decreases in immune responses. These features of nanovaccines-laden SMN patch are important for developing advanced COVID-19 vaccines with global accessibility.
2021-09-02 Supporting information
Beukes EW, Andersson G, Fagelson MA, Manchaiah V
Internet Interv 25 100402
10.1016/j.invent.2021.100402
Internet-based cognitive behavioral therapy (ICBT) for tinnitus is an evidence-based intervention. The components of ICBT for tinnitus have, however, not been dismantled and thus the effectiveness of the different therapeutic components is unknown. It is, furthermore, not known if heterogeneous tinnitus subgroups respond differently to ICBT. This dismantling study aimed to explore the contribution of applied relaxation within ICBT for reducing tinnitus distress and comorbidities associated with tinnitus. A secondary aim was to assess whether outcomes varied for three tinnitus subgroups, namely those with significant tinnitus severity, those with low tinnitus severity, and those with significant depression. A parallel randomized controlled trial design ( n = 126) was used to compare audiologist-guided applied relaxation with the full ICBT intervention. Recruitment was online and via the intervention platform. Assessments were completed at four-time points including a 2-month follow-up period. The primary outcome was tinnitus severity as measured by the Tinnitus Functional Index. Secondary outcomes were included for anxiety, depression, insomnia, negative tinnitus cognitions, health-related quality of life, hearing disability, and hyperacusis. Treatment engagement variables including the number of logins, number of modules opened, and the number of messages sent. Both an intention-to-treat analysis and completer's only analysis were undertaken. Engagement was low which compromised results as the full intervention was undertaken by few participants. Both the ICBT and applied relaxation resulted in large reduction of tinnitus severity (within-group effect sizes d = 0.87 and 0.68, respectively for completers only analysis), which were maintained, or further improved at follow-up. These reductions in tinnitus distress were greater for the ICBT group, with a small effect size differences (between-group d = 0.15 in favor of ICBT for completers only analysis). Tinnitus distress decreased the most at post-intervention for those with significant depression at baseline. Both ICBT and applied relaxation contributed to significant reductions on most secondary outcome measures, with no group differences, except for a greater reduction of hyperacusis in the ICBT group. Due to poor compliance partly attributed to the COVID-19 pandemic results were compromised. Further studies employing strategies to improve compliance and engagement are required. The intervention's effectiveness increased with initial level of tinnitus distress; those with the highest scores at intake experienced the most substantial changes on the outcome measures. This may suggest tailoring of interventions according to tinnitus severity. Larger samples are needed to confirm this.
2021-09-00 Dataset, demographic questionnaire and metadata
Simnica D, Schultheiß C, Mohme M, Paschold L, Willscher E, [...], Binder M
Clin Transl Immunol 10 (9) e1340
10.1002/cti2.1340
T cells have an essential role in the antiviral defence. Public T-cell receptor (TCR) clonotypes are expanded in a substantial proportion of COVID-19 patients. We set out to exploit their potential use as read-out for COVID-19 T-cell immune responses. We searched for COVID-19-associated T-cell clones with public TCRs, as defined by identical complementarity-determining region 3 (CDR3) beta chain amino acid sequence that can be reproducibly detected in the blood of COVID-19 patients. Of the different clonotype identification algorithms used in this study, deep sequencing of brain tissue of five patients with fatal COVID-19 delivered 68 TCR clonotypes with superior representation across 140 immune repertoires of unrelated COVID-19 patients. Mining of immune repertoires from subjects not previously exposed to the virus showed that these clonotypes can be found in almost 20% of pre-pandemic immune repertoires of healthy subjects, with lower representation in repertoires from risk groups like individuals above the age of 60 years or patients with cancer. Together, our data show that at least a proportion of the SARS-CoV-2 T-cell response is mediated by public TCRs that are present in repertoires of unexposed individuals. The lower representation of these clones in repertoires of risk groups or failure to expand such clones may contribute to more unfavorable clinical COVID-19 courses.
2021-08-28
Asano T, Boisson B, Onodi F, Matuozzo D, Moncada-Velez M, [...],
Sci Immunol 6 (62) eabl4348
10.1126/sciimmunol.abl4348
2021-08-19 GEO GSE181787: Database entry containing information on samples and some raw data.
Hoffmann D, Mereiter S, Jin Oh Y, Monteil V, Elder E, [...], Penninger JM
EMBO J e108375
10.15252/embj.2021108375
New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. The 22 N-glycan sites of Spike remain highly conserved among SARS-CoV-2 variants, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike and the receptor binding domain (RBD) of SARS-CoV-2. Two lectins, Clec4g and CD209c, were identified to strongly bind to Spike. Clec4g and CD209c binding to Spike was dissected and visualized in real time and at single molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD-ACE2 interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g and CD209c significantly reduced SARS-CoV-2 infections. These data report the first extensive map and 3D structural modelling of lectin-Spike interactions and uncovers candidate receptors involved in Spike binding and SARS-CoV-2 infections. The capacity of CLEC4G and mCD209c lectins to block SARS-CoV-2 viral entry holds promise for pan-variant therapeutic interventions.
2021-08-10 Structural models for used in virtual screening
Razzaq M, Iglesias MJ, Ibrahim-Kosta M, Goumidi L, Soukarieh O, [...], Trégouët D
Sci Rep 11 (1) 14015
10.1038/s41598-021-93390-7
Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10-7) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.
2021-07-07 Proteomics data
Sandberg JT, Varnaitė R, Christ W, Chen P, Muvva JR, [...], Karolinska COVID‐19 Study Group
Clin Transl Immunol 10 (7) e1306
10.1002/cti2.1306
Humoral and cellular immunity to SARS-CoV-2 following COVID-19 will likely contribute to protection from reinfection or severe disease. It is therefore important to characterise the initiation and persistence of adaptive immunity to SARS-CoV-2 amidst the ongoing pandemic. Here, we conducted a longitudinal study on hospitalised moderate and severe COVID-19 patients from the acute phase of disease into convalescence at 5 and 9 months post-symptom onset. Utilising flow cytometry, serological assays as well as B cell and T cell FluoroSpot assays, we assessed the magnitude and specificity of humoral and cellular immune responses during and after human SARS-CoV-2 infection. During acute COVID-19, we observed an increase in germinal centre activity, a substantial expansion of antibody-secreting cells and the generation of SARS-CoV-2-neutralising antibodies. Despite gradually decreasing antibody levels, we show persistent, neutralising antibody titres as well as robust specific memory B cell responses and polyfunctional T cell responses at 5 and 9 months after symptom onset in both moderate and severe COVID-19 patients. Our findings describe the initiation and, importantly, persistence of cellular and humoral SARS-CoV-2-specific immunological memory in hospitalised COVID-19 patients long after recovery, likely contributing towards protection against reinfection.
2021-07-05 Supplementary Information (contains visualisations on clinical chemistry values, Memory B cell and T cell FluoroSpots, and Flow cytometry gating strategy)
Britton T, Trapman P, Ball F
R Soc Open Sci 8 (7) 210386
10.1098/rsos.210386
The COVID-19 pandemic has hit different regions differently. The current disease-induced immunity level î in a region approximately equals the cumulative fraction infected, which primarily depends on two factors: (i) the initial potential for COVID-19 in the region (R 0), and (ii) the preventive measures put in place. Using a mathematical model including heterogeneities owing to age, social activity and susceptibility, and allowing for time-varying preventive measures, the risk for a new epidemic wave and its doubling time are investigated. Focus lies on quantifying the minimal overall effect of preventive measures p Min needed to prevent a future outbreak. It is shown that î plays a more influential roll than when immunity is obtained from vaccination. Secondly, by comparing regions with different R 0 and î it is shown that regions with lower R 0 and low î may need higher preventive measures (p Min) compared with regions having higher R 0 but also higher î, even when such immunity levels are far from herd immunity. Our results are illustrated on different regions but these comparisons contain lots of uncertainty due to simplistic model assumptions and insufficient data fitting, and should accordingly be interpreted with caution.
2021-07-00 Supplementary Information (contains information on Matlab files, summary statistics, R0 values, and data visualisations)
Altay O, Arif M, Li X, Yang H, Aydın M, [...], Mardinoglu A
Adv. Sci. 2101222
10.1002/advs.202101222
2021-06-28 Raw, patient-level characteristics and data
Krambrich J, Akaberi D, Ling J, Hoffman T, Svensson L, [...], Lundkvist Å
Virol J 18 (1) 109
10.1186/s12985-021-01556-6
The ongoing SARS-CoV-2 pandemic has spread rapidly worldwide and disease prevention is more important than ever. In the absence of a vaccine, knowledge of the transmission routes and risk areas of infection remain the most important existing tools to prevent further spread. Here we investigated the presence of the SARS-CoV-2 virus in the hospital environment at the Uppsala University Hospital Infectious Disease ward by RT-qPCR and determined the infectivity of the detected virus in vitro on Vero E6 cells. SARS-CoV-2 RNA was detected in several areas, although attempts to infect Vero E6 cells with positive samples were unsuccessful. However, RNase A treatment of positive samples prior to RNA extraction did not degrade viral RNA, indicating the presence of SARS-CoV-2 nucleocapsids or complete virus particles protecting the RNA as opposed to free viral RNA. Our results show that even in places where a moderate concentration (Ct values between 30 and 38) of SARS-CoV-2 RNA was found; no infectious virus could be detected. This suggests that the SARS-CoV-2 virus in the hospital environment subsides in two states; as infectious and as non-infectious. Future work should investigate the reasons for the non-infectivity of SARS-CoV-2 virions.
2021-06-02 Ct values for all collected samples at the Uppsala University infectious disease ward
Galien S, Hultström M, Lipcsey M, Stattin K, Frithiof R, [...], Uppsala Intensive Care COVID-19 Research Group
Thromb J 19 (1) 38
10.1186/s12959-021-00272-z
Deep vein thrombosis (DVT) is common in critically ill patients with Coronavirus disease 2019 (COVID-19) and may cause fatal pulmonary embolism (PE) prior to diagnosis due to subtle clinical symptoms. The aim of this study was to explore the feasibility of bedside screening for DVT in critically ill COVID-19 patients performed by physicians with limited experience of venous ultrasound. We further aimed to compare inflammation, coagulation and organ dysfunction in patients with and without venous thromboembolism (VTE). This observational study included patients with COVID-19 admitted to the intensive care unit (ICU) of a tertiary hospital in Sweden and screened for DVT with proximal compression ultrasound of the lower extremities between April and July 2020. Screening was performed by ICU residents having received a short online education and one hands-on-session. Pathological screening ultrasound was confirmed by formal ultrasound whereas patients with negative screening underwent formal ultrasound on clinical suspicion. Clinical data, laboratory findings and follow-up were extracted from medical records. Of 90 eligible patients, 56 were screened by seven ICU residents with no (n = 5) or limited (n = 2) previous experience of DVT ultrasound who performed a median of 4 (IQR 2-19) examinations. Four (7.1%) patients had pathological screening ultrasound of which three (5.6%) were confirmed by formal ultrasound. None of the 52 patients with negative screening ultrasound were diagnosed with DVT during follow-up. Six patients were diagnosed with PE of which four prior to negative screening and two following negative and positive screening respectively. Patients with VTE (n = 8) had higher median peak D-dimer (24.0 (IQR 14.2-50.5) vs. 2.8 (IQR 1.7-7.2) mg/L, p = 0.004), mean peak C-reactive protein (363 (SD 80) vs. 285 (SD 108) mg/L, p = 0.033) and median peak plasma creatinine (288 (IQR 131-328) vs. 94 (IQR 78-131) μmol/L, p = 0.009) compared to patients without VTE (n = 48). Five patients (63%) with VTE received continuous renal replacement therapy compared to six patients (13%) without VTE (p = 0.005). ICU residents with no or limited experience could detect DVT with ultrasound in critically ill COVID-19 patients following a short education. VTE was associated with kidney dysfunction and features of hyperinflammation and hypercoagulation. ClinicalTrials ID: NCT04316884 . Registered 20 March 2020.
2021-06-02 Metadata record
Brueggemann AB, Jansen van Rensburg MJ, Shaw D, McCarthy ND, Jolley KA, [...], Zhou F
The Lancet Digital Health 3 (6) e360-e370
10.1016/S2589-7500(21)00077-7
Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 837 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27-0·37]) and 82% at 8 weeks (0·18 [0·14-0·23]) following the week in which significant changes in population movements were recorded. The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).
2021-06-00 Data processing, visualisation, analysis code
Mehregan A, Pérez-Conesa S, Zhuang Y, Elbahnsi A, Pasini D, [...], Delemotte L
bioRxiv
10.1101/2021.05.28.446179
2021-05-28 Input files and simulations
Chen X, Saccon E, Appelberg KS, Mikaeloff F, Rodriguez JE, [...], Gupta S
Cell Death Discov 7 (1) 114
10.1038/s41420-021-00487-z
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce the susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV, and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon-stimulated genes and their role in the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.
2021-05-18
Mahdi A, Błaszczyk P, Dłotko P, Salvi D, Chan TS, [...], Tarassenko L
Sci Rep 11 (1)
10.1038/s41598-021-88481-4
2021-04-29
Patel H, Ashton NJ, Dobson RJ, Anderson LM, Yilmaz A, [...], Zetterberg H
Sci Rep 11 (1)
https://doi.org/10.1038/s41598-021-85877-0
The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in the majority of individuals leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. The purpose of this study is to explore the proteomic differences between mild, severe and critical COVID-19 positive patients. Blood protein profiling was performed on 59 COVID-19 mild (n=26), severe (n=9) or critical (n=24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/. Our results demonstrate that dynamic changes in blood proteins that associate with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic target.
2021-04-23
Rosen J, Noreland M, Stattin K, Lipcsey M, Frithiof R, [...], Hultström M
Research Square
10.21203/rs.3.rs-419853/v1
2021-04-19 Metadata record
Patel H, Ashton NJ, Dobson RJB, Andersson L, Yilmaz A, [...], Zetterberg H
Sci Rep 11 (1) 6357
10.1038/s41598-021-85877-0
The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/ . Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.
2021-03-18
Cotugno N, Ruggiero A, Bonfante F, Petrara MR, Zicari S, [...], Palma P
Cell Rep 34 (11) 108852
10.1016/j.celrep.2021.108852
As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4 +CD40L+ T cells and Spike-specific B cells were associated with the anti-SARS-CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT+ patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.
2021-03-16
Dillner J, Elfström KM, Blomqvist J, Eklund C, Lagheden C, [...], Conneryd Lundgren K
Sci Rep 11 (1) 5160
10.1038/s41598-021-84356-w
The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. We invited all employees (n = 15,300) at work at the Karolinska University Hospital, Stockholm, Sweden to participate in a study examining SARS-Cov-2 antibodies in relation to registered sick leave. For consenting 12,928 healthy hospital employees antibodies to SARS-CoV-2 could be determined and compared to participant sick leave records. Subjects with viral serum antibodies were not at excess risk for future sick leave (adjusted odds ratio (OR) controlling for age and sex: 0.85 [95% confidence interval (CI) (0.85 (0.43-1.68)]. By contrast, subjects with antibodies had an excess risk for sick leave in the weeks prior to testing [adjusted OR in multivariate analysis: 3.34 (2.98-3.74)]. Thus, presence of viral antibodies marks past disease and protection against excess risk of future disease. Knowledge of whether exposed subjects have had disease in the past or are at risk for future disease is essential for planning of control measures.Trial registration: First registered on 02/06/20, ClinicalTrials.gov NCT04411576.
2021-03-04 Available on request
Papazoglou A, Conen A, Haubitz S, Tschopp M, Guignard VJ, [...], Enz TJ
J Clin Med 10 (5)
10.3390/jcm10050896
Postmortem pathological examinations, animal studies, and anecdotal reports suggest that coronavirus disease 2019 (COVID-19) could potentially affect intraocular tissue. However, published evidence is scarce and conflicting. In our study, we screened 100 eyes of 50 patients hospitalized for COVID-19. Relevant medical and ophthalmological history was assessed as well as symptoms, laboratory results, specific treatments, clinical course, and outcome. Ophthalmic exams including assessment of best corrected visual acuity (BCVA), intraocular pressure (IOP), color perception, ocular motility, ophthalmoscopy as well as optical coherence tomography (OCT) of the macula and the optic disc was performed at hospital admission and 29 to 192 days later. Of the 50 patients included, 14 (28%) were female. Median age was 64.5 (range 29-90) years. COVID-19 severity was mild in 15 (30%), severe in 30 (60%), and critical in five cases (10%). At baseline, median BCVA was 0.1 (0-1.8) Logarithm of the Minimum Angle of Resolution (LogMAR) and median IOP was 16 (8-22) mmHg. At follow-up, no relevant changes in BCVA and IOP were documented. No signs of active intraocular inflammation or optic nerve affection were found and OCT findings were widely stable during the observation period. Our findings suggest that COVID-19 does not regularly affect intraocular tissue.
2021-02-24 Patient characteristics, medical treatment regiments, symptoms, laboratory findings, ophthalmic findings, systemic symtoms for each patient
Snitz K, Honigstein D, Weissgross R, Ravia A, Mishor E, [...], Sobel N
medRxiv
10.1101/2021.02.18.21251422
2021-02-23 GitLab: raw data and analysis code, Matlab
Sherina N, Piralla A, Du L, Wan H, Kumagai-Braesch M, [...], Pan-Hammarström Q
Med (N Y)
10.1016/j.medj.2021.02.001
Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody levels and specific memory B- and T-cell responses in convalescent coronavirus disease-2019 (COVID-19) patients. Altogether 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain antibody levels over a period of eight months. In addition, level of SARS-CoV-2 neutralizing antibodies, specific memory B- and T-cell responses were tested in a subset of samples. Anti-SARS-CoV-2 antibodies were present in 85% of the samples collected within 4 weeks after onset of symptoms in COVID-19 patients. Levels of specific IgM/IgA antibodies declined after 1 month while levels of specific IgG antibodies and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG antibodies were still present, though at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B- and T-cell responses developed with time and were persistent in all patients followed up till 6-8 months. Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 might persist for at least 6-8 months, regardless of disease severity. Development of medium or long-term protective immunity through vaccination might thus be possible. EU-ATAC consortium, the Italian Ministry of Health and SciLife/KAW.
2021-02-10 Demographic and clinical characteristics of the COVID-19 patients (N=122 Italian, N=12 Swedish)
Lourda M, Dzidic M, Hertwig L, Bergsten H, Palma Medina LM, [...], None
medRxiv
https://doi.org/10.1101/2021.01.27.21250591
2021-01-31 Karolinska KI/K Covid19 Immune atlas
Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, [...], Villapol S
medRxiv
10.1101/2021.01.27.21250617
2021-01-29 Available in paper: Characteristics of studies included in the meta-analysis; long term effects in patients recovering from COVID-19
Falck-Jones S, Vangeti S, Yu M, Falck-Jones R, Cagigi A, [...], Smed-Sorensen A
J Clin Invest 131 (6)
10.1172/JCI144734
The immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFNγ production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.
2021-01-28 Available on request
Hultström M, Fromell K, Larsson A, Quaggin SE, Betsholtz C, [...], Jeansson M
medRxiv
10.1101/2021.01.13.21249429
2021-01-15 Metadata record
Elec AD, Oltean M, Goldis P, Cismaru C, Lupse M, [...], Elec FI
Int J Infect Dis
10.1016/j.ijid.2021.01.023
The lack of effective COVID-19 treatments mandated the repurposing of several drugs, including antiretrovirals (ARV) and remdesivir (RDV). These compounds may induce acute kidney injuries and are not recommended in patients with poor renal function, such as kidney transplant recipients (KTx). We reviewed the records of 42 KTx with COVID-19, some of them receiving ARV (n = 10) or RDV (n = 8) as part of the COVID-19 management. Most patients were male (71%) with a median age of 52 years and median GFR 56 mL/min and had mild (36%), moderate (19%), severe (31%), and critical (12%) disease. Subgroups (patients receiving ARV, RDV, or no antivirals) were comparable regarding patient age, comorbidities or immunosuppression. Seven patients (16,6%) died during hospitalization. Acute kidney injury was found in 24% KTx at admission. Upon discharge, eGFR increased in 32% and decreased in 39% of the KTx compared with the admission. The decrease was more prevalent in the RDV group (80%) compared with KTx without any antiviral treatment (29%) (p < 0.05). Most patients (62%) returned to baseline eGFR values within one month from discharge. The proportion was similar between the patients receiving antiviral treatment or not. KTx run a high risk of COVID-19-related renal impairment. Antivirals appear safe for use without major risks for kidney injury.
2021-01-13 Patient demographics, management and outcome in 42 kidney recipients with COVID-19
Iravani B, Peter MG, Arshamian A, Olsson MJ, Hummel T, [...], Lundström JN
bioRxiv
10.1101/2021.01.11.426175
2021-01-13 Available on request
Kermani NZ, None , Song WJ, Badi Y, Versi A, [...], Chung KF
Respir Res 22 (1) 101876
10.1186/s12931-020-01605-8
Bats are reservoirs for a large number of viruses which have potential to cause major human disease outbreaks, including the current coronavirus disease 2019 (COVID-19) pandemic. Major efforts are underway to understand bat immune response to viruses, whereas much less is known about their immune responses to bacteria. In this study, MR1-restricted T (MR1T) cells were detected through the use of MR1 tetramers in circulation and tissues of Pteropus alecto (Pa) bats. Pa MR1T cells exhibited weak responses to MR1-presented microbial metabolites at resting state. However, following priming with MR1-presented agonist they proliferated, upregulated critical transcription factors and cytolytic proteins, and gained transient expression of Th1/17-related cytokines and antibacterial cytotoxicity. Collectively, these findings show that the Pa bat immune system encompasses an abundant and functionally conserved population of MR1T cells with mucosal-associated invariant T-like characteristics, suggesting that MR1 and MR1T cells also play a significant role in bat immune defense.
2021-01-07 Available on request
Spangler D, Blomberg H, Smekal D
Scand J Trauma Resusc Emerg Med 29 (1) 3
10.1186/s13049-020-00826-6
The novel coronavirus disease 2019 (Covid-19) pandemic has affected prehospital care systems across the world, but the prehospital presentation of affected patients and the extent to which prehospital care providers are able to identify them is not well characterized. In this study, we describe the presentation of Covid-19 patients in a Swedish prehospital care system, and asses the predictive value of Covid-19 suspicion as documented by dispatch and ambulance nurses. Data for all patients with dispatch, ambulance, and hospital records between January 1-August 31, 2020 were extracted. A descriptive statistical analysis of patients with and without hospital-confirmed Covid-19 was performed. In a subset of records beginning from April 14, we assessed the sensitivity and specificity of documented Covid-19 suspicion in dispatch and ambulance patient care records. A total of 11,894 prehospital records were included, of which 481 had a primary hospital diagnosis code related to-, or positive test results for Covid-19. Covid-19-positive patients had considerably worse outcomes than patients with negative test results, with 30-day mortality rates of 24% vs 11%, but lower levels of prehospital acuity (e.g. emergent transport rates of 14% vs 22%). About half (46%) of Covid-19-positive patients presented to dispatchers with primary complaints typically associated with Covid-19. Six thousand seven hundred seventy-six records were included in the assessment of predictive value. Sensitivity was 76% (95% CI 71-80) and 82% (78-86) for dispatch and ambulance suspicion respectively, while specificities were 86% (85-87) and 78% (77-79). While prehospital suspicion was strongly indicative of hospital-confirmed Covid-19, based on the sensitivity identified in this study, prehospital suspicion should not be relied upon as a single factor to rule out the need for isolation precautions. The data provided may be used to develop improved guidelines for identifying Covid-19 patients in the prehospital setting.
2021-01-06 Available on request
Pilotto A, Masciocchi S, Volonghi I, De Giuli V, Caprioli F, [...], Padovani A
Clin Infect Dis
10.1093/cid/ciaa1933
2021-01-04
  • Available in paper: Clinical features, imaging and CSF biochemical analyses of SARS-CoV-2 encephalitis cases
  • Available in paper: Clinical features, imaging and CSF biochemical analyses of COV-Enc cases
Ahlström B, Frithiof R, Hultström M, Larsson I, Strandberg G, [...], Lipcsey M
Acta Anaesthesiol Scand 65 (4) 525-533
10.1111/aas.13781
Abstract Background: Several studies have recently addressed factors associated with severe Coronavirus disease 2019 (COVID-19); however, some medications and comorbidities have yet to be evaluated in a large matched cohort. We therefore explored the role of relevant comorbidities and medications in relation to the risk of intensive care unit (ICU) admission and mortality. Methods: All ICU COVID-19 patients in Sweden until 27 May 2020 were matched to population controls on age and sex to assess the risk of ICU admission. Cases were identified, comorbidities and medications were retrieved from high-quality registries. Three conditional logistic regression models were used for risk of ICU admission and three Cox proportional hazards models for risk of ICU mortality, one with comorbidities, one with medications and finally with both models combined, respectively. Results: We included 1981 patients and 7924 controls. Hypertension, type 2 diabetes mellitus, chronic renal failure, asthma, obesity, being a solid organ transplant recipient and immunosuppressant medications were independent risk factors of ICU admission and oral anticoagulants were protective. Stroke, asthma, chronic obstructive pulmonary disease and treatment with renin-angiotensin-aldosterone inhibitors (RAASi) were independent risk factors of ICU mortality in the pre-specified primary analyses; treatment with statins was protective. However, after adjusting for the use of continuous renal replacement therapy, RAASi were no longer an independent risk factor. Conclusion: In our cohort oral anticoagulants were protective of ICU admission and statins was protective of ICU death. Several comorbidities and ongoing RAASi treatment were independent risk factors of ICU admission and ICU mortality. This article is protected by
2021-01-04 Available on request
Virhammar J, Nääs A, Fällmar D, Cunningham JL, Klang A, [...], Rostami E
European Journal of Neurology
10.1111/ene.14703
Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19), and biomarkers of central nervous system (CNS) injury are reported to be increased in plasma but not extensively studied in cerebrospinal fluid (CSF). This study examined CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain [NfL] protein, glial fibrillary acidic protein [GFAp], and total tau), was performed and compared to neurological features and disease severity. Neurological symptoms included altered mental status (42%), headache (42%), and central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis, and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL protein, total tau, and GFAp were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL protein correlated with disease severity, time in intensive care, and level of consciousness. NfL protein in CSF was higher in patients with central neurological symptoms. Although limited by the small sample size, our data suggest that levels of NfL protein, GFAp, and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF workup where pathological findings are scarce. NfL protein, in particular, is associated with central neurological symptoms and disease severity.
2020-12-28
  • Provided in the article: patient characteristics and biomarkers in cerebrospinal fluid for 19 patients
  • Available on request
Dopico XC, Muschiol S, Christian M, Hanke L, Sheward DJ, [...], Karlsson Hedestam GB
medRxiv
10.1101/2020.12.24.20248821
2020-12-26
Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, [...], OHDSI-COVID-19 consortium
Rheumatology (Oxford)
10.1093/rheumatology/keaa771
Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA. We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%. A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis. HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation. Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.
2020-12-25 Data aggregated by data source
2020-12-22 Available on request
Dillner J, Elfström KM, Blomqvist J, Engstrand L, Uhlén M, [...], Lundgren KC
medRxiv
10.1101/2020.12.13.20248122
2020-12-14 Available on request
Robertson J, Gostner JM, Nilsson S, Andersson L, Fuchs D, [...], Gisslen M
Infect Dis . 2020 Dec 10;20(1):942. Dec 10; 20 (1) 942
10.1186/s12879-020-05671-7
Background The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is rapidly spreading worldwide. There is limited information about prognostic markers that could help clinicians to identify COVID-19 patients with a poor prognosis. Serum levels of the immune activation marker neopterin has shown to be of prognostic value in patients with SARS. The aim of this study was to investigate whether serum neopterin is associated with the severity of COVID-19. Methods We included 34 patients with confirmed COVID-19 between March 3 and March 30, 2020. Fifteen patients had mild disease and did not require hospitalization, whereas 19 patients developed severe COVID-19 requiring intensive care. Concentrations of serum neopterin, tryptophan, and kynurenine were measured at and repeatedly after inclusion. Results We found a more than two-fold higher mean concentration of neopterin in severely ill patients (mean value 42.0 nmol/L (SD 18.2)) compared to patients with mild symptoms (16.9 nmol/L (SD 11.0)). All of the severe cases had elevated neopterin concentrations (>9.1 nmol/L) at the initial sampling with values ranging from 17.2 to 86.7 nmol/L. In comparison, 10 of 15 patients with mild disease had neopterin levels above 9.1 nmol/L, with concentrations in the range from 4.9 to 31.6 nmol/L. Neopterin levels gradually decreased during the course of COVID-19, but severe cases maintained elevated levels for a longer period. Moreover, lower levels of tryptophan and higher levels of kynurenine, indicating an increased tryptophan catabolism, were seen in the group with severe cases. Conclusions In conclusion, we found that serum neopterin levels are associated with the severity of COVID-19. Our findings suggest that neopterin could be used as a prognostic marker, but further studies are needed to elucidate how it can be used in clinical praxis.
2020-12-10 Available on request
Cagigi A, Yu M, Falck-Jones S, Vangeti S, Österberg B, [...], Smed-Sörensen A
medRxiv
10.1101/2020.11.25.20238592
2020-12-06 Available on request
Hofman P, Ilié M, Chamorey E, Brest P, Schiappa R, [...], Calabrese F
ESMO Open 6 (1) 100024
10.1016/j.esmoop.2020.100024
This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.
2020-12-02 Available on request
Morales DR, Conover MM, You SC, Pratt N, Kostka K, [...], Suchard MA
The Lancet Digital Health 3 (2) e98-e114
10.1016/s2589-7500(20)30289-2
2020-12-00 Data aggregated by data source
Appelberg S, Gupta S, Svensson Akusjärvi S, Ambikan AT, Mikaeloff F, [...], Neogi U
Emerg Microbes Infect 9 (1) 1748-1760
10.1080/22221751.2020.1799723
How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.
2020-12-00
Kirschenbaum D, Imbach LL, Jane Rushing E, Frauenknecht KBM, Gascho R T D, [...], Frontzek K
Neuropathol Appl Neurobiol
10.1111/nan.12677
Coronavirus disease 19 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2), has become a worldwide pandemic (1). Symptoms of COVID-19 vary widely and range from asymptomatic disease to severe pneumonia and multiorgan failure (2). A severe disease course is more likely in older patients and patients with pre-existing respiratory and cardiovascular conditions (2). Patients with severe Sars-CoV-2 infection may present with ischaemic stroke (3, 4) or even fatal intracerebral haemorrhage (5). To date, little is known about the neuropathological sequelae of COVID-19. The largest published autopsy series of COVID-19 neuropathology reported microthrombi and acute haemorrhagic infarction in a significant number of patients (6), while another more recent study found evidence of lymphocytic encephalitis and meningitis (7). Endotheliitis of the brain and extraneural organs has been shown in Sars-CoV infected patients (8). Similarly, it is a recurrent feature in the lungs and other peripheral organs of Sars-CoV-2 infected patients (9) but has not yet been reported in the central nervous system. We speculated that cerebrovascular pathology in COVID-19 patients could be a direct consequence of hitherto unidentified cerebral endotheliitis caused by Sars-CoV-2.
2020-11-29 Provided in the article: Clinical and pathological characteristics of four patients
Jonmarker S, Hollenberg J, Dahlberg M, Stackelberg O, Litorell J, [...], Cronhjort M
Crit Care 24 (1) 653
10.1186/s13054-020-03375-7
A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500-4500 IU tinzaparin or 2500-5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13-0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43-1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04. Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.
2020-11-23 Available on request due to privacy restrictions
Ludvigsson JF
Acta Paediatr
10.1111/apa.15673
Persistent symptoms in adults after COVID-19 are emerging and the term long COVID is increasingly appearing in the literature. However, paediatric data are scarce . This paper contains a case report of five Swedish children and the long-term symptoms reported by their parents. It also includes a systematic literature review of the MEDLINE, EMBASE and Web of Science databases and the medRxiv/bioRxiv preprint servers up to 2 November 2020. The five children with potential long covid had a median age of 12 years (range 9-15) and four were girls. They had symptoms for 6-8 months after their clinical diagnoses of COVID-19. None were hospitalised at diagnosis, but one was later admitted for peri-myocarditis. All five children had fatigue, dyspnoea, heart palpitations or chest pain and four had headaches, difficulties concentrating, muscle weakness, dizziness and sore throats. Some had improved after 6-8 months, but they all suffered from fatigue and none had fully returned to school. The systematic review identified 179 publications and 19 of these were deemed relevant and read in detail. None contained any information on long COVID in children. Children may experience similar long COVID symptoms to adults and females may be more affected.
2020-11-17 Provided in the article: clinical data reported by parents of five children with long-term effects of COVID-19
Elofsson A, Bryant P
medRxiv
10.1101/2020.07.03.20145649
In response to the pandemic development of the novel coronavirus (SARS-CoV-2), governments worldwide have implemented strategies of suppression by non-pharmaceutical interventions (NPIs). Such NPIs include social distancing, school closures, limiting international travel and complete lockdown. Worldwide the NPIs enforced to limit the spread of COVID-19 are now being lifted. Understanding how the risk increases when NPIs are lifted is important for decision making. Treating NPIs equally across countries and regions limits the possibility for modelling differences in epidemic response, as the response to the NPIs influences can vary between regions and this can affect the epidemic outcome, so do the strength and speed of lifting these. Our solution to this is to measure mobility changes from mobile phone data and their impacts on the basic reproductive number. We model the epidemic in all US states to compare the difference in outcome if NPIs are lifted or retained. We show that keeping NPIs just a few weeks longer has a substantial impact on the epidemic outcome.
2020-11-17 Analysis code and data
Susek KH, Gran C, Ljunggren HG, Alici E, Nahi H
Eur J Haematol. 105 (6) 751-754
10.1111/ejh.13502
COVID‐19 has emerged as a global pandemic. Cancer patients have been reported to be at higher risk for adverse outcome of COVID‐19. Studies are ongoing to decipher the risk factors and risk groups among cancer patients as well as strategies to refine treatment approaches. Here, we report eight patients with multiple myeloma that underwent immunomodulatory therapies with daratumumab or lenalidomide‐based combination treatments and one patient with smoldering multiple myeloma, all of which presented with symptomatic COVID‐19. We report that patients that succumbed to COVID‐19 presented with either progressive tumor disease under daratumumab treatment or were in remission under lenalidomide‐dexamethasone treatment.
2020-11-17 Provided in the article: Characteristics, treatments, COVID-19-related outcomes, additional laboratory and clinical data for 9 patients
Stebbing J, Sánchez Nievas G, Falcone M, Youhanna S, Richardson P, [...], Lauschke VM
Sci Adv 7 (1)
10.1126/sciadv.abe4724
Using AI we identified baricitinib as possessing anti-viral and anti-cytokine efficacy. We now show a 71% (95% CI 0.15-0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age 81 years). A further 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold. RNA-Seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and super-resolution microscopy, baricitinib exerts activity rapidly through the inhibition of host proteins (numb associated kinases), uniquely amongst anti-virals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivizes further randomized controlled trials.
2020-11-13
Saguti F, Magnil E, Enache L, Churqui MP, Johansson A, [...], Norder H
Water Res 189 116620
10.1016/j.watres.2020.116620
SARS-CoV-2 was discovered among humans in Wuhan, China in late 2019, and then spread rapidly, causing a global pandemic. The virus was found to be transmitted mainly by respiratory droplets from infected persons or by direct contact. It was also shown to be excreted in feces, why we investigated whether the virus could be detected in wastewater and if so, to which extent its levels reflects its spread in society. Samples of wastewater from the city of Gothenburg, and surrounding municipalities in Sweden were collected daily from mid-February until June 2020 at the Rya wastewater treatment plant. Flow proportional samples of wastewater were collected to ensure that comparable amounts were obtained for analysis. Daily samples were pooled into weekly samples. Virus was concentrated on a filter and analyzed by RT-qPCR. The amount of SARS-CoV-2 varied with peaks approximately every four week, preceding variations in number of newly hospitalized patients by 19-21 days. At that time virus testing for COVID-19 was limited to patients with severe symptoms. Local differences in viral spread was shown by analyzing weekly composite samples of wastewater from five sampling sites for four weeks. The highest amount of virus was found from the central, eastern, and northern parts of the city. SARS-CoV-2 was also found in the treated effluent wastewater from the WWTP discharged into the recipient, the Göta River, although with a reduction of 4-log 10. The viral peaks with regular temporal intervals indicated that SARS-CoV-2 may have a cluster spread, probably reflecting that the majority of infected persons only spread the disease during a few days. Our results are important for both the planning of hospital care and to rapidly identify and intervene against local spread of the virus.
2020-11-10 Provided in the article: amount of SARS-CoV-2 in wastewater in Gothenburg per week between February and June 2020
Asif S, Frithiof R, Lipcsey M, Kristensen B, Alving K, [...], Hultström M
Crit Care 24 (1) 639
10.1186/s13054-020-03362-y
2020-11-06 Available on request
García M, Kokkinou E, Carrasco García A, Parrot T, Palma Medina LM, [...], Group tKKCS
Clin Transl Immunol 9 (12)
10.1002/cti2.1224
Objectives The role of innate lymphoid cells (ILCs) in coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unknown. Understanding the immune response in COVID-19 could contribute to unravel the pathogenesis and identification of treatment targets. To describe the phenotypic landscape of circulating ILCs in COVID-19 patients and to identify ILC phenotypes correlated to serum biomarkers, clinical markers, and laboratory parameters relevant in COVID-19. Methods Blood samples collected from moderately (n=11) and severely ill (n=12) COVID-19 patients as well as healthy control donors (n=16), were analyzed with 18-parameter flow cytometry. Using supervised and unsupervised approaches, we examined the ILC activation status and homing profile. Clinical and laboratory parameters were obtained from all COVID-19 patients and serum biomarkers were analyzed with multiplex immunoassays. Results ILCs were largely depleted from the circulation of COVID-19 patients compared with healthy controls. Remaining circulating ILCs from patients revealed increased frequencies of ILC2 in moderate COVID-19, with a concomitant decrease of ILC precursors (ILCp), as compared with controls. ILC2 and ILCp showed an activated phenotype with increased CD69 expression, whereas expression levels of the chemokine receptors CXCR3 and CCR4 were significantly altered in ILC2 and ILCp, and ILC1, respectively. The activated ILC profile of COVID-19 patients was associated with soluble inflammatory markers, while frequencies of ILC subsets were correlated with laboratory parameters that reflect the disease severity. Conclusion This study provides insights into the potential role of ILCs in immune responses against SARS-CoV-2, particularly linked to the severity of COVID-19.
2020-11-04 Karolinska KI/K Covid19 Immune atlas
Lundberg OHM, Lengquist M, Spångfors M, Annborn M, Bergmann D, [...], Friberg H
Crit Care 24 (1) 636
10.1186/s13054-020-03351-1
Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis. In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis. Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better. Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.
2020-11-04 Available on request
Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, [...], OHDSI-COVID-19 consortium
Lancet Rheumatol 2 (11) e698-e711
10.1016/S2665-9913(20)30276-9
Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4. The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]). Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.
2020-11-00 Data aggregated by data source
Marklund E, Leach S, Axelsson H, Nyström K, Norder H, [...], Gisslén M
PLoS One 15 (10) e0241104
10.1371/journal.pone.0241104
To accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset. SARS-CoV-2-specific IgG antibody levels were quantified using two clinically validated and widely used commercial serological assays (Architect, Abbott Laboratories and iFlash 1800, YHLO), detecting antibodies against the spike and nucleocapsid proteins. Forty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P = 0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset. Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys.
2020-10-21 Raw data
Castro Dopico X, Hanke L, Sheward DJ, Muschiol S, Aleman S, [...], Karlsson Hedestam GB
medRxiv
10.1101/2020.07.17.20155937
Serology is critical for understanding pathogen-specific immune responses, but is fraught with difficulty, not least because the strength of antibody (Ab) response varies greatly between individuals and mild infections generally generate lower Ab titers (1-3). We used robust IgM, IgG and IgA Ab tests to evaluate anti-SARS-CoV-2 responses in individuals PCR+ for virus RNA (n=105) representing different categories of disease severity, including mild cases. All PCR+ individuals in the study became IgG-positive against pre-fusion trimers of the virus spike (S) glycoprotein, but titers varied greatly. Elevated IgA, IL-6 and neutralizing responses were present in intensive care patients. Additionally, blood donors and pregnant women (n=2,900) sampled throughout the first wave of the pandemic in Stockholm, Sweden, further demonstrated that anti-S IgG titers differed several orders of magnitude between individuals, with an increase of low titer values present in the population at later time points (4,5). To improve upon current methods to identify low titers and extend the utility of individual measures (6,7), we used our PCR+ individual data to train machine learning algorithms to assign likelihood of past infection. Using these tools that assigned probability to individual responses against S and the receptor binding domain (RBD), we report SARS-CoV-2-specific IgG in 13.7% of healthy donors five months after the peak of spring COVID-19 deaths, when mortality and ICU occupancy in the country due to the virus were at low levels. These data further our understanding of antibody responses to the virus and provide solutions to problems in serology data analysis.
2020-10-19 Inferring seroprevalence from ELISA data, without choosing a cutoff
Almskog LM, Wikman A, Svensson J, Wanecek M, Bottai M, [...], Ågren A
J Thromb Thrombolysis
10.1007/s11239-020-02312-3
High prevalence of thrombotic events in severely ill COVID-19 patients have been reported. Pulmonary embolism as well as microembolization of vital organs may in these individuals be direct causes of death. The identification of patients at high risk of developing thrombosis may lead to targeted, more effective prophylactic treatment. The primary aim of this study was to test whether rotational thromboelastometry (ROTEM) at admission indicates hypercoagulopathy and predicts the disease severity, assessed as care level, in COVID-19 patients. The study was designed as a prospective, observational study where COVID-19 patients over 18 years admitted to hospital were eligible for inclusion. Patients were divided into two groups depending on care level: (1) regular wards or (2) wards with specialized ventilation support. Conventional coagulation tests, blood type and ROTEM were taken at admission. 60 patients were included; age 61 (median), 67% men, many with comorbidities (e.g. hypertension, diabetes). The ROTEM variables Maximum Clot Firmness (EXTEM-/FIBTEM-MCF) were higher in COVID-19 patients compared with in healthy controls (p < 0.001) and higher in severely ill patients compared with in patients at regular wards (p < 0.05). Our results suggest that hypercoagulopathy is present early in patients with mild to moderate disease, and more pronounced in severe COVID-19 pneumonia. Non-O blood types were not overrepresented in COVID-19 positive patients. ROTEM variables showed hypercoagulopathy at admission and this pattern was more pronounced in patients with increased disease severity. If this feature is to be used to predict the risk of thromboembolic complications further studies are warranted.
2020-10-17 Raw data
Rudberg A, Havervall S, Månberg A, Jernbom Falk A, Aguilera K, [...], Thålin C
Nat Commun 11 (1) 5064
10.1038/s41467-020-18848-0
SARS-CoV-2 may pose an occupational health risk to healthcare workers. Here, we report the seroprevalence of SARS-CoV-2 antibodies, self-reported symptoms and occupational exposure to SARS-CoV-2 among healthcare workers at a large acute care hospital in Sweden. The seroprevalence of IgG antibodies against SARS-CoV-2 was 19.1% among the 2149 healthcare workers recruited between April 14th and May 8th 2020, which was higher than the reported regional seroprevalence during the same time period. Symptoms associated with seroprevalence were anosmia (odds ratio (OR) 28.4, 95% CI 20.6-39.5) and ageusia (OR 19.2, 95% CI 14.3-26.1). Seroprevalence was also associated with patient contact (OR 2.9, 95% CI 1.9-4.5) and covid-19 patient contact (OR 3.3, 95% CI 2.2-5.3). These findings imply an occupational risk for SARS-CoV-2 infection among healthcare workers. Continued measures are warranted to assure healthcare workers safety and reduce transmission from healthcare workers to patients and to the community.
2020-10-08 Data available upon request and collaboration inquiries welcome.
Parrot T, Gorin J, Ponzetta A, Maleki KT, Kammann T, [...], Sandberg JK
Sci Immunol 5 (51)
10.1126/sciimmunol.abe1670
Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69 high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis.
2020-09-28 Karolinska KI/K Covid19 Immune atlas
Frithiof R, Rostami E, Kumlien E, Virhammar J, Fällmar D, [...], Punga AR
Research square
10.21203/rs.3.rs-78038/v1
2020-09-22 Available on request
Dillner J, Elfström M, Blomqvist J, Eklund C, Lagheden C, [...], Conneryd Lundgren K
medRxiv
10.1101/2020.09.14.20194308
Background: The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. Method: We analyzed 12928 healthy hospital employees for SARS-CoV-2 antibodies and compared results to participant sick leave records (Clinical trial registration: ClinicalTrials.gov NCT04411576). Results: Subjects with viral serum antibodies were not at excess risk for future sick leave (Odds Ratio (OR): 0.85 (95% Confidence Interval (CI) (0.85 (0.43-1.68)). By contrast, subjects with antibodies had an excess risk for sick leave in the past weeks (OR: 3.34 (2.98-3.74)). Conclusion: Presence of viral antibodies marks past disease and protection against excess risk of future disease.
2020-09-18 Pseudonymised, individual-level data available on request.
Bryant P, Elofsson A
PeerJ 8 e9879
10.7717/peerj.9879
As governments across Europe have issued non-pharmaceutical interventions (NPIs) such as social distancing and school closing, the mobility patterns in these countries have changed. Most states have implemented similar NPIs at similar time points. However, it is likely different countries and populations respond differently to the NPIs and that these differences cause mobility patterns and thereby the epidemic development to change. We build a Bayesian model that estimates the number of deaths on a given day dependent on changes in the basic reproductive number, R0, due to differences in mobility patterns. We utilise mobility data from Google mobility reports using five different categories: retail and recreation, grocery and pharmacy, transit stations, workplace and residential. The importance of each mobility category for predicting changes in R0 is estimated through the model. The changes in mobility have a considerable overlap with the introduction of governmental NPIs, highlighting the importance of government action for population behavioural change. The shift in mobility in all categories shows high correlations with the death rates 1 month later. Reduction of movement within the grocery and pharmacy sector is estimated to account for most of the decrease in R0. Our model predicts 3-week epidemic forecasts, using real-time observations of changes in mobility patterns, which can provide governments with direct feedback on the effects of their NPIs. The model predicts the changes in a majority of the countries accurately but overestimates the impact of NPIs in Sweden and Denmark and underestimates them in France and Belgium. We also note that the exponential nature of all epidemiological models based on the basic reproductive number, R0 cause small errors to have extensive effects on the predicted outcome.
2020-09-15 Modelling code and data
Ling J, Hickman RA, Li J, Lu X, Lindahl JF, [...], Järhult JD
Viruses 12 (9)
10.3390/v12091026
During the COVID-19 pandemic, the virus evolved, and we therefore aimed to provide an insight into which genetic variants were enriched, and how they spread in Sweden. We analyzed 348 Swedish SARS-CoV-2 sequences freely available from GISAID obtained from 7 February 2020 until 14 May 2020. We identified 14 variant sites ≥5% frequency in the population. Among those sites, the D936Y substitution in the viral Spike protein was under positive selection. The variant sites can distinguish 11 mutational profiles in Sweden. Nine of the profiles appeared in Stockholm in March 2020. Mutational profiles 3 (B.1.1) and 6 (B.1), which contain the D936Y mutation, became the predominant profiles over time, spreading from Stockholm to other Swedish regions during April and the beginning of May. Furthermore, Bayesian phylogenetic analysis indicated that SARS-CoV-2 could have emerged in Sweden on 27 December 2019, and community transmission started on February 1st with an evolutionary rate of 1.5425 × 10 -3 substitutions per year. Our study provides novel knowledge on the spatio-temporal dynamics of Swedish SARS-CoV-2 variants during the early pandemic. Characterization of these viral variants can provide precious insights on viral pathogenesis and can be valuable for diagnostic and drug development approaches.
2020-09-14 Spatial temporal appearance of each variant and their mutation profile and clade information; Other supplementary materials.
Glans H, Gredmark-Russ S, Olausson M, Falck-Jones S, Varnaite R, [...], Brave A
Infect Dis . 2020 Dec 10;20(1):942. 21 (1) 494
10.1186/s12879-021-06202-8
To understand the risk of transmission of SARS-CoV-2 in hospitalized COVID-19 patients we simultaneously assessed the presence of SARS-CoV-2 RNA, live infectious virus in the airways, and virus-specific IgG and neutralizing antibodies in sera in 36 hospitalized COVID-19 patients. SARS-CoV-2 could be cultured from four patients, all with low or undetectable antibody response. Our data suggests that the level of SARS-CoV-2 antibodies may correlate to risk for shedding live SARS-CoV-2 virus in hospitalized COVID-19 patients.
2020-09-13 Available on request
Bortz RH, Florez C, Laudermilch E, Wirchnianski AS, Lasso G, [...], Chandran K
mSphere 6 (2)
10.1128/mSphere.00224-21
The COVID-19 global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to place an immense burden on societies and healthcare systems. A key component of COVID-19 control efforts is serologic testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test makes it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.
2020-09-11 Available on request
Virhammar J, Kumlien E, Fällmar D, Frithiof R, Jackmann S, [...], Rostami E
Neurology 95 (10) 445-449
10.1212/wnl.0000000000010250
Here, we report a case of COVID-19–related acute necrotizing encephalopathy where SARS-CoV-2 RNA was found in CSF 19 days after symptom onset after testing negative twice. Although monocytes and protein levels in CSF were only marginally increased, and our patient never experienced a hyperinflammatory state, her neurologic function deteriorated into coma. MRI of the brain showed pathologic signal symmetrically in central thalami, subinsular regions, medial temporal lobes, and brain stem. Extremely high concentrations of the neuronal injury markers neurofilament light and tau, as well as an astrocytic activation marker, glial fibrillary acidic protein, were measured in CSF. Neuronal rescue proteins and other pathways were elevated in the in-depth proteomics analysis. The patient received IV immunoglobulins and plasma exchange. Her neurologic status improved, and she was extubated 4 weeks after symptom onset. This case report highlights the neurotropism of SARS-CoV-2 in selected patients and emphasizes the importance of repeated lumbar punctures and CSF analyses in patients with suspected COVID-19 and neurologic symptoms.
2020-09-08 Proteomic data
Larsson E, Brattström O, Agvald-Öhman C, Grip J, Campoccia Jalde F, [...], Karolinska Intensive Care COVID-19 Study Group
Acta Anaesthesiol Scand 65 (1) 76-81
10.1111/aas.13694
Information on characteristics and outcomes of intensive care unit (ICU) patients with COVID-19 remains limited. We examined characteristics, clinical course and early outcomes of patients with COVID-19 admitted to ICU. We included all 260 patients with COVID-19 admitted to nine ICUs at the Karolinska University Hospital (Stockholm, Sweden) between 9 March and 20 April 2020. Primary outcome was in-hospital mortality among patients with definite outcomes (discharged from ICU or death), as of 30 April 2020 (study end point). Secondary outcomes included ICU length of stay, the proportion of patients receiving mechanical ventilation and renal replacement therapy, and hospital discharge destination. Of 260 ICU patients with COVID-19, 208 (80.0%) were men, the median age was 59 (IQR 51-65) years, 154 (59.2%) had at least one comorbidity, and the median duration of symptoms preceding ICU admission was 11 (IQR 8-14) days. Sixty-two (23.8%) patients remained in ICU at study end point. Among the 198 patients with definite outcomes, ICU length of stay was 12 (IQR, 6-18) days, 163 (82.3%) received mechanical ventilation, 28 (14.1%) received renal replacement therapy, 60 (30.3%) died, 62 (31.3%) were discharged home, 47 (23.7%) were discharged to ward, and 29 (14.6%) were discharged to another health care facility. On multivariable logistic regression analysis, older age and admission from the emergency department was associated with higher mortality. This study presents detailed data on clinical characteristics and early outcomes of consecutive patients with COVID-19 admitted to ICU in a large tertiary hospital in Sweden.
2020-09-06 Available on request
Soratto TAT, Darban H, Bjerkner A, Coorens M, Albert J, [...], Andersson B
Microbiol Resour Announc 9 (35)
10.1128/mra.00934-20
2020-08-27 ENA PRJEB39632: SARS-CoV-2 genomes from late April in Stockholm, Sweden
Rodriguez L, Pekkarinen PT, Lakshmikanth T, Tan Z, Consiglio CR, [...], Brodin P
Cell Rep Med 1 (5) 100078
10.1016/j.xcrm.2020.100078
Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.
2020-08-25
Maucourant C, Filipovic I, Ponzetta A, Aleman S, Cornillet M, [...], Karolinska COVID-19 Study Group
Sci Immunol 5 (50)
10.1126/sciimmunol.abd6832
Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56 bright NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease.
2020-08-21
Lindahl JF, Hoffman T, Esmaeilzadeh M, Olsen B, Winter R, [...], Lundkvist Å
Infect Ecol Epidemiol 10 (1) 1789036
10.1080/20008686.2020.1789036
The COVID-19 pandemic is growing and spread in the Swedish elderly care system during April 2020. The increasing number of employees on sick-leave due to COVID-19 created severe logistic problems. Some elderly care homes therefore started to screen their personnel to secure the safety of the elderly and to avoid unnecessary quarantine of potentially immune employees. Secondary data from a screening with a COVID-19 rapid test for detection of SARS-CoV-2-specific IgM and IgG of 1,005 employees in 22 elderly care homes in Stockholm, Sweden, were analyzed. Seropositive employees were found in 21 out of the 22 care homes. In total, 23% (231/1,005) of the employees tested positive for antibodies against SARS-CoV-2, and 14.3% (144/1,005) were found positive for IgM (either alone or combined with IgG), indicating recent or present infection. Of those that tested seropositive, 46.5% did not report any clinical symptoms, indicating pre- or asymptomatic infections. Reported symptoms with the highest correlation with seropositivity were fever and loss of smell and taste. These results suggest that antibody testing of employees in elderly care homes is valuable for surveillance of disease development and a crucial screening tool in the effort to decrease the death toll in this pandemic.
2020-08-05 Serological responses of 1,005 employees to SARS-CoV-2 at 22 different elderly care homes in Stockholm
Böhmer MM, Buchholz U, Corman VM, Hoch M, Katz K, [...], Zapf A
Lancet Infect Dis 20 (8) 920-928
10.1016/S1473-3099(20)30314-5
In December, 2019, the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, causing COVID-19, a respiratory disease presenting with fever, cough, and often pneumonia. WHO has set the strategic objective to interrupt spread of SARS-CoV-2 worldwide. An outbreak in Bavaria, Germany, starting at the end of January, 2020, provided the opportunity to study transmission events, incubation period, and secondary attack rates. A case was defined as a person with SARS-CoV-2 infection confirmed by RT-PCR. Case interviews were done to describe timing of onset and nature of symptoms and to identify and classify contacts as high risk (had cumulative face-to-face contact with a confirmed case for ≥15 min, direct contact with secretions or body fluids of a patient with confirmed COVID-19, or, in the case of health-care workers, had worked within 2 m of a patient with confirmed COVID-19 without personal protective equipment) or low risk (all other contacts). High-risk contacts were ordered to stay at home in quarantine for 14 days and were actively followed up and monitored for symptoms, and low-risk contacts were tested upon self-reporting of symptoms. We defined fever and cough as specific symptoms, and defined a prodromal phase as the presence of non-specific symptoms for at least 1 day before the onset of specific symptoms. Whole genome sequencing was used to confirm epidemiological links and clarify transmission events where contact histories were ambiguous; integration with epidemiological data enabled precise reconstruction of exposure events and incubation periods. Secondary attack rates were calculated as the number of cases divided by the number of contacts, using Fisher's exact test for the 95% CIs. Patient 0 was a Chinese resident who visited Germany for professional reasons. 16 subsequent cases, often with mild and non-specific symptoms, emerged in four transmission generations. Signature mutations in the viral genome occurred upon foundation of generation 2, as well as in one case pertaining to generation 4. The median incubation period was 4·0 days (IQR 2·3-4·3) and the median serial interval was 4·0 days (3·0-5·0). Transmission events were likely to have occurred presymptomatically for one case (possibly five more), at the day of symptom onset for four cases (possibly five more), and the remainder after the day of symptom onset or unknown. One or two cases resulted from contact with a case during the prodromal phase. Secondary attack rates were 75·0% (95% CI 19·0-99·0; three of four people) among members of a household cluster in common isolation, 10·0% (1·2-32·0; two of 20) among household contacts only together until isolation of the patient, and 5·1% (2·6-8·9; 11 of 217) among non-household, high-risk contacts. Although patients in our study presented with predominately mild, non-specific symptoms, infectiousness before or on the day of symptom onset was substantial. Additionally, the incubation period was often very short and false-negative tests occurred. These results suggest that although the outbreak was controlled, successful long-term and global containment of COVID-19 could be difficult to achieve. All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.
2020-08-00
Qiao XM, Xu XF, Zi H, Liu GX, Li BH, [...], Wang X
Front Med (Lausanne) 7 349
10.3389/fmed.2020.00349
Background: The frequent emergence of the re-positive patients with COVID-19 is a potential threat worldwide. This study aimed to describe data from admission to follow-up for patients with COVID-19 and analyze the possible causes for re-positive nucleic acid tests to provide more scientific basis for reducing the numbers of re-positive patients after discharge. Methods: We retrospectively recorded 15 patients with COVID-19 admitted to the Xianyang Central Hospital, China. The baseline, exposure histories, clinical syndromes, laboratory characteristics, nucleic acid, and follow-up tests were analyzed, and the radiological characteristics of re-positive patient at different periods were compared. Results: Eight (53.33%) patients had the history of travel to Wuhan, four (26.67%) patients had close contact with confirmed patients, and one (6.67%) patient had close contact with suspected patients. After treatment, all patients had two consecutively negative nucleic acid tests and were discharged from hospital. All patients were followed up for more than 14 days, and the average time from discharge to the first follow-up was 14.67 ± 3.31 days (from 9 to 22 days). Most patients showed no clinical symptoms and negative nucleic acid tests, while one patient had an itchy throat, her CT scan showed a light density shadow in the right lower lobe of the lung, and the nucleic acid was once again positive. The second follow-up of the other 14 patients (except the re-positive one) was conducted 20.80 ± 7.78 days (from 13 to 30 days) after discharge, and all of them had negative nucleic acid tests. The positive patient was immediately readmitted and received a new round of treatment. Her family members and colleagues remained healthy until now. Conclusions: The quality of nucleic acid testing reagents should be enhanced, and the training of nucleic acid sampling operators should be strengthened to reduce the false-negative results in the nucleic acid of SARS-CoV-2; the clinical specimens of throat and nasopharynx swabs can be collected at the same time; IgM- and IgG-specific antibodies of SARS-CoV-2 should be carried out for discharged patients; the radiological characteristics should be evaluated strictly; and the discharge standard can be specified according to the baseline and severity of disease of patients.
2020-06-23 All data provided in the article
Jia JS, Lu X, Yuan Y, Xu G, Jia J, [...], Christakis NA
Nature 582 (7812) 389-394
10.1038/s41586-020-2284-y
Sudden, large-scale and diffuse human migration can amplify localized outbreaks of disease into widespread epidemics 1-4. Rapid and accurate tracking of aggregate population flows may therefore be epidemiologically informative. Here we use 11,478,484 counts of mobile phone data from individuals leaving or transiting through the prefecture of Wuhan between 1 January and 24 January 2020 as they moved to 296 prefectures throughout mainland China. First, we document the efficacy of quarantine in ceasing movement. Second, we show that the distribution of population outflow from Wuhan accurately predicts the relative frequency and geographical distribution of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) until 19 February 2020, across mainland China. Third, we develop a spatio-temporal 'risk source' model that leverages population flow data (which operationalize the risk that emanates from epidemic epicentres) not only to forecast the distribution of confirmed cases, but also to identify regions that have a high risk of transmission at an early stage. Fourth, we use this risk source model to statistically derive the geographical spread of COVID-19 and the growth pattern based on the population outflow from Wuhan; the model yields a benchmark trend and an index for assessing the risk of community transmission of COVID-19 over time for different locations. This approach can be used by policy-makers in any nation with available data to make rapid and accurate risk assessments and to plan the allocation of limited resources ahead of ongoing outbreaks.
2020-06-00 Population outflow data from Wuhan from January 1-24, 2020; COVID-19 case counts as of February 19 and other data for 296 prefectures in mainland China
Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, [...], Penninger JM
Cell 181 (4) 905-913.e7
10.1016/j.cell.2020.04.004
We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
2020-05-14
Gao J, Liu JQ, Wen HJ, Liu H, Hu WD, [...], Wang XJ
Respir Res 21 (1) 96
10.1186/s12931-020-01363-7
The novel coronavirus disease (COVID-19) outbreak started in December 2019 in Wuhan, China, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The CT image is used to assess the disease progress, whereas the continued two times of negative results from SARS-CoV-2 nucleic acid detection had been considered as a criterion for ending antiviral treatment. We compared the two COVID-19 cases with similar backgrounds and CT image repeated intervals under treatment. Our report highlighted the unsynchronized expression in the changes of CT image and nucleic acid detection in COVID-19, and lasting positive nucleic acid test result in patients recovered from pneumonia. It may be contributed to recognize the disease and improve prevention.
2020-04-22 Provided in the article: CT images for 2 patients over 12 days