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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. Only projects which openly share data or analysis code that has re-use potential are included.

Last updated: 2022-05-08

Project Last updated Available data
Hammer Q, Dunst J, Christ W, Picarazzi F, Wendorff M, [...], Malmberg K
Cell Rep 110503
Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.
Luttens A, Gullberg H, Abdurakhmanov E, Vo DD, Akaberi D, [...], Carlsson J
J Am Chem Soc
Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.
Olofsson T, Vilhelmsson A
Data Brief 40 107698
The Swedish approach to managing the 2020-2021 COVID-19 pandemic has received significant attention in international scholarly work and press. For this dataset, we have reviewed governmental and media archives to build a detailed timeline that chronicles significant policies, interventions, and events in the Swedish management of COVID-19. The dataset contains summary descriptions of what took place, when it happened, and who the principal actors involved were. Links to primary sources are provided for each entry. Because of the level of detail and saturation, the dataset offers a detailed account of Swedish pandemic governance and will benefit anyone working on Swedish pandemic management or doing comparative work between Sweden and other jurisdictions.
Huffman JE, Butler-Laporte G, Khan A, Pairo-Castineira E, Drivas TG, [...], Zeberg H
Nat Genet
The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.
Hanke L, Das H, Sheward DJ, Perez Vidakovics L, Urgard E, [...], McInerney GM
Nat Commun 13 (1) 155
Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer-dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.
Kozielski F, Sele C, Talibov VO, Lou J, Dong D, [...], Knecht W
RSC Chem Biol 3 (1) 44-55
Since the emergence of SARS-CoV-2 in 2019, Covid-19 has developed into a serious threat to our health, social and economic systems. Although vaccines have been developed in a tour-de-force and are now increasingly available, repurposing of existing drugs has been less successful. There is a clear need to develop new drugs against SARS-CoV-2 that can also be used against future coronavirus infections. Non-structural protein 10 (nsp10) is a conserved stimulator of two enzymes crucial for viral replication, nsp14 and nsp16, exhibiting exoribonuclease and methyltransferase activities. Interfering with RNA proofreading or RNA cap formation represents intervention strategies to inhibit replication. We applied fragment-based screening using nano differential scanning fluorometry and X-ray crystallography to identify ligands targeting SARS-CoV-2 nsp10. We identified four fragments located in two distinct sites: one can be modelled to where it would be located in the nsp14-nsp10 complex interface and the other in the nsp16-nsp10 complex interface. Microscale thermophoresis (MST) experiments were used to quantify fragment affinities for nsp10. Additionally, we showed by MST that the interaction by nsp14 and 10 is weak and thereby that complex formation could be disrupted by small molecules. The fragments will serve as starting points for the development of more potent analogues using fragment growing techniques and structure-based drug design.
Wang J, Dalla Barba F, Roccon A, Sardina G, Soldati A, [...], Picano F
J R Soc Interface 19 (186) 20210819
The outbreak of the COVID-19 pandemic highlighted the importance of accurately modelling the pathogen transmission via droplets and aerosols emitted while speaking, coughing and sneezing. In this work, we present an effective model for assessing the direct contagion risk associated with these pathogen-laden droplets. In particular, using the most recent studies on multi-phase flow physics, we develop an effective yet simple framework capable of predicting the infection risk associated with different respiratory activities in different ambient conditions. We start by describing the mathematical framework and benchmarking the model predictions against well-assessed literature results. Then, we provide a systematic assessment of the effects of physical distancing and face coverings on the direct infection risk. The present results indicate that the risk of infection is vastly impacted by the ambient conditions and the type of respiratory activity, suggesting the non-existence of a universal safe distance. Meanwhile, wearing face masks provides excellent protection, effectively limiting the transmission of pathogens even at short physical distances, i.e. 1 m.
Ehling RA, Weber CR, Mason DM, Friedensohn S, Wagner B, [...], Reddy ST
Cell Rep 110242
Characterization of COVID-19 antibodies has largely focused on memory B cells; however, it is the antibody-secreting plasma cells that are directly responsible for the production of serum antibodies, which play a critical role in resolving SARS-CoV-2 infection. Little is known about the specificity of plasma cells, largely because plasma cells lack surface antibody expression, thereby complicating their screening. Here, we describe a technology pipeline that integrates single-cell antibody repertoire sequencing and mammalian display to interrogate the specificity of plasma cells from 16 convalescent patients. Single-cell sequencing allows us to profile antibody repertoire features and identify expanded clonal lineages. Mammalian display screening is used to reveal that 43 antibodies (of 132 candidates) derived from expanded plasma cell lineages are specific to SARS-CoV-2 antigens, including antibodies with high affinity to the SARS-CoV-2 receptor-binding domain (RBD) that exhibit potent neutralization and broad binding to the RBD of SARS-CoV-2 variants (of concern/interest).
Capraz T, Kienzl NF, Laurent E, Perthold JW, Föderl-Höbenreich E, [...], Stadlmann J
Elife 10
Infection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently undergoing clinical tests for the treatment of COVID-19. We used 3D structural models and molecular dynamics simulations to define the ACE2 N-glycans that critically influence Spike-ACE2 complex formation. Engineering of ACE2 N-glycosylation by site-directed mutagenesis or glycosidase treatment resulted in enhanced binding affinities and improved virus neutralization without notable deleterious effects on the structural stability and catalytic activity of the protein. Importantly, simultaneous removal of all accessible N-glycans from recombinant soluble human ACE2 yields a superior SARS-CoV-2 decoy receptor with promise as effective treatment for COVID-19 patients.
Pimenoff VN, Elfström M, Conneryd Lundgren K, Klevebro S, Melen E, [...], Dillner J
PLoS One 16 (12) e0260453
A majority of SARS-CoV-2 infections are transmitted from a minority of infected subjects, some of which may be symptomatic or pre-symptomatic. We aimed to quantify potential infectiousness among asymptomatic healthcare workers (HCWs) in relation to prior or later symptomatic disease. We previously (at the onset of the SARS-CoV-2 epidemic) performed a cohort study of SARS-CoV-2 infections among 27,000 healthcare workers (HCWs) at work in the capital region of Sweden. We performed both SARS-CoV-2 RT-PCR and serology. Furthermore, the cohort was comprehensively followed for sick leave, both before and after sampling. In the present report, we used the cohort database to quantify potential infectiousness among HCWs at work. Those who had sick leave either before or after sampling were classified as post-symptomatic or pre-symptomatic, whereas the virus-positive subjects with no sick leave were considered asymptomatic. About 0.2% (19/9449) of HCW at work were potentially infectious and pre-symptomatic (later had disease) and 0.17% (16/9449) were potentially infectious and asymptomatic (never had sick leave either before nor after sampling). Thus, 33% and 28% of all the 57 potentially infectious subjects were pre-symptomatic or asymptomatic, respectively. When a questionnaire was administered to HCWs with past infection, only 10,5% of HCWs had had no indication at all of having had SARS-CoV-2 infection ("truly asymptomatic"). Our findings provide a unique quantification of the different groups of asymptomatic, potentially infectious HCWs.
Rahman M, Irmler M, Keshavan S, Introna M, Beckers J, [...], Upadhyay S
Viruses 13 (12)
The SARS-CoV-2 spike protein mediates attachment of the virus to the host cell receptor and fusion between the virus and the cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection, and constitutes the viral component of mRNA-based COVID-19 vaccines. Therefore, in this work we assessed the effect of exposure (24 h) to 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n = 6 per exposure condition). Corresponding sham exposed samples served as a control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes (NCI-H441). Exposure to S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p ≤ 0.01). Pathway analysis revealed enrichment of canonical pathways such as interferon (IFN) signaling, influenza, coronavirus, and anti-viral response in the bro-ALI. Secreted levels of interleukin (IL) 4 and IL12 were significantly (p < 0.05) increased, whereas IL6 decreased in the bro-ALI. In the case of alv-ALI, enriched terms involving p53, APRIL (a proliferation-inducing ligand) tight junction, integrin kinase, and IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p < 0.05) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL13, and tumor necrosis factor alpha were detected in alv-ALI, whereas IL12 was decreased. Altered levels of these cytokines are also associated with lung fibrotic response. In conclusion, we observed a typical anti-viral response in the bronchial model and a pro-fibrotic response in the alveolar model. The bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of SARS-CoV-2 variants of concern at different lung regions.
Rosén J, Noreland M, Stattin K, Lipcsey M, Frithiof R, [...], Uppsala Intensive Care COVID-19 Research Group
PLoS One 16 (12) e0261315
We investigated the prevalence of ECG abnormalities and their association with mortality, organ dysfunction and cardiac biomarkers in a cohort of COVID-19 patients admitted to the intensive care unit (ICU). This cohort study included patients with COVID-19 admitted to the ICU of a tertiary hospital in Sweden. ECG, clinical data and laboratory findings during ICU stay were extracted from medical records and ECGs obtained near ICU admission were reviewed by two independent physicians. Eighty patients had an acceptable ECG near ICU-admission. In the entire cohort 30-day mortality was 28%. Compared to patients with normal ECG, among whom 30-day mortality was 16%, patients with ECG fulfilling criteria for prior myocardial infarction had higher mortality, 63%, odds ratio (OR) 9.61 (95% confidence interval (CI) 2.02-55.6) adjusted for Simplified Acute Physiology Score 3 and patients with ST-T abnormalities had 50% mortality and OR 6.05 (95% CI 1.82-21.3) in univariable analysis. Both prior myocardial infarction pattern and ST-T pathology were associated with need for vasoactive treatment and higher peak plasma levels of troponin-I, NT-pro-BNP (N-terminal pro-Brain Natriuretic Peptide), and lactate during ICU stay compared to patients with normal ECG. ECG with prior myocardial infarction pattern or acute ST-T pathology at ICU admission is associated with death, need for vasoactive treatment and higher levels of biomarkers of cardiac damage and strain in severely ill COVID-19 patients, and should alert clinicians to a poor prognosis.
Agback T, Dominguez F, Frolov I, Frolova EI, Agback P
PLoS One 16 (12) e0251834
Structural characterization of the SARS-CoV-2 full length nsp1 protein will be an essential tool for developing new target-directed antiviral drugs against SARS-CoV-2 and for further understanding of intra- and intermolecular interactions of this protein. As a first step in the NMR studies of the protein, we report the 1H, 13C and 15N resonance backbone assignment as well as the Cβ of the apo form of the full-lengthSARS-CoV-2 nsp1 including the folded domain together with the flaking N- and C- terminal intrinsically disordered fragments. The 19.8 kD protein was characterized by high-resolution NMR. Validation of assignment have been done by using two different mutants, H81P and K129E/D48E as well as by amino acid specific experiments. According to the obtained assignment, the secondary structure of the folded domain in solution was almost identical to its previously published X-ray structure as well as another published secondary structure obtained by NMR, but some discrepancies have been detected. In the solution SARS-CoV-2 nsp1 exhibited disordered, flexible N- and C-termini with different dynamic characteristics. The short peptide in the beginning of the disordered C-terminal domain adopted two different conformations distinguishable on the NMR time scale. We propose that the disordered and folded nsp1 domains are not fully independent units but are rather involved in intramolecular interactions. Studies of the structure and dynamics of the SARS-CoV-2 mutant in solution are on-going and will provide important insights into the molecular mechanisms underlying these interactions.
Nakanishi T, Pigazzini S, Degenhardt F, Cordioli M, Butler-Laporte G, [...], Ganna A
J Clin Invest 131 (23)
Abstract Background There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality—and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.
2021-12-01 Procedures for accessing data can be found here (data cannot be publicly shared)
Roxhed N, Bendes A, Dale M, Mattsson C, Hanke L, [...], Schwenk JM
Nat Commun 12 (1)
2021-12-00 Analysis code (in R)
Axfors C, Schmitt AM, Janiaud P, van’t Hooft J, Abd-Elsalam S, [...], Hemkens LG
Nat Commun 12 (1) 2349
Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: ). We systematically identified unpublished RCTs (, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
2021-12-00 Coded data from each included study and data analysis code
Perez-Valera M, Martinez-Canton M, Gallego-Selles A, Galván-Alvarez V, Gelabert-Rebato M, [...], Calbet JAL
Scand J Med Sci Sports 31 (12) 2249-2258
The study aimed to determine the levels of skeletal muscle angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) protein expression in men and women and assess whether ACE2 expression in skeletal muscle is associated with cardiorespiratory fitness and adiposity. The level of ACE2 in vastus lateralis muscle biopsies collected in previous studies from 170 men (age: 19-65 years, weight: 56-137 kg, BMI: 23-44) and 69 women (age: 18-55 years, weight: 41-126 kg, BMI: 22-39) was analyzed in duplicate by western blot. VO2 max was determined by ergospirometry and body composition by DXA. ACE2 protein expression was 1.8-fold higher in women than men (p = 0.001, n = 239). This sex difference disappeared after accounting for the percentage of body fat (fat %), VO2 max per kg of legs lean mass (VO2 max-LLM) and age (p = 0.47). Multiple regression analysis showed that the fat % (β = 0.47) is the main predictor of the variability in ACE2 protein expression in skeletal muscle, explaining 5.2% of the variance. VO2 max-LLM had also predictive value (β = 0.09). There was a significant fat % by VO2 max-LLM interaction, such that for subjects with low fat %, VO2 max-LLM was positively associated with ACE2 expression while as fat % increased the slope of the positive association between VO2 max-LLM and ACE2 was reduced. In conclusion, women express higher amounts of ACE2 in their skeletal muscles than men. This sexual dimorphism is mainly explained by sex differences in fat % and cardiorespiratory fitness. The percentage of body fat is the main predictor of the variability in ACE2 protein expression in human skeletal muscle.
2021-12-00 De-identified participant data can be requested from the senior author, but data cannot be publicly shared
Cornillet M, Strunz B, Rooyackers O, Ponzetta A, Chen P, [...], Björkström NK
Eur J Immunol
Corona disease 2019 (COVID-19) affects multiple organ systems. Recent studies have indicated perturbations in the circulating metabolome linked to COVID-19 severity. However, several questions pertain with respect to the metabolome in COVID-19. We performed an in-depth assessment of 1129 unique metabolites in 27 hospitalized COVID-19 patients and integrated results with large-scale proteomic and immunology data to capture multiorgan system perturbations. More than half of the detected metabolic alterations in COVID-19 were driven by patient-specific confounding factors ranging from comorbidities to xenobiotic substances. Systematically adjusting for this, a COVID-19-specific metabolic imprint was defined which, over time, underwent a switch in response to severe acute respiratory syndrome coronavirus-2 seroconversion. Integration of the COVID-19 metabolome with clinical, cellular, molecular, and immunological severity scales further revealed a network of metabolic trajectories aligned with multiple pathways for immune activation, and organ damage including neurological inflammation and damage. Altogether, this resource refines our understanding of the multiorgan system perturbations in severe COVID-19 patients.
Murray B, Kerfoot E, Chen L, Deng J, Graham MS, [...], Ourselin S
Sci Data 8 (1) 297
The Covid Symptom Study, a smartphone-based surveillance study on COVID-19 symptoms in the population, is an exemplar of big data citizen science. As of May 23rd, 2021, over 5 million participants have collectively logged over 360 million self-assessment reports since its introduction in March 2020. The success of the Covid Symptom Study creates significant technical challenges around effective data curation. The primary issue is scale. The size of the dataset means that it can no longer be readily processed using standard Python-based data analytics software such as Pandas on commodity hardware. Alternative technologies exist but carry a higher technical complexity and are less accessible to many researchers. We present ExeTera, a Python-based open source software package designed to provide Pandas-like data analytics on datasets that approach terabyte scales. We present its design and capabilities, and show how it is a critical component of a data curation pipeline that enables reproducible research across an international research group for the Covid Symptom Study.
Axfors C, Janiaud P, Schmitt AM, Van't Hooft J, Smith ER, [...], Hemkens LG
Infect Dis . 2020 Dec 10;20(1):942. 21 (1) 1170
Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). In this collaborative systematic review and meta-analysis, clinical trial registries (, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
Sheward DJ, Mandolesi M, Urgard E, Kim C, Hanke L, [...], Murrell B
Cell Rep Med 2 (11) 100450
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with resistance to neutralizing antibodies are threatening to undermine vaccine efficacy. Vaccination and infection have led to widespread humoral immunity against the pandemic founder (Wu-Hu-1). Against this background, it is critical to assess the outcomes of subsequent immunization with variant antigens. It is not yet clear whether heterotypic boosts would be compromised by original antigenic sin, where pre-existing responses to a prior variant dampen responses to a new one, or whether the memory B cell repertoire would bridge the gap between Wu-Hu-1 and VOCs. We show, in macaques immunized with Wu-Hu-1 spike, that a single dose of adjuvanted beta variant receptor binding domain (RBD) protein broadens neutralizing antibody responses to heterologous VOCs. Passive transfer of plasma sampled after Wu-Hu-1 spike immunization only partially protects K18-hACE2 mice from lethal challenge with a beta variant isolate, whereas plasma sampled following heterotypic RBD boost protects completely against disease.
2021-11-16 Code used for analyses
Hober A, Tran-Minh KH, Foley D, McDonald T, Vissers JP, [...], Edfors F
Elife 10
Reliable, robust, large-scale molecular testing for SARS-CoV-2 is essential for monitoring the ongoing Covid-19 pandemic. We have developed a scalable analytical approach to detect viral proteins based on peptide immunoaffinity enrichment combined with liquid chromatography - mass spectrometry (LC-MS). This is a multiplexed strategy, based on targeted proteomics analysis and read-out by LC-MS, capable of precisely quantifying and confirming the presence of SARS-CoV-2 in PBS swab media from combined throat/nasopharynx/saliva samples.<br />The results reveal that the levels of SARS-CoV-2 measured by LC-MS correlate well with their corresponding RT-PCR readout (r=0.79). The analytical workflow shows similar turnaround times as regular RT-PCR instrumentation with a quantitative readout of viral proteins corresponding to cycle thresholds (Ct) equivalents ranging from 21 to 34. Using RT-PCR as a reference, we demonstrate that the LC-MS-based method has 100% negative percent agreement (estimated specificity) and 95% positive percent agreement (estimated sensitivity) when analyzing clinical samples collected from asymptomatic individuals with a Ct within the limit of detection of the mass spectrometer (Ct ≤30). These results suggest that a scalable analytical method based on LC-MS has a place in future pandemic preparedness centers to complement current virus detection technologies.
Bocci M, Oudenaarden C, Sàenz-Sardà X, Simrén J, Edén A, [...], Pietras K
Int J Mol Sci 22 (21)
A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.
2021-10-27 Supplementary materials
Carapito R, Li R, Helms J, Carapito C, Gujja S, [...], Bahram S
Sci. Transl. Med. eabj7521
[Figure: see text].
Deutsch EW, Omenn GS, Sun Z, Maes M, Pernemalm M, [...], Schwenk JM
J. Proteome Res.
The study of proteins circulating in blood offers tremendous opportunities to diagnose, stratify, or possibly prevent diseases. With recent technological advances and the urgent need to understand the effects of COVID-19, the proteomic analysis of blood-derived serum and plasma has become even more important for studying human biology and pathophysiology. Here we provide views and perspectives about technological developments and possible clinical applications that use mass-spectrometry(MS)- or affinity-based methods. We discuss examples where plasma proteomics contributed valuable insights into SARS-CoV-2 infections, aging, and hemostasis and the opportunities offered by combining proteomics with genetic data. As a contribution to the Human Proteome Organization (HUPO) Human Plasma Proteome Project (HPPP), we present the Human Plasma PeptideAtlas build 2021-07 that comprises 4395 canonical and 1482 additional nonredundant human proteins detected in 240 MS-based experiments. In addition, we report the new Human Extracellular Vesicle PeptideAtlas 2021-06, which comprises five studies and 2757 canonical proteins detected in extracellular vesicles circulating in blood, of which 74% (2047) are in common with the plasma PeptideAtlas. Our overview summarizes the recent advances, impactful applications, and ongoing challenges for translating plasma proteomics into utility for precision medicine.
2021-10-21 Union of proteins in both the plasma and blood extracellular vesicle PeptideAtlas builds, along with the crudely estimated log10 abundances and functional annotations
Rivero-García I, Castresana-Aguirre M, Guglielmo L, Guala D, Sonnhammer ELL
Sci Rep 11 (1) 20687
This analysis presents a systematic evaluation of the extent of therapeutic opportunities that can be obtained from drug repurposing by connecting drug targets with disease genes. When using FDA-approved indications as a reference level we found that drug repurposing can offer an average of an 11-fold increase in disease coverage, with the maximum number of diseases covered per drug being increased from 134 to 167 after extending the drug targets with their high confidence first neighbors. Additionally, by network analysis to connect drugs to disease modules we found that drugs on average target 4 disease modules, yet the similarity between disease modules targeted by the same drug is generally low and the maximum number of disease modules targeted per drug increases from 158 to 229 when drug targets are neighbor-extended. Moreover, our results highlight that drug repurposing is more dependent on target proteins being shared between diseases than on polypharmacological properties of drugs. We apply our drug repurposing and network module analysis to COVID-19 and show that Fostamatinib is the drug with the highest module coverage.
2021-10-19 Code, raw data, analysis results, and figures are all available in bitbucket
Martin S, Heslan C, Jégou G, Eriksson LA, Le Gallo M, [...], Avril T
iScience 103185
SARS-CoV-2 pandemic has elicited a unique mobilization of the scientific community to develop efficient tools to understand and combat infection. Like other coronavirae, SARS-CoV-2 hijacks host cell secretory machinery to produce viral proteins that compose the nascent virions; including Spike (S), Envelope (E) and Membrane (M) proteins, the most exposed transmembrane proteins to the host immune system. As antibody response is part of the anti-viral immune arsenal, we investigate the immunogenic potential of S, E and M using a human cell-based system to mimic membrane insertion and N-glycosylation. Both S and M elicit specific Ig production in SARS-CoV-2 patients. Patients with moderate and severe diseases exhibit elevated Ig responses. Finally, reduced Ig binding was observed with Spike G614 compared to D614 variant. Altogether, our assay points towards an unexpected immune response against M and represents a powerful tool to test humoral responses against actively evolving SARS-CoV-2 variants and vaccine effectiveness.
2021-09-29 clinical and raw data related to serological assay
Das J, Idh N, Sikkeland LIB, Paues J, Lerm M
Epigenetics 1-12
Flow cytometry is a classical approach used to define cell types in peripheral blood. While DNA methylation signatures have been extensively employed in recent years as an alternative to flow cytometry to define cell populations in peripheral blood, this approach has not been tested in lung-derived samples. Here, we compared bronchoalveolar lavage with a more cost-effective and less invasive technique based on sputum induction and developed a DNA methylome-based algorithm that can be used to deconvolute the cell types in such samples. We analysed the DNA methylome profiles of alveolar macrophages and lymphocytes cells isolated from the pulmonary compartment. The cells were isolated using two different methods, sputum induction and bronchoalveolar lavage. A strong positive correlation between the DNA methylome profiles of cells obtained with the two isolation methods was found. We observed the best correlation of the DNA methylomes when both isolation methods captured cells from the lower parts of the lungs. We also identified unique patterns of CpG methylation in DNA obtained from the two cell populations, which can be used as a signature to discriminate between the alveolar macrophages and lymphocytes by means of open-source algorithms. We validated our findings with external data and obtained results consistent with the previous findings. Our analysis opens up a new possibility to identify different cell populations from lung samples and promotes sputum induction as a tool to study immune cell populations from the lung.
2021-09-05 R scripts to analyze the Alveolar macrophages (HLA-DR+/CD3-) and lymphocytes (CD3+) specific cell types from DNA methylation analysis
Martin DP, Weaver S, Tegally H, San JE, Shank SD, [...], Kosakovsky Pond SL
The independent emergence late in 2020 of the B.1.1.7, B.1.351, and P.1 lineages of SARS-CoV-2 prompted renewed concerns about the evolutionary capacity of this virus to overcome public health interventions and rising population immunity. Here, by examining patterns of synonymous and non-synonymous mutations that have accumulated in SARS-CoV-2 genomes since the pandemic began, we find that the emergence of these three "501Y lineages" coincided with a major global shift in the selective forces acting on various SARS-CoV-2 genes. Following their emergence, the adaptive evolution of 501Y lineage viruses has involved repeated selectively favored convergent mutations at 35 genome sites, mutations we refer to as the 501Y meta-signature. The ongoing convergence of viruses in many other lineages on this meta-signature suggests that it includes multiple mutation combinations capable of promoting the persistence of diverse SARS-CoV-2 lineages in the face of mounting host immune recognition.
Beukes EW, Andersson G, Fagelson MA, Manchaiah V
Internet Interv 25 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
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.
Mäkelä P, Rossow I, Moan IS, Bye EK, Kilian C, [...], Allebeck P
Int J Methods Psychiatr Res e1892
To examine (1) how a rapid data collection using a convenience sample fares in estimating change in alcohol consumption when compared to more conventional data sources, and (2) how alcohol consumption changed in Finland and Norway during the first months of the COVID-19 pandemic. Three different types of data sources were used for the 2nd quarter of 2020 and 2019: sales statistics combined with data on unrecorded consumption; the rapid European Alcohol Use and COVID-19 (ESAC) survey (Finland: n = 3800, Norway: n = 17,092); and conventional population surveys (Finland: n = 2345, Norway: n1 = 1328, n2 = 2189, n3 = 25,708). Survey measures of change were retrospective self-reports. The statistics indicate that alcohol consumption decreased in Finland by 9%, while little change was observed in Norway. In all surveys, reporting a decrease in alcohol use was more common than reporting an increase (ratios 2-2.6 in Finland, 1.3-2 in Norway). Compared to conventional surveys, in the ESAC survey fewer respondents reported no change and past-year alcohol consumption was higher. The rapid survey using convenience sampling gave similar results on change in drinking as conventional surveys but higher past-year drinking, suggesting self-selection effects. Aspects of the pandemic driving alcohol consumption down were equally strong or stronger than those driving it up.
2021-08-27 Database with codebook for the European Alcohol Use and COVID-19 Survey (figshare entry)
Hoffmann D, Mereiter S, Jin Oh Y, Monteil V, Elder E, [...], Penninger JM
EMBO J e108375
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
Kerr JR, Schneider CR, Recchia G, Dryhurst S, Sahlin U, [...], van der Linden S
BMJ Open 11 (8) e048025
Describe demographical, social and psychological correlates of willingness to receive a COVID-19 vaccine. Series of online surveys undertaken between March and October 2020. A total of 25 separate national samples (matched to country population by age and sex) in 12 different countries were recruited through online panel providers (n=25 334). Reported willingness to receive a COVID-19 vaccination. Reported willingness to receive a vaccine varied widely across samples, ranging from 63% to 88%. Multivariate logistic regression analyses reveal sex (female OR=0.59, 95% CI 0.55 to 0.64), trust in medical and scientific experts (OR=1.28, 95% CI 1.22 to 1.34) and worry about the COVID-19 virus (OR=1.47, 95% CI 1.41 to 1.53) as the strongest correlates of stated vaccine acceptance considering pooled data and the most consistent correlates across countries. In a subset of UK samples, we show that these effects are robust after controlling for attitudes towards vaccination in general. Our results indicate that the burden of trust largely rests on the shoulders of the scientific and medical community, with implications for how future COVID-19 vaccination information should be communicated to maximise uptake.
Rietdijk J, Tampere M, Pettke A, Georgiev P, Lapins M, [...], Carreras-Puigvert J
BMC Biol 19 (1) 156
The emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the discovery of antiviral drugs, the majority tend to focus on the effects of such drugs on a given virus, its constituent proteins, or enzymatic activity, often neglecting the consequences on host cells. This may lead to partial assessment of the efficacy of the tested anti-viral compounds, as potential toxicity impacting the overall physiology of host cells may mask the effects of both viral infection and drug candidates. Here we present a method able to assess the general health of host cells based on morphological profiling, for untargeted phenotypic drug screening against viral infections. We combine Cell Painting with antibody-based detection of viral infection in a single assay. We designed an image analysis pipeline for segmentation and classification of virus-infected and non-infected cells, followed by extraction of morphological properties. We show that this methodology can successfully capture virus-induced phenotypic signatures of MRC-5 human lung fibroblasts infected with human coronavirus 229E (CoV-229E). Moreover, we demonstrate that our method can be used in phenotypic drug screening using a panel of nine host- and virus-targeting antivirals. Treatment with effective antiviral compounds reversed the morphological profile of the host cells towards a non-infected state. The phenomics approach presented here, which makes use of a modified Cell Painting protocol by incorporating an anti-virus antibody stain, can be used for the unbiased morphological profiling of virus infection on host cells. The method can identify antiviral reference compounds, as well as novel antivirals, demonstrating its suitability to be implemented as a strategy for antiviral drug repurposing and drug discovery.
Wang K, Goldenberg A, Dorison CA, Miller JK, Uusberg A, [...], Moshontz H
Nat Hum Behav 5 (8) 1089-1110
The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 12 May 2020. The protocol, as accepted by the journal, can be found at
2021-08-00 Raw data, processed data and code
Manica M, Guzzetta G, Riccardo F, Valenti A, Poletti P, [...], Merler S
Nat Commun 12 (1) 4570
To counter the second COVID-19 wave in autumn 2020, the Italian government introduced a system of physical distancing measures organized in progressively restrictive tiers (coded as yellow, orange, and red) imposed on a regional basis according to real-time epidemiological risk assessments. We leverage the data from the Italian COVID-19 integrated surveillance system and publicly available mobility data to evaluate the impact of the three-tiered regional restriction system on human activities, SARS-CoV-2 transmissibility and hospitalization burden in Italy. The individuals' attendance to locations outside the residential settings was progressively reduced with tiers, but less than during the national lockdown against the first COVID-19 wave in the spring. The reproduction number R(t) decreased below the epidemic threshold in 85 out of 107 provinces after the introduction of the tier system, reaching average values of about 0.95-1.02 in the yellow tier, 0.80-0.93 in the orange tier and 0.74-0.83 in the red tier. We estimate that the reduced transmissibility resulted in averting about 36% of the hospitalizations between November 6 and November 25, 2020. These results are instrumental to inform public health efforts aimed at preventing future resurgence of cases.
2021-07-27 Mobility and epidemiological data
Ringlander J, Olausson J, Nyström K, Härnqvist T, Jakobsson HE, [...], Lindh M
Infect Dis (Lond) 1-8
Reinfections with SARS-CoV-2 have been reported and most cases were classified as mild. Reports of persistent infection with SARS-CoV-2 are rare. To investigate the frequency of recurrent and persistent infection with SARS-CoV-2. Possible cases of reinfection and persistent infection were retrospectively identified in a database of 59,998 patients. Deep sequencing of SARS-CoV-2 genomes was performed. We report the first case of COVID-19 reinfection in Sweden and three cases of infection with persistence over several months. The rate of sequencing-verified reinfection was 0.02% (one patient out of 6014 patients testing positive during the period). The reinfected patient had mild symptoms during the second episode, which might reflect partial immunity. The frequency of reinfection during the first wave of the pandemic in western Sweden was very low. Our results indicate that elderly with a putative reinfection more likely have persistent COVID-19.
2021-07-24 Nucleotide differences between the first infection and second infection strains from one patient with reinfection
Fyles M, Fearon E, Overton C, University of Manchester COVID-19 Modelling Group , Wingfield T, [...], House T
Philos Trans R Soc Lond B Biol Sci 376 (1829) 20200267
We explore strategies of contact tracing, case isolation and quarantine of exposed contacts to control the SARS-CoV-2 epidemic using a branching process model with household structure. This structure reflects higher transmission risks among household members than among non-household members. We explore strategic implementation choices that make use of household structure, and investigate strategies including two-step tracing, backwards tracing, smartphone tracing and tracing upon symptom report rather than test results. The primary model outcome is the effect of contact tracing, in combination with different levels of physical distancing, on the growth rate of the epidemic. Furthermore, we investigate epidemic extinction times to indicate the time period over which interventions must be sustained. We consider effects of non-uptake of isolation/quarantine, non-adherence, and declining recall of contacts over time. Our results find that, compared to self-isolation of cases without contact tracing, a contact tracing strategy designed to take advantage of household structure allows for some relaxation of physical distancing measures but cannot completely control the epidemic absent of other measures. Even assuming no imported cases and sustainment of moderate physical distancing, testing and tracing efforts, the time to bring the epidemic to extinction could be in the order of months to years. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.
2021-07-19 Data and code
Solís Arce JS, Warren SS, Meriggi NF, Scacco A, McMurry N, [...], Omer SB
Nat Med
Widespread acceptance of COVID-19 vaccines is crucial for achieving sufficient immunization coverage to end the global pandemic, yet few studies have investigated COVID-19 vaccination attitudes in lower-income countries, where large-scale vaccination is just beginning. We analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, including a total of 44,260 individuals. We find considerably higher willingness to take a COVID-19 vaccine in our LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). Vaccine acceptance in LMICs is primarily explained by an interest in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy. Health workers are the most trusted sources of guidance about COVID-19 vaccines. Evidence from this sample of LMICs suggests that prioritizing vaccine distribution to the Global South should yield high returns in advancing global immunization coverage. Vaccination campaigns should focus on translating the high levels of stated acceptance into actual uptake. Messages highlighting vaccine efficacy and safety, delivered by healthcare workers, could be effective for addressing any remaining hesitancy in the analyzed LMICs.
2021-07-16 Individual participant data (de-identified), analytic code and replication file
Recalde M, Roel E, Pistillo A, Sena AG, Prats-Uribe A, [...], Duarte-Salles T
Int J Obes (Lond)
A detailed characterization of patients with COVID-19 living with obesity has not yet been undertaken. We aimed to describe and compare the demographics, medical conditions, and outcomes of COVID-19 patients living with obesity (PLWO) to those of patients living without obesity. We conducted a cohort study based on outpatient/inpatient care and claims data from January to June 2020 from Spain, the UK, and the US. We used six databases standardized to the OMOP common data model. We defined two non-mutually exclusive cohorts of patients diagnosed and/or hospitalized with COVID-19; patients were followed from index date to 30 days or death. We report the frequency of demographics, prior medical conditions, and 30-days outcomes (hospitalization, events, and death) by obesity status. We included 627 044 (Spain: 122 058, UK: 2336, and US: 502 650) diagnosed and 160 013 (Spain: 18 197, US: 141 816) hospitalized patients with COVID-19. The prevalence of obesity was higher among patients hospitalized (39.9%, 95%CI: 39.8-40.0) than among those diagnosed with COVID-19 (33.1%; 95%CI: 33.0-33.2). In both cohorts, PLWO were more often female. Hospitalized PLWO were younger than patients without obesity. Overall, COVID-19 PLWO were more likely to have prior medical conditions, present with cardiovascular and respiratory events during hospitalization, or require intensive services compared to COVID-19 patients without obesity. We show that PLWO differ from patients without obesity in a wide range of medical conditions and present with more severe forms of COVID-19, with higher hospitalization rates and intensive services requirements. These findings can help guiding preventive strategies of COVID-19 infection and complications and generating hypotheses for causal inference studies.
2021-07-15 Analytic code
Millroth P, Frey R
J Anxiety Disord 83 102454
In the face of the COVID-19 pandemic it is important to identify factors that make people particularly vulnerable of developing mental-health issues in order to provide case-specific treatments. In this article, we examine the roles of two psychological constructs - originally put forth in the behavioral decision sciences - in predicting interindividual differences in fear responses: general risk aversion (GRA) and intolerance of uncertainty (IU). We first provide a review of these constructs and illustrate why they may play important roles in shaping anxiety-related disorders. Thereafter we present an empirical study that collected survey data from 550 U.S. residents, comprising self-assessments of dispositions towards risk and uncertainty, anxiety- and depression levels, as well as demographic variables - to thus test the extent to which these psychological constructs are predictive of strong fear responses related to COVID-19 (i.e., mortal fear, racing heart). The results from Bayesian multi-model inference analyses showed that GRA and IU were more powerful predictors of fear responses than demographic variables. Moreover, the predictive power of these constructs was independent of general anxiety- and depression levels. Subsequent mediation analyses showed that the effects of GRA and IU were both direct and indirect via anxiety. We conclude by discussing possible treatment options, but also highlight that future research needs to further examine causal pathways and conceptual overlaps.
2021-07-14 Survey data
Rück C, Mataix-Cols D, Malki K, Adler M, Flygare O, [...], Sidorchuk A
BMJ Open 11 (7) e049302
There is concern that the COVID-19 pandemic will be associated with an increase in suicides, but evidence supporting a link between pandemics and suicide is limited. Using data from the three influenza pandemics of the 20th century, we aimed to investigate whether an association exists between influenza deaths and suicide deaths. Time series analysis. Sweden. Deaths from influenza and suicides extracted from the Statistical Yearbook of Sweden for 1910-1978, covering three pandemics (the Spanish influenza, the Asian influenza and the Hong Kong influenza). Annual suicide rates in Sweden among the whole population, men and women. Non-linear autoregressive distributed lag models was implemented to explore if there is a short-term and/or long-term relationship of increases and decreases in influenza death rates with suicide rates during 1910-1978. Between 1910 and 1978, there was no evidence of either short-term or long-term significant associations between influenza death rates and changes in suicides (β coefficients of 0.00002, p=0.931 and β=0.00103, p=0.764 for short-term relationship of increases and decreases in influenza death rates, respectively, with suicide rates, and β=-0.0002, p=0.998 and β=0.00211, p=0.962 for long-term relationship of increases and decreases in influenza death rates, respectively, with suicide rates). The same pattern emerged in separate analyses for men and women. We found no evidence of short-term or long-term association between influenza death rates and suicide death rates across three 20th century pandemics.
2021-07-07 Numbers of deaths by influenza and suicide and total population for 1910-1978
Razzaq M, Iglesias MJ, Ibrahim-Kosta M, Goumidi L, Soukarieh O, [...], Trégouët D
Sci Rep 11 (1) 14015
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.
Sandberg JT, Varnaitė R, Christ W, Chen P, Muvva JR, [...], Karolinska COVID‐19 Study Group
Clin Transl Immunol 10 (7) e1306
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)
Meili KW, Jonsson H, Lindholm L, Månsdotter A
Scand J Public Health 14034948211023633
Measures against COVID-19 potentially impact quality of life in different ways. The capability approach by Amartya Sen with a broad and consistent framework for measuring quality of life is suited to capture the various consequences. We aimed to examine (a) whether individuals experienced change in 10 capability dimensions during the first half of 2020, (b) which dimensions were affected most, and (c) whether changes were unequally distributed in terms of gender, education, income, geography, housing, living situation and place of birth. We assessed self-reported capability change in Sweden in 10 capability dimensions in a cross-sectional online survey among 500 participants on a five-item Likert scale. We analysed the distribution of answers by comparing the balance of positive and negative perceived changes and used mixed effects logistic regression to examine associations with background characteristics of the participants. Reported perceived negative changes outweighed positive changes, and a higher proportion stated negative perceived changes if they also stated having low capability in the same dimension. In the capabilities of financial situation, political resources and health, the proportions of perceived negative change were highest. Odds for perceived negative change compared to no or positive change were higher for higher incomes, living in medium-sized municipalities, being born outside Europe, living in the south of Sweden, and renting instead of owning housing. Self-reported negative capability change, and associated inequalities related to socioeconomic position, place of birth and regional residence should be of concern for policymakers.
2021-07-02 Dataset: capability change covid-19
Britton T, Trapman P, Ball F
R Soc Open Sci 8 (7) 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
2021-06-28 Raw, patient-level characteristics and data
Lindholt MF, Jørgensen F, Bor A, Petersen MB
BMJ Open 11 (6) e048172
The management of the COVID-19 pandemic hinges on the approval of safe and effective vaccines but, equally importantly, on high vaccine acceptance among people. To facilitate vaccine acceptance via effective health communication, it is key to understand levels of vaccine scepticism and the demographic, psychological and political predictors. To this end, we examine the levels and predictors of acceptance of an approved COVID-19 vaccine. We examine the levels and predictors of acceptance of an approved COVID-19 vaccine in large online surveys from eight Western democracies that differ in terms of the severity of the pandemic and their response: Denmark, France, Germany, Hungary, Sweden, Italy, UK and USA (total N=18 231). Survey respondents were quota sampled to match the population margins on age, gender and geographical location for each country. The study was conducted from September 2020 to February 2021, allowing us to assess changes in acceptance and predictors as COVID-19 vaccine programmes were rolled out. The outcome of the study is self-reported acceptance of a COVID-19 vaccine approved and recommended by health authorities. The data reveal large variations in vaccine acceptance that ranges from 83% in Denmark to 47% in France and Hungary. Lack of vaccine acceptance is associated with lack of trust in authorities and scientists, conspiratorial thinking and a lack of concern about COVID-19. Most national levels of vaccine acceptance fall below estimates of the required threshold for herd immunity. The results emphasise the long-term importance of building trust in preparations for health emergencies such as the current pandemic. For health communication, the results emphasise the importance of focusing on personal consequences of infections and debunking of myths to guide communication strategies.
2021-06-15 Dataset: vaccine acceptance in Denmark, France, Germany, Hungary, Sweden, Italy, UK and USA; September 2020 to February 2021.
O'Toole A, Hill V
Wellcome Open Res 6 121
Late in 2020, two genetically-distinct clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with mutations of biological concern were reported, one in the United Kingdom and one in South Africa. Using a combination of data from routine surveillance, genomic sequencing and international travel we track the international dispersal of lineages B.1.1.7 and B.1.351 (variant 501Y-V2). We account for potential biases in genomic surveillance efforts by including passenger volumes from location of where the lineage was first reported, London and South Africa respectively. Using the software tool grinch (global report investigating novel coronavirus haplotypes), we track the international spread of lineages of concern with automated daily reports, Further, we have built a custom tracking website ( which hosts this daily report and will continue to include novel SARS-CoV-2 lineages of concern as they are detected.
Krambrich J, Akaberi D, Ling J, Hoffman T, Svensson L, [...], Lundkvist Å
Virol J 18 (1) 109
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
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
Louca P, Murray B, Klaser K, Graham MS, Mazidi M, [...], Menni C
BMJ Nutr Prev Health 4 (1) 149-157
Dietary supplements may ameliorate SARS-CoV-2 infection, although scientific evidence to support such a role is lacking. We investigated whether users of the COVID-19 Symptom Study app who regularly took dietary supplements were less likely to test positive for SARS-CoV-2 infection. App-based community survey. 445 850 subscribers of an app that was launched to enable self-reported information related to SARS-CoV-2 infection for use in the general population in the UK (n=372 720), the USA (n=45 757) and Sweden (n=27 373). Self-reported regular dietary supplement usage (constant use during previous 3 months) in the first waves of the pandemic up to 31 July 2020. SARS-CoV-2 infection confirmed by viral RNA reverse transcriptase PCR test or serology test before 31 July 2020. In 372 720 UK participants (175 652 supplement users and 197 068 non-users), those taking probiotics, omega-3 fatty acids, multivitamins or vitamin D had a lower risk of SARS-CoV-2 infection by 14% (95% CI (8% to 19%)), 12% (95% CI (8% to 16%)), 13% (95% CI (10% to 16%)) and 9% (95% CI (6% to 12%)), respectively, after adjusting for potential confounders. No effect was observed for those taking vitamin C, zinc or garlic supplements. On stratification by sex, age and body mass index (BMI), the protective associations in individuals taking probiotics, omega-3 fatty acids, multivitamins and vitamin D were observed in females across all ages and BMI groups, but were not seen in men. The same overall pattern of association was observed in both the US and Swedish cohorts. In women, we observed a modest but significant association between use of probiotics, omega-3 fatty acid, multivitamin or vitamin D supplements and lower risk of testing positive for SARS-CoV-2. We found no clear benefits for men nor any effect of vitamin C, garlic or zinc. Randomised controlled trials are required to confirm these observational findings before any therapeutic recommendations can be made.
Brueggemann AB, Jansen van Rensburg MJ, Shaw D, McCarthy ND, Jolley KA, [...], Zhou F
The Lancet Digital Health 3 (6) e360-e370
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
Noske GD, Nakamura AM, Gawriljuk VO, Fernandes RS, M. A. Lima G, [...], Godoy AS
Journal of Molecular Biology 167118
Mehregan A, Pérez-Conesa S, Zhuang Y, Elbahnsi A, Pasini D, [...], Delemotte L
2021-05-28 Input files and simulations
Yelagandula R, Bykov A, Vogt A, Heinen R, Özkan E, [...], Elling U
Nat Commun 12 (1) 3132
The COVID-19 pandemic has demonstrated the need for massively-parallel, cost-effective tests monitoring viral spread. Here we present SARSeq, saliva analysis by RNA sequencing, a method to detect SARS-CoV-2 and other respiratory viruses on tens of thousands of samples in parallel. SARSeq relies on next generation sequencing of multiple amplicons generated in a multiplexed RT-PCR reaction. Two-dimensional, unique dual indexing, using four indices per sample, enables unambiguous and scalable assignment of reads to individual samples. We calibrate SARSeq on SARS-CoV-2 synthetic RNA, virions, and hundreds of human samples of various types. Robustness and sensitivity were virtually identical to quantitative RT-PCR. Double-blinded benchmarking to gold standard quantitative-RT-PCR performed by human diagnostics laboratories confirms this high sensitivity. SARSeq can be used to detect Influenza A and B viruses and human rhinovirus in parallel, and can be expanded for detection of other pathogens. Thus, SARSeq is ideally suited for differential diagnostic of infections during a pandemic.
Chen X, Saccon E, Appelberg KS, Mikaeloff F, Rodriguez JE, [...], Gupta S
Cell Death Discov 7 (1) 114
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.
Hosen I, Pakpour AH, Sakib N, Hussain N, al Mamun F, [...], Mamun MA
PLoS One 16 (5) e0251151
2021-05-03 Dataset: socio-demographic characteristics, sources from where participants get information regarding COVID-19, participants’ knowledge concerning COVID-19, participants’ behavior in preventing COVID-19 etc.
Kharlamova N, Dunn N, Bedri SK, Jerling S, Almgren M, [...], Fogdell-Hahn A
Front Immunol 12 666114
Patients with chronic inflammatory diseases are often treated with immunosuppressants and therefore are of particular concern during the SARS-CoV-2 pandemic. Serological tests will improve our understanding of the infection and immunity in this population, unless they tests give false positive results. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays using samples from patients with chronic inflammatory diseases collected prior to April 2019, thus defined as negative. Samples from patients with multiple sclerosis (MS, n=10), rheumatoid arthritis (RA, n=47) with or without rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibodies (anti-CCP2) and systemic lupus erythematosus (SLE, n=10) with or without RF, were analyzed for SARS-CoV-2 antibodies using 17 commercially available lateral flow assays (LFA), two ELISA kits and one in-house developed IgG multiplex bead-based assay. Six LFA and the in-house validated IgG assay correctly produced negative results for all samples. However, the majority of assays (n=13), gave false positive signal for samples from patients with RA and SLE. This was most notable in samples from RF positive RA patients. No false positive samples were detected in any assay using samples from patients with MS. Poor specificity of commercial serological assays could possibly be, at least partly, due to interfering antibodies in samples from patients with chronic inflammatory diseases. For these patients, the risk of false positivity should be considered when interpreting results of the SARS-CoV-2 serological assays.
2021-05-03 False Positive Results in SARS-CoV-2 Serological Tests for Samples From Patients With Chronic Inflammatory Diseases
Mahdi A, Błaszczyk P, Dłotko P, Salvi D, Chan TS, [...], Tarassenko L
Sci Rep 11 (1)
Alrawashdeh HM, Al-Tammemi AB, Alzawahreh MK, Al-Tamimi A, Elkholy M, [...], Ghoul I
BMC Public Health 21 (1) 811
Healthcare professionals including physicians were subjected to an increased workload during the COVID-19 crisis, leaving them exposed to significant physical and psychological distress. Therefore, our present study aimed to (i) assess the prevalence of burnout and levels of job satisfaction among physicians in Jordan, and (ii) explore physicians' opinions, experiences, and perceptions during the pandemic crisis. This was a mixed-method study that utilized a structured web-based questionnaire and semi-structured individual interviews. The 10-Item Burnout Measure-Short version (BMS), and the 5-Item Short Index of Job Satisfaction (SIJS) were adopted to assess occupational burnout and job satisfaction, respectively. Semi-structured interviews were conducted, based on a conceptual framework that was developed from Herzberg's Two-Factor Theory of Motivation and Job Demands-Resources Model. Descriptive statistics and regression models, as well as inductive thematic analysis, were used to analyze quantitative and qualitative data, respectively. A total of 973 survey responses and 11 interviews were included in our analysis. The prevalence of burnout among physicians was (57.7%). Several significant factors were positively associated with burnout, including female gender, working at highly loaded hospitals, working for long hours, doing night shifts, lack of sufficient access to personal protective equipment, and being positively tested for SARS-CoV-2. Regarding job satisfaction, regression analysis revealed that age was positively associated with higher levels of job satisfaction. On contrary, being a general practitioner or specialist, working at highly loaded hospitals, low salaries, and suffering from burnout have predicted lower levels of job satisfaction. Besides, four themes have emerged from the thematic analysis: (i) Work-induced psychological distress during the pandemic, (ii) Decision-driven satisfactory and dissatisfactory experiences, (iii) Impact of the pandemic on doctor-patient communication and professional skills, and (iv) Economic impacts of the pandemic crisis and lockdown. A significant physical and psychological burden was associated with the COVID-19 pandemic. Reliable efforts should be implemented aiming at protecting physicians' physical and mental wellbeing, enhancing their working conditions, and raising awareness about burnout. Evidence-based decisions and proper utilization of financial and human resources at institutional and national levels are believed to be crucial for the sustainability of the health workforce, especially in crises.
2021-04-28 Raw dataset: individual-level demographic, occupational, COVID-19, burnout, etc. data
Patel H, Ashton NJ, Dobson RJ, Anderson LM, Yilmaz A, [...], Zetterberg H
Sci Rep 11 (1)
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 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.
Steele J, Androulakis-Korakakis P, Carlson L, Williams D, Phillips S, [...], Fisher JP
Sports Med
Understanding the impact of lockdown upon resistance training (RT), and how people adapted their RT behaviours, has implications for strategies to maintain engagement in similar positive health behaviours. Further, doing so will provide a baseline for investigation of the long-term effects of these public health measures upon behaviours and perceptions, and facilitate future follow-up study. To determine how the onset of coronavirus (COVID-19), and associated 'lockdown', affected RT behaviours, in addition to motivation, perceived effectiveness, enjoyment, and intent to continue, in those who regularly performed RT prior to the pandemic. We conducted an observational, cross-sectional study using online surveys in multiple languages (English, Danish, French, German, Italian, Portuguese, Slovakian, Swedish, and Japanese) distributed across social media platforms and through authors' professional and personal networks. Adults (n = 5389; median age = 31 years [interquartile range (IQR) = 25, 38]), previously engaged in RT prior to lockdown (median prior RT experience = 7 years [IQR = 4, 12]) participated. Outcomes were self-reported RT behaviours including: continuation of RT during lockdown, location of RT, purchase of specific equipment for RT, method of training, full-body or split routine, types of training, repetition ranges, exercise number, set volumes (per exercise and muscle group), weekly frequency of training, perception of effort, whether training was planned/recorded, time of day, and training goals. Secondary outcomes included motivation, perceived effectiveness, enjoyment, and intent to continue RT. A majority of individuals (82.8%) maintained participation in RT during-lockdown. Marginal probabilities from generalised linear models and generalised estimating equations for RT behaviours were largely similar from pre- to during-lockdown. There was reduced probability of training in privately owned gyms (~ 59% to ~ 7%) and increased probability of training at home (~ 18% to ~ 89%); greater probability of training using a full-body routine (~ 38% to ~ 51%); reduced probability of resistance machines (~ 66% to ~ 13%) and free weight use (~ 96% to ~ 81%), and increased probability of bodyweight training (~ 62% to ~ 82%); reduced probability of moderate repetition ranges (~ 62-82% to ~ 55-66%) and greater probability of higher repetition ranges (~ 27% to ~ 49%); and moderate reduction in the perception of effort experienced during-training (r = 0.31). Further, individuals were slightly less likely to plan or record training during lockdown and many changed their training goals. Additionally, perceived effectiveness, enjoyment, and likelihood of continuing current training were all lower during-lockdown. Those engaged in RT prior to lockdown these behaviours with only slight adaptations in both location and types of training performed. However, people employed less effort, had lower motivation, and perceived training as less effective and enjoyable, reporting their likelihood of continuing current training was similar or lower than pre-lockdown. These results have implications for strategies to maintain engagement in positive health behaviours such as RT during-restrictive pandemic-related public health measures. PRE-REGISTRATION: . The preprint version of this work is available on SportRχiv: .
2021-04-19 Dataset: Survey data
Rosen J, Noreland M, Stattin K, Lipcsey M, Frithiof R, [...], Hultström M
Research Square
2021-04-19 Metadata record
Klaric L, Gisby JS, Papadaki A, Muckian MD, Macdonald-Dunlop E, [...], Peters JE
2021-04-07 All data are available in the paper and supplementary material
Sheward DJ, Mandolesi M, Kim C, Hanke L, Vidakovics LP, [...], Murrell B
2021-04-05 code to complete analyses and instructions to acquire data
Kubik S, Marques AC, Xing X, Silvery J, Bertelli C, [...], Xu Z
Clin Microbiol Infect
SARS-CoV-2 genotyping has been instrumental to monitor viral evolution and transmission during the pandemic. The quality of the sequence data obtained from these genotyping efforts depends on several factors, including the quantity/integrity of the input material, the technology as well as laboratory-specific implementation. The current lack of guidelines for SARS-CoV-2 genotyping leads to inclusion of error-containing genome sequences in genomic epidemiology studies. We aimed at establishing clear and broadly applicable recommendations for reliable virus genotyping. We established and used a sequencing data analysis workflow that reliably identifies and removes technical artifacts, which can result in miscalls when using alternative pipelines, to process clinical samples and synthetic viral genomes with an amplicon-based genotyping approach. We evaluated the impact of experimental factors, including viral load and sequencing depth, on correct sequence determination. We found that at least 1000 viral genomes are necessary to confidently detect variants in the SARS-CoV-2 genome at frequencies of 10% or higher. The broad applicability of our recommendations was validated in over 200 clinical samples from six independent laboratories. The genotypes we determined for clinical isolates with sufficient quality cluster by sampling location and period. Our analysis also supports the rise in frequency of 20A.EU1 and 20A.EU2, two recently reported European strains whose dissemination was facilitated by travelling during the summer of 2020. We present much-needed recommendations for reliable determination of SARS-CoV-2 genome sequence and demonstrate their broad applicability in a large cohort of clinical samples.
Funk T, Pharris A, Spiteri G, Bundle N, Melidou A, [...], COVID study groups
Euro Surveill 26 (16)
We compared 19,207 cases of SARS-CoV-2 variant B.1.1.7/S gene target failure (SGTF), 436 B.1.351 and 352 P.1 to non-variant cases reported by seven European countries. COVID-19 cases with these variants had significantly higher adjusted odds ratios for hospitalisation (B.1.1.7/SGTF: 1.7, 95% confidence interval (CI): 1.0-2.9; B.1.351: 3.6, 95% CI: 2.1-6.2; P.1: 2.6, 95% CI: 1.4-4.8) and B.1.1.7/SGTF and P.1 cases also for intensive care admission (B.1.1.7/SGTF: 2.3, 95% CI: 1.4-3.5; P.1: 2.2, 95% CI: 1.7-2.8).
2021-04-00 All data is included in the supplementary material
Messner CB, Demichev V, Bloomfield N, Yu JSL, White M, [...], Ralser M
Nat Biotechnol
Accurate quantification of the proteome remains challenging for large sample series and longitudinal experiments. We report a data-independent acquisition method, Scanning SWATH, that accelerates mass spectrometric (MS) duty cycles, yielding quantitative proteomes in combination with short gradients and high-flow (800 µl min -1) chromatography. Exploiting a continuous movement of the precursor isolation window to assign precursor masses to tandem mass spectrometry (MS/MS) fragment traces, Scanning SWATH increases precursor identifications by ~70% compared to conventional data-independent acquisition (DIA) methods on 0.5-5-min chromatographic gradients. We demonstrate the application of ultra-fast proteomics in drug mode-of-action screening and plasma proteomics. Scanning SWATH proteomes capture the mode of action of fungistatic azoles and statins. Moreover, we confirm 43 and identify 11 new plasma proteome biomarkers of COVID-19 severity, advancing patient classification and biomarker discovery. Thus, our results demonstrate a substantial acceleration and increased depth in fast proteomic experiments that facilitate proteomic drug screens and clinical studies.
Blanco N, Stafford K, Lavoie MC, Brandenburg A, Górna MW, [...], Merski M
Epidemiol. Infect. 1-25
2021-03-25 Raw, original data and fits data set
Beridze G, Triolo F, Grande G, Fratiglioni L, Calderón-Larrañaga A
2021-03-20 Data available through the the Swedish National study on Aging and Care in Kungsholmen
Cotugno N, Ruggiero A, Bonfante F, Petrara MR, Zicari S, [...], Palma P
Cell Rep 34 (11) 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.
Danlos FX, Grajeda-Iglesias C, Durand S, Sauvat A, Roumier M, [...], Kroemer G
Cell Death Dis 12 (3) 258
The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
2021-03-11 All metabolomics data (supplementary tables)
Hothorn T, Bopp M, Günthard H, Keiser O, Roelens M, [...], Crowther M
BMJ Open 11 (3) e042387
Severity of the COVID-19 has been previously reported in terms of absolute mortality in SARS-CoV-2 positive cohorts. An assessment of mortality relative to mortality in the general population is presented. Retrospective population-based study. Individual information on symptomatic confirmed SARS-CoV-2 patients and subsequent deaths from any cause were compared with the all-cause mortality in the Swiss population of 2018. Starting 23 February 2020, mortality in COVID-19 patients was monitored for 80 days and compared with the population mortality observed in the same time of year starting 23 February 2018. 5 102 300 inhabitants of Switzerland aged 35-95 without COVID-19 (general population in spring 2018) and 20 769 persons tested positively for COVID-19 during the first wave in spring 2020. Sex-specific and age-specific mortality rates were estimated using Cox proportional hazards models. Absolute probabilities of death were predicted and risk was assessed in terms of relative mortality by taking the ratio between the sex-specific and age-specific absolute mortality in COVID-19 patients and the corresponding mortality in the 2018 general population. Absolute mortalities increased with age and were higher for males compared with females, both in the general population and in positively tested persons. A confirmed SARS-CoV-2 infection substantially increased the probability of death across all patient groups at least eightfold. The highest relative mortality risks were observed among males and younger patients. Male COVID-19 patients exceeded the population hazard for males (HR 1.21, 95% CI 1.02 to 1.44). An additional year of age increased the population hazard in COVID-19 patients only marginally (HR 1.00, 95% CI 1.00 to 1.01). Healthcare professionals, decision-makers and societies are provided with an additional population-adjusted assessment of COVID-19 mortality risk. In combination with absolute measures of risk, the relative risks presented here help to develop a more comprehensive understanding of the actual impact of COVID-19.
2021-03-08 Data, R and Stata code
Dillner J, Elfström KM, Blomqvist J, Eklund C, Lagheden C, [...], Conneryd Lundgren K
Sci Rep 11 (1) 5160
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, NCT04411576.
2021-03-04 Available on request
Vlachos J, Hertegård E, B Svaleryd H
Proc Natl Acad Sci U S A 118 (9)
To reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), most countries closed schools, despite uncertainty if school closures are an effective containment measure. At the onset of the pandemic, Swedish upper-secondary schools moved to online instruction, while lower-secondary schools remained open. This allows for a comparison of parents and teachers differently exposed to open and closed schools, but otherwise facing similar conditions. Leveraging rich Swedish register data, we connect all students and teachers in Sweden to their families and study the impact of moving to online instruction on the incidence of SARS-CoV-2 and COVID-19. We find that, among parents, exposure to open rather than closed schools resulted in a small increase in PCR-confirmed infections (odds ratio [OR] 1.17; 95% CI [CI95] 1.03 to 1.32). Among lower-secondary teachers, the infection rate doubled relative to upper-secondary teachers (OR 2.01; CI95 1.52 to 2.67). This spilled over to the partners of lower-secondary teachers, who had a higher infection rate than their upper-secondary counterparts (OR 1.29; CI95 1.00 to 1.67). When analyzing COVID-19 diagnoses from healthcare visits and the incidence of severe health outcomes, results are similar for teachers, but weaker for parents and teachers' partners. The results for parents indicate that keeping lower-secondary schools open had minor consequences for the overall transmission of SARS-CoV-2 in society. The results for teachers suggest that measures to protect teachers could be considered.
  • Analysis code
  • Data available from Statistics Sweden, the Public Health Agency, the National Board of Health and Welfare
Böhm S, Woudenberg T, Chen D, Marosevic DV, Böhmer MM, [...], Katz K
Epidemiol Infect 149 e65
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) led to a significant disease burden and disruptions in health systems. We describe the epidemiology and transmission characteristics of early coronavirus disease 2019 (COVID-19) cases in Bavaria, Germany. Cases were reverse transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infections, reported from 20 January-19 March 2020. The incubation period was estimated using travel history and date of symptom onset. To estimate the serial interval, we identified pairs of index and secondary cases. By 19 March, 3546 cases were reported. A large proportion was exposed abroad (38%), causing further local transmission. Median incubation period of 256 cases with exposure abroad was 3.8 days (95%CI: 3.5-4.2). For 95% of infected individuals, symptom onset occurred within 10.3 days (95%CI: 9.1-11.8) after exposure. The median serial interval, using 53 pairs, was 3.5 days (95%CI: 3.0-4.2; mean: 3.9, s.d.: 2.2). Travellers returning to Germany had an important influence on the spread of SARS-CoV-2 infections in Bavaria in early 2020. Especially in times of low incidence, public health agencies should identify holiday destinations, and areas with ongoing local transmission, to monitor potential importation of SARS-CoV-2 infections. Travellers returning from areas with ongoing community transmission should be advised to quarantine to prevent re-introductions of COVID-19.
2021-03-02 Incubation period data: earliest and latest point of exposure, date_of_onset, country, age, sex
Manisty C, Treibel TA, Jensen M, Semper A, Joy G, [...], Moon JC
EBioMedicine 65 103259
SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r = 0.57, p<0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16-18 weeks, r = 0.57, p<0.0001). By 21 weeks' follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling revealed faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). Mild SARS-CoV-2 infection is associated with heterogeneous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. In mild infection, anti-S1 serology alone may underestimate incident infections. The mechanisms that underpin faster clearance and lower rates of sustained anti-S1 production may impact on the longevity of humoral immunity. Charitable donations via Barts Charity, Wellcome Trust, NIHR.
2021-03-01 Applications for access to the individual participant de-identified data (including data dictionaries) and samples can be made to the access committee
Papazoglou A, Conen A, Haubitz S, Tschopp M, Guignard VJ, [...], Enz TJ
J Clin Med 10 (5)
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
2021-02-23 GitLab: raw data and analysis code, Matlab
Ledberg A
Front Public Health 9 579948
Influenza viruses have caused disease outbreaks in human societies for a long time. Influenza often has rapid onset and relatively short duration, both in the individual and in the population. The case fatality rate varies for different strains of the virus, as do the effects on total mortality. Outbreaks related to coronavirus infections have recently become a global concern but much less is known about the dynamics of these outbreaks and their effects on mortality. In this work, disease outbreaks in Sweden, in the time period of 1860-2020, are characterized and compared to the currently ongoing COVID-19 outbreak. The focus is on outbreaks with a sharp increase in all-cause mortality. Outbreak onset is defined as the time point when death counts start to increase consistently for a period of at least 10 days. The duration of the outbreak is defined as the time period in which mortality rates are elevated. Excess mortality is estimated by standard methods. In total there were 15 outbreaks detected in the time period, the first 14 were likely caused by influenza virus infections, the last by SARS-CoV-2. The mortality dynamics of the SARS-CoV-2 outbreak is shown to be similar to outbreaks due to influenza virus, and in terms of the number of excess deaths, it is the worst outbreak in Sweden since the "Spanish flu" of 1918-1919.
2021-02-18 Analysis code and data: daily death counts for Sweden from 1860 to 31.08.2020; the total population of Sweden for the years 1860 to 2019 (from Statistics Sweden).
Feldman M, Lacey Krylova V, Farrow P, Donovan L, Zandamela E, [...], Baker K
PLoS One 16 (2) e0244924
Healthcare workers (HCWs) are at the frontline of the Coronavirus Disease 2019 (COVID-19) pandemic response, yet there is a paucity of literature on their knowledge, attitudes and practices (KAP) in relation to the pandemic. Community Health Workers (CHWs) in Mozambique are known locally as agentes polivalentes elementares (APEs). While technical guidance surrounding COVID-19 is available to support APEs, communicating this information has been challenging due to restrictions on travel, face-to-face group meetings and training, imposed from May to August 2020. A digital health platform, upSCALE, that already supports 1,213 APEs and 299 supervisors across three provinces, is being used to support APEs on effective COVID-19 management by delivering COVID-19 sensitive SMS messages, training modules and a COVID-19 KAP survey. The KAP survey, conducted from June 2020 to August 2020, consisted of 10 questions. Of 1,065 active upSCALE APEs, 28% completed the survey. Results indicate that only a small proportion of APEs listed the correct COVID-19 symptoms, transmission routes and appropriate prevention measures (n = (25%), n = (16%) and n = (39%), respectively) specifically included in national health education materials. Misconceptions were mainly related to transmission routes, high risk individuals and asymptomatic patients. 84% said they followed all government prevention guidelines. The results from the KAP survey were used to support the rapid development and deployment of targeted COVID-19 awareness and education materials for the APEs. A follow-up KAP survey is planned for November 2020. Adapting the existing upSCALE platform enabled a better understanding, in real time, of the KAP of APEs around COVID-19 management. Subsequently, supporting delivery of tailored messages and education, vital for ensuring a successful COVID-19 response.
2021-02-10 The Covid-19 pandemic: knowledge, attitudes and practice among healthcare workers in Mozambique, Survey 1, 2020
Tomić D, Davidović D, Szasz AM, Rezeli M, Pirkić B, [...], Rogina BM
Inform Med Unlocked 23 100529
Spike glycoprotein is essential for the reproduction of the SARS-CoV-2 virus, and its inhibition using already approved antiviral drugs may open new avenues for treatment of patients with the COVID-19 disease. Because of that we analyzed the inhibition of SARS-CoV-2 spike glycoprotein with FDA-approved antiviral drugs and their double and triple combinations. We used the Vini in silico model of cancer to perform this virtual drug screening, showing HIV drugs to be the most effective. Besides, the combination of cobicistat-abacavir-rilpivirine HIV drugs demonstrated the highest in silico efficacy of inhibiting SARS-CoV-2 spike glycoprotein. Therefore, a clinical trial of cobicistat-abacavir-rilpivirine on a limited number of COVID-19 patients in moderately severe and severe condition is warranted.
Lopez-Leon S, Wegman-Ostrosky T, Perelman C, Sepulveda R, Rebolledo PA, [...], Villapol S
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)
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
Alekseenko A, Barrett D, Pareja-Sanchez Y, Howard R, Strandback E, [...], Pelechano V
Sci Rep 11 (1) 1820
RT-LAMP detection of SARS-CoV-2 has been shown as a valuable approach to scale up COVID-19 diagnostics and thus contribute to limiting the spread of the disease. Here we present the optimization of highly cost-effective in-house produced enzymes, and we benchmark their performance against commercial alternatives. We explore the compatibility between multiple DNA polymerases with high strand-displacement activity and thermostable reverse transcriptases required for RT-LAMP. We optimize reaction conditions and demonstrate their applicability using both synthetic RNA and clinical patient samples. Finally, we validated the optimized RT-LAMP assay for the detection of SARS-CoV-2 in raw nasopharyngeal samples from 184 patients. We anticipate that optimized and affordable reagents for RT-LAMP will facilitate the expansion of SARS-CoV-2 testing globally, especially in sites and settings with limited economic resources.
Langegård U, Kiani K, Nielsen SJ, Svensson P
BMC Nurs 20 (1) 23
The use of distance education using digital tools in higher education has increased over the last decade, particularly during the COVID-19 pandemic. Therefore, this study aimed to describe and evaluate nursing students' experiences of the pedagogical transition from traditional campus based learning to distance learning using digital tools. The nursing course Symptom and signs of illness underwent a transition from campus based education to distance learning using digital tools because of the COVID-19 pandemic. This pedagogical transition in teaching was evaluated using both quantitative and qualitative data analysis. Focus group interviews (n = 9) were analysed using qualitative content analysis to explore students' experiences of the pedagogical transition and to construct a web-based questionnaire. The questionnaire comprised 14 items, including two open-ended questions. The questionnaire was delivered to all course participants and responses were obtained from 96 of 132 students (73%). Questionnaire data were analyzed using descriptive statistics and comments from the open-ended questions were used as quotes to highlight the quantitative data. The analysis of the focus group interviews extracted three main dimensions: didactic aspects of digital teaching, study environment, and students' own resources. Social interaction was an overall theme included in all three dimensions. Data from the questionnaire showed that a majority of students preferred campus based education and experienced deterioration in all investigated dimensions after the pedagogical transition. However, approximately one-third of the students appeared to prefer distance learning using digital tools. The main finding was that the pedagogical transition to distance education reduced the possibility for students' social interactions in their learning process. This negatively affected several aspects of their experience of distance learning using digital tools, such as reduced motivation. However, the heterogeneity in the responses suggested that a blended learning approach may offer pedagogical benefits while maintaining an advantageous level of social interaction.
2021-01-19 Available on request
Persson BD, John L, Rafie K, Strebl M, Frängsmyr L, [...], Arnberg N
Proc Natl Acad Sci U S A 118 (3)
Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion-CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors.
2021-01-19 PDB 7AJP: Crystal Structure of Human Adenovirus 56 Fiber Knob
Hultstrom M, Fromell K, Larsson A, Quaggin SE, Betsholtz C, [...], Jeansson M
2021-01-15 Metadata record
Tian JH, Patel N, Haupt R, Zhou H, Weston S, [...], Smith G
Nat Commun 12 (1) 372
The COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd protection and control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) from the full-length spike (S) protein that is stable in the prefusion conformation. NVX-CoV2373 S form 27.2-nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicit high titer anti-S IgG that blocks hACE2 receptor binding, neutralize virus, and protects against SARS-CoV-2 challenge with no evidence of vaccine-associated enhanced respiratory disease. NVX-CoV2373 also elicits multifunctional CD4 + and CD8+ T cells, CD4+ follicular helper T cells (Tfh), and antigen-specific germinal center (GC) B cells in the spleen. In baboons, low-dose levels of NVX-CoV2373 with Matrix-M was also highly immunogenic and elicited high titer anti-S antibodies and functional antibodies that block S-protein binding to hACE2 and neutralize virus infection and antigen-specific T cells. These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2373 with Matrix-M (NCT04368988).
2021-01-14 Various raw data
Björkman A, Engström M, Winblad U, Holmström IK
BMC Nurs 20 (1)
2021-01-14 Available on request
Elec AD, Oltean M, Goldis P, Cismaru C, Lupse M, [...], Elec FI
Int J Infect Dis
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
2021-01-13 Available on request
Koenig PA, Das H, Liu H, Kümmerer BM, Gohr FN, [...], Schmidt FI
Science 371 (6530) eabe6230
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. Here, we generated four neutralizing nanobodies that target the receptor-binding domain of the SARS-CoV-2 spike protein. We defined two distinct binding epitopes using x-ray crystallography and cryo-electron microscopy. Based on the structures, we engineered multivalent nanobodies with more than 100-fold improved neutralizing activity than monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor-binding competition, while other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion, and rendered the virions non-infectious.
Sallam M, Dababseh D, Eid H, Al-Mahzoum K, Al-Haidar A, [...], Mahafzah A
Vaccines 9 (1) 42
2021-01-12 Available on request
Kermani NZ, None , Song WJ, Badi Y, Versi A, [...], Chung KF
Respir Res 22 (1) 101876
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
Brandal LT, Ofitserova TS, Meijerink H, Rykkvin R, Lund HM, [...], Winje BA
Euro Surveill 26 (1)
2021-01-07 Available in paper; Detection of SARS-CoV-2 in saliva samples from paediatric COVID-19 index cases and their school contacts
Spangler D, Blomberg H, Smekal D
Scand J Trauma Resusc Emerg Med 29 (1) 3
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
Ahlström B, Frithiof R, Hultström M, Larsson I, Strandberg G, [...], Lipcsey M
Acta Anaesthesiol Scand 65 (4) 525-533
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
Pilotto A, Masciocchi S, Volonghi I, De Giuli V, Caprioli F, [...], Padovani A
Clin Infect Dis
  • 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
Maricic T, Nickel O, Aximu-Petri A, Essel E, Gansauge M, [...], Pääbo S
PLoS One 15 (12) e0244824
SARS-CoV-2 causes substantial morbidity and mortality in elderly and immunocompromised individuals, particularly in retirement homes, where transmission from asymptomatic staff and visitors may introduce the infection. Here we present a cheap and fast screening method based on direct RT-qPCR to detect SARS-CoV-2 in single or pooled gargle lavages ("mouthwashes"). This method detects individuals with large viral loads (Ct≤29) and we use it to test all staff at a nursing home daily over a period of three weeks in order to reduce the risk that the infection penetrates the facility. This or similar approaches can be implemented to protect hospitals, nursing homes and other institutions in this and future viral epidemics.
2020-12-31 All data are available in the supplementary information
Pettke A, Tampere M, Pronk R, Wallner O, Falk A, [...], Puumalainen MR
Viruses 13 (1) 37
RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in several cell models and rescued ZIKV-induced neurotoxicity in brain organoids. The compound's mechanism-of-action was pinpointed to late steps in the virus life cycle, impairing the formation of new virus particles. Collectively, in this study, we expand the antiviral activity of new small molecule inhibitors to a new virus class of Flaviviruses, but also uncover compounds' mechanism of action, which are important for the further development of antivirals.
2020-12-29 The effect of novel antiviral compounds against ZIKV in several cell models; other supporting data
Dopico XC, Muschiol S, Christian M, Hanke L, Sheward DJ, [...], Karlsson Hedestam GB
Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, [...], OHDSI-COVID-19 consortium
Rheumatology (Oxford)
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; id=34498). The full study protocol and analysis source code can be found at
2020-12-25 Data aggregated by data source
2020-12-22 Available on request
Beneria A, Arnedo M, Contreras S, Pérez-Carrasco M, Garcia-Ruiz I, [...], Rius JB
BMC Med Educ 20 (1) 515
Non-technical skills such as leadership, communication, or situation awareness should lead to effective teamwork in a crisis. This study aimed to analyse the role of these skills in the emotional response of health professionals to the COVID-19 pandemic. Before the COVID-19 outbreak, 48 doctors and 48 nurses participated in a simulation-based teamwork training program based on teaching non-technical skills through simulation. In May 2020, this group of professionals from a COVID-19 referral hospital was invited to participate in a survey exploring stress, anxiety, and depression, using the PSS-14 (Perceived Stress Scale) and the HADS (Hospital Anxiety and Depression Scale) measures. A control group that did not receive the training was included. We conducted a logistic regression to assess whether having attended a simulation-based teamwork training program modified the probability of presenting psychological distress (PSS-14 > 18 or HADS> 12). A total of 141 healthcare professionals were included, 77 in the intervention group and 64 in the control group. Based on the PSS-14, 70.1% of the intervention group and 75% of the control group (p = 0.342) had symptoms of stress. Having contact with COVID-19 patients [OR 4.16(1.64-10.52)]; having minors in charge [OR 2.75 (1.15-6.53)]; working as a doctor [0.39(0.16-0.95)], and being a woman [OR 2.94(1.09-7.91)] were related with PSS14 symptoms. Based on the HADS, 54.6% of the intervention group and 42.2% of the control group (p = 0.346) had symptoms of anxiety or depression. Having contact with COVID-19 patients [OR 2.17(1.05-4.48)] and having minors in charge [OR 2.14(1.06-4.32)] were related to HADS symptoms. Healthcare professionals who attended COVID-19 patients showed higher levels of anxiety and depression [OR 2.56(1.03-6.36) (p = 0.043)]. Healthcare professionals trained in non-technical skills through simulation tended towards higher levels of anxiety and depression and fewer levels of stress, during the COVID-19 pandemic.
2020-12-21 Available on request
Fadista J, Kraven LM, Karjalainen J, Andrews SJ, Geller F, [...], None
EBioMedicine 65 103277
Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10 -8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls). We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10 -3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10-2) . The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors. Novo Nordisk Foundation and Oak Foundation.
Kennedy B, Martinell M, Hammar U, van Zoest V, Kristiansson RS, [...], Fall T
2020-12-16 Available on request
Dillner J, Elfström KM, Blomqvist J, Engstrand L, Uhlén M, [...], Lundgren KC
2020-12-14 Available on request
Godman B, Haque M, Islam S, Iqbal S, Urmi UL, [...], Sefah I
Front Public Health 8 585832
Background: Countries have introduced a variety of measures to prevent and treat COVID-19 with medicines and personal protective equipment (PPE), with some countries adopting preventative strategies earlier than others. However, there has been considerable controversy surrounding some treatments. This includes hydroxychloroquine where the initial hype and misinformation lead to shortages, price rises and suicides. Price rises and shortages have also been seen for PPE. Such activities can have catastrophic effects on patients where there are high co-payment levels and issues of affordability. Consequently, there is a need to investigate this further. Objective: Assess changes in the availability, utilization and prices of relevant medicines and PPE during the pandemic among a range of Asian countries. Our approach: Narrative literature review combined with interviews among community pharmacists to assess changes in consumption, prices and shortages of medicines and PPE from the beginning of March 2020 until end of May 2020. In addition, suggestions on ways to reduce misinformation. Results: 308 pharmacists took part from five Asian countries. There was an appreciable increase in the utilization of antimicrobials in Pakistan (in over 88% of pharmacies), with lower increases or no change in Bangladesh, India, Malaysia and Vietnam. Encouragingly, there was increased use of vitamins/immune boosters and PPE across the countries, as well as limited price rises for antimicrobials in India, Malaysia and Vietnam, although greater price rises seen for analgesics and vitamin C/immune boosters. Appreciable price increases were also seen for PPE across some countries. Conclusion: Encouraging to see increases in utilization of vitamins/immune boosters and PPE. However, increases in the utilization and prices of antimicrobials is a concern that needs addressing alongside misinformation and any unintended consequences from the pandemic. Community pharmacists can play a key role in providing evidence-based advice, helping to moderate prices, as well as helping address some of the unintended consequences of the pandemic.
2020-12-14 Available on request
Hemati M, Soosanabadi M, Ghorashi T, Ghaffari H, Vahedi A, [...], Kokhaei P
J Cell Physiol
The rapid spread of coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2, poses a huge demand for immediate diagnosis. Real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) of nasopharyngeal (NP) and oropharyngeal (OP) swabs have been used to confirm the clinical diagnosis. To avoid the risk of viral-exposure of laboratory workers, thermal inactivation is currently recommended but has unknown effects on the accuracy of the rRT-PCR results. Thirty-six NP/OP specimens were collected from COVID-19 patients and subjected to thermal inactivation (60°C for 30 min) or the RNA extraction processes to activate the form. Here, our data showed that the concentration of extracted-RNA increases upon thermal inactivation compared to the active form (p = .028). Significantly higher levels of RNA copy number were obtained in inactivated compared to the active samples for both N and ORF1ab genes (p = .009, p = .032, respectively). Thermal inactivation elevated concentration and copy number of extracted-RNA, possibly through viral-capsid degradation and/or nucleoprotein denaturation.
2020-12-11 All data is included in the paper
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
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
Mondino E, Di Baldassarre G, Mård J, Ridolfi E, Rusca M
Sci Data 7 (1) 434
Knowing how people perceive multiple risks is essential to the management and promotion of public health and safety. Here we present a dataset based on a survey (N = 4,154) of public risk perception in Italy and Sweden during the COVID-19 pandemic. Both countries were heavily affected by the first wave of infections in Spring 2020, but their governmental responses were very different. As such, the dataset offers unique opportunities to investigate the role of governmental responses in shaping public risk perception. In addition to epidemics, the survey considered indirect effects of COVID-19 (domestic violence, economic crises), as well as global (climate change) and local (wildfires, floods, droughts, earthquakes, terror attacks) threats. The survey examines perceived likelihoods and impacts, individual and authorities' preparedness and knowledge, and socio-demographic indicators. Hence, the resulting dataset has the potential to enable a plethora of analyses on social, cultural and institutional factors influencing the way in which people perceive risk.
2020-12-10 Raw dataset: perceived likelihoods and impacts, individual and authorities’ preparedness and knowledge, socio-demographic characteristics (N=2,033 in Italy, N=2,121 in Sweden)
Tampere M, Pettke A, Salata C, Wallner O, Koolmeister T, [...], Puumalainen MR
Viruses 12 (12) 1423
Petrazzuolo A, Le Naour J, Vacchelli E, Gaussem P, Ellouze S, [...], Kroemer G
Oncoimmunology 9 (1) 1857112
Formyl peptide receptor 1 (FPR1) is a pattern-recognition receptor that detects bacterial as well as endogenous danger-associated molecular patterns to trigger innate immune responses by myeloid cells. A single nucleotide polymorphism, rs867228 (allelic frequency 19-20%), in the gene coding for FPR1 accelerates the manifestation of multiple carcinomas, likely due to reduced anticancer immunosurveillance secondary to a defect in antigen presentation by dendritic cells. Another polymorphism in FPR1, rs5030880 (allelic frequency 12-13%), has been involved in the resistance to plague, correlating with the fact that FPR1 is the receptor for Yersinia pestis. Driven by the reported preclinical effects of FPR1 on lung inflammation and fibrosis, we investigated whether rs867228 or rs5030880 would affect the severity of coronavirus disease-19 (COVID-19). Data obtained on patients from two different hospitals in Paris refute the hypothesis that rs867228 or rs5030880 would affect the severity of COVID-19.
2020-12-08 Allelic frequencies of FPR1 SNPs and characteristics of patient population from Hôpital Cochin and Hôpital Européen George Pompidou
Hofman P, Ilié M, Chamorey E, Brest P, Schiappa R, [...], Calabrese F
ESMO Open 6 (1) 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
Mohammad MA, Koul S, Gale CP, Alfredsson J, James S, [...], Erlinge D
J Intern Med
We aimed to study the effect of social containment mandates on ACS presentation during COVID-19 pandemic using location activity and mobility data from mobile phone map services. We conducted a cross-sectional study using data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) including all ACS presentations during the pandemic until May 07, 2020. Using a count regression model, we adjusted for day of the week, daily weather, and incidence of COVID-19. A 10% increase in activity around areas of residence was associated with 38% lower rates of ACS hospitalisations whereas increased activity relating to retail and recreation, grocery stores and pharmacies, workplaces as well as mode of mobility was associated with 10-20% higher rates of ACS hospitalisations. Government policy regarding social containment mandates has important public health implications for medical emergencies like ACS and may explain the decline in ACS presentations observed during COVID-19 pandemic.
2020-12-01 Available on request
Delavari S, Abolhassani H, Abolnezhadian F, Babaha F, Iranparast S, [...], Aghamohamamdi A
J Clin Immunol
Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents.
2020-12-01 General laboratory tests, immunologic investigation, computed tomographies of the chest of 17 primary immunodeficient patients infected with COVID-19
Morales DR, Conover MM, You SC, Pratt N, Kostka K, [...], Suchard MA
The Lancet Digital Health 3 (2) e98-e114
2020-12-00 Data aggregated by data source
Nyman E, Lindh M, Lövfors W, Simonsson C, Persson A, [...], Cedersund G
CPT Pharmacometrics Syst. Pharmacol. 9 (12) 707-717
Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g., asthma and atherosclerosis. Anti-inflammatory drugs come with side effects that may be aggravated by high and fluctuating drug concentrations. To remedy this, an anti-inflammatory drug should have an appropriate pharmacokinetic half-life or better still, a sustained anti-inflammatory drug response. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti-inflammatory response to a common glucocorticoid drug, dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism-a slow release of dexamethasone from the receptor-drug complex. The developed model is in agreement with time-resolved training and testing data and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge-driven drug development to find sustained anti-inflammatory responses and fewer side effects.
2020-12-00 Experimental data and data analysis code
Mohammad MA, Koul S, Olivecrona GK, Gӧtberg M, Tydén P, [...], Erlinge D
Heart 106 (23) 1812-1818
Most reports on the declining incidence of myocardial infarction (MI) during the COVID-19 have either been anecdotal, survey results or geographically limited to areas with lockdowns. We examined the incidence of MI during the COVID-19 pandemic in Sweden, which has remained an open society with a different public health approach fighting COVID-19. We assessed the incidence rate (IR) as well as the incidence rate ratios (IRRs) of all MI referred for coronary angiography in Sweden using the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR), during the COVID-19 pandemic in Sweden (1 March 2020-7 May 2020) in relation to the same days 2015-2019. A total of 2443 MIs were referred for coronary angiography during the COVID-19 pandemic resulting in an IR 36 MIs/day (204 MIs/100 000 per year) compared with 15 213 MIs during the reference period with an IR of 45 MIs/day (254 MIs/100 000 per year) resulting in IRR of 0.80, 95% CI (0.74 to 0.86), p<0.001. Results were consistent in all investigated patient subgroups, indicating no change in patient category seeking cardiac care. Kaplan-Meier event rates for 7-day case fatality were 439 (2.3%) compared with 37 (2.9%) (HR: 0.81, 95% CI (0.58 to 1.13), p=0.21). Time to percutaneous coronary intervention (PCI) was shorter during the pandemic and PCI was equally performed, indicating no change in quality of care during the pandemic. The COVID-19 pandemic has significantly reduced the incidence of MI referred for invasive treatment strategy. No differences in overall short-term case fatality or quality of care indicators were observed.
2020-12-00 Available on request
Appelberg S, Gupta S, Svensson Akusjärvi S, Ambikan AT, Mikaeloff F, [...], Neogi U
Emerg Microbes Infect 9 (1) 1748-1760
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.
Hultström M, Persson B, Eriksson O, Lipcsey M, Frithiof R, [...], Nilsson B
Crit Care 24 (1) 496
No abstract available
2020-12-00 Available on request
Pakpour AH, Al Mamun F, Hosen I, Griffiths MD, Mamun MA
Data Brief 33 106621
This paper presents the dataset concerning knowledge, preventive behavior, psychological consequences, and suicidal behavior regarding the COVID-19 pandemic in Bangladesh. Data were collected through an online based cross-sectional survey between April 1 and April 10 in 64 districts at the early stage of the COVID-19 pandemic in Bangladesh. A total of 10,067 participants' data were recruited for analysis. The survey contained items concerning (i) socio-demographic information, (ii) knowledge concerning COVID-19, (iii) behavior towards COVID-19, (iv) lockdown and economic issues, (v) assessment of fear of COVID-19, (vi) assessment of insomnia, (vii) assessment of depression, and (viii) assessment of suicidal ideation. Data were analyzed utilizing SPSS (version 22) and are represented as frequencies and percentages based on responses to the whole survey. Given that the data were collected across the whole nation, government authorities and healthcare policymakers can use the data to develop various models and/or policies regarding preventive strategies and help raise awareness through health education towards COVID-19.
Kirschenbaum D, Imbach LL, Jane Rushing E, Frauenknecht KBM, Gascho R T D, [...], Frontzek K
Neuropathol Appl Neurobiol
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
Fellman D, Ritakallio L, Waris O, Jylkkä J, Laine M
Front Psychol 11 576466
Increasing evidence indicates that the coronavirus disease 2019 (COVID-19) pandemic is associated with adverse psychological effects, including heightened levels of anxiety. This study examined whether COVID-19-related anxiety levels during the early stage of the pandemic predicted demanding working memory (WM) updating performance. Altogether, 201 healthy adults (age range, 18-50) mostly from North America and the British Isles were recruited to this study via the crowdsourcing site The results showed that higher levels of COVID-19-related anxiety during the first weeks of the pandemic outbreak were associated with poorer WM performance as measured by the n-back paradigm. Critically, the unique role of COVID-19-related anxiety on WM could not be explained by demographic factors, or other psychological factors such as state and trait anxiety or fluid intelligence. Moreover, across three assessment points spanning 5-6 weeks, COVID-19-related anxiety levels tended to decrease over time. This pattern of results may reflect an initial psychological "shock wave" of the pandemic, the cognitive effects of which may linger for some time, albeit the initial anxiety associated with the pandemic would change with habituation and increasing information. Our results contribute to the understanding of cognitive-affective reactions to a major disaster.
2020-11-26 Available on request
Lundon DJ, Mohamed N, Lantz A, Goltz HH, Kelly BD, [...], Tewari AK
Front Public Health 8 571364
Importance: The COVID-19 pandemic exploits existing inequalities in social determinants of health (SDOH) in disease burden and access to healthcare. Few studies have examined these emerging disparities using indicators of SDOH. Objective: To evaluate predictors of COVID-19 test positivity, morbidity, and mortality and their implications for inequalities in SDOH and for future policies and health care improvements. Design, Setting, and Participants: A cross sectional analysis was performed on all patients tested for COVID-19 on the basis of symptoms with either a history of travel to at risk regions or close contact with a confirmed case, across the Mount Sinai Health System (MSHS) up until April 26th 2020. Main Outcomes and Measures: Primary outcome was death from COVID-19 and secondary outcomes were test positivity, and morbidity (e.g., hospitalization and intubation caused by COVID-19). Results: Of 20,899 tested patients, 8,928 tested positive, 1,701 were hospitalized, 684 were intubated, and 1,179 died from COVID-19. Age, sex, race/ethnicity, New York City borough (derived from first 3 digits of zip-code), and English as preferred language were significant predictors of test positivity, hospitalization, intubation and COVID-19 mortality following multivariable logistic regression analyses. Conclusions and Relevance: People residing in poorer boroughs were more likely to be burdened by and die from COVID-19. Our results highlight the importance of integrating comprehensive SDOH data into healthcare efforts with at-risk patient populations.
2020-11-24 Available on request
Jonmarker S, Hollenberg J, Dahlberg M, Stackelberg O, Litorell J, [...], Cronhjort M
Crit Care 24 (1) 653
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. NCT04412304 June 2, 2020, retrospectively registered.
2020-11-23 Available on request due to privacy restrictions
Duchene S, Featherstone L, de Blasio BF, Holmes EC, Bohlin J, [...], Pettersson JHO
Many countries have attempted to control COVID-19 through the implementation of non-pharmaceutical interventions. However, it remains unclear how different control strategies have impacted SARS-CoV-2 virus transmission dynamics at the local level. Using complete SARS-CoV-2 genomes, we inferred the relative frequencies of virus importation and exportation, as well as virus transmission chain dynamics in Nordic countries - Denmark, Finland, Iceland, Norway and Sweden - during the first months of the pandemic. Our analyses revealed that Sweden experienced more numerous transmission chains, which tended to have more cases, and were of longer duration, a set of features that increased with time. Together with Denmark, Sweden was also a net exporter of SARS-CoV-2. Hence, Sweden effectively constituted an epidemiological and evolutionary ‘refugia’ that enabled the virus to maintain active transmission and spread to other geographic localities. This analysis highlights the utility of genomic surveillance where active transmission chain monitoring is a key metric.
2020-11-18 Data available on GISAID, accession numbers found here (in the Supplementary Material)
Elofsson A, Bryant P
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
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
Elofsson A, Bryant P
Background When modelling the dispersion of an epidemic using R0, one only considers the average number of individuals each infected individual will infect. However, we know from extensive studies of social networks that there is significant variation in the number of connections and thus social contacts each individual has. Individuals with more social contacts are more likely to attract and spread infection. These individuals are likely the drivers of the epidemic, so-called superspreaders. When many superspreaders are immune, it becomes more difficult for the disease to spread, as the connectedness of the social network dramatically decreases. If one assumes all individuals being equally connected and thus as likely to spread disease as in a SIR model, this is not true. Methods To account for the impact of social network structure on epidemic development, we model the dispersion of SARS-CoV-2 on a dynamic preferential attachment graph which changes appearance proportional to observed mobility changes. We sample a serial interval distribution that determines the probability of dispersion for all infected nodes each day. We model the dispersion in different age groups using age-specific infection fatality rates. We vary the infection probabilities in different age groups and analyse the outcome. Results The impact of movement on network dynamics plays a crucial role in the spread of infections. We find that higher movement results in higher spread due to an increased probability of new connections being made within a social network. We show that saturation in the dispersion can be reached much earlier on a preferential attachment graph compared to spread on a random graph, which is more similar to estimations using R0. Conclusions We provide a novel method for modelling epidemics by using a dynamic network structure related to observed mobility changes. The social network structure plays a crucial role in epidemic development, something that is often overlooked.
2020-11-17 Code, data, and results related to modelling the spread of COVID-19 on a dynamic social network with spread reduction according to Google mobility changes
Zeng HL, Dichio V, Rodríguez Horta E, Thorell K, Aurell E
Proc Natl Acad Sci USA 202012331
2020-11-17 Data is included in the article and supplementary information
Ludvigsson JF
Acta Paediatr
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
Stebbing J, Sánchez Nievas G, Falcone M, Youhanna S, Richardson P, [...], Lauschke VM
Sci Adv 7 (1)
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.
Saguti F, Magnil E, Enache L, Churqui MP, Johansson A, [...], Norder H
Water Res 189 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
Wacker A, Weigand JE, Akabayov SR, Altincekic N, Bains JK, [...], Zetzsche H
Nucleic Acids Res 48 (22) 12415-12435
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5' end, the ribosomal frameshift segment and the 3'-untranslated region (3'-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
Al-Tammemi AB, Akour A, Alfalah L
Front Psychol 11 562213
Since the spread of COVID-19 on a global scale, most of efforts at national and international levels were directed to mitigate the spread of the disease and its physical harm, paying less attention to the psychological impacts of COVID-19 on global mental health especially at early stages of the pandemic. This study aimed to assess and explore (i) The levels of psychological distress and its correlates (ii) Motivation for distance learning (iii) Coping activities and pandemic related concerns, among university students in Jordan in the midst of COVID-19 pandemic. A cross-sectional study was conducted using an online self-administered questionnaire. The measure of psychological distress was obtained using the 10-item Kessler Psychological Distress Scale, while other questions have explored our study's second and third aims. A total of 381 completed questionnaires were included in the analysis. Female participants slightly predominated the sample ( n = 199, 52.2%). The respondents aged 18-38 years (mean 22.6 years, SD: 3.16). Concerning distress severity, most of respondents were regarded as having severe psychological distress (n = 265, 69.5%). 209 students (54.9%) reported that they had no motivation for distance learning. Ordinal logistic regression revealed a significant correlation between distress severity and many predictors. Among the predictors that were found to act as protective factors against higher levels of distress included older age (aOR = 0.64, P = 0.022; 95% CI: 0.44-0.94), and having a strong motivation for distance learning (aOR = 0.10, P = 0.048; 95% CI: 0.01-0.96). In contrary, being a current smoker (aOR = 1.99, P = 0.049; 95% CI: 1.10-3.39), and having no motivation for distance learning (aOR = 2.49, P = 0.007; 95% CI: 1.29-4.80) acted as risk factors for having higher levels of psychological distress among the students. The most common coping activity reported was spending more time on social media platforms (n = 269, 70.6%), and 209 students (54.9%) reported distance learning as their most distressing concern. The COVID-19 pandemic and related control measures could impact the mental health of individuals, including students. We recommend a nationwide psychological support program to be incorporated into Jordan's preparedness plan and response strategy in combating the COVID-19 pandemic.
2020-11-06 Available on request
Custódio TF, Das H, Sheward DJ, Hanke L, Pazicky S, [...], Löw C
Nat Commun 11 (1)
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC50 of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed an unusual conformation of the spike where two RBDs are in the ‘up’ ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.
García M, Kokkinou E, Carrasco García A, Parrot T, Palma Medina LM, [...], Group tKKCS
Clin Transl Immunol 9 (12)
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
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
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
Pellert M, Lasser J, Metzler H, Garcia D
Front Big Data 3 32
To track online emotional expressions on social media platforms close to real-time during the COVID-19 pandemic, we built a self-updating monitor of emotion dynamics using digital traces from three different data sources in Austria. This allows decision makers and the interested public to assess dynamics of sentiment online during the pandemic. We used web scraping and API access to retrieve data from the news platform, Twitter, and a chat platform for students. We documented the technical details of our workflow to provide materials for other researchers interested in building a similar tool for different contexts. Automated text analysis allowed us to highlight changes of language use during COVID-19 in comparison to a neutral baseline. We used special word clouds to visualize that overall difference. Longitudinally, our time series showed spikes in anxiety that can be linked to several events and media reporting. Additionally, we found a marked decrease in anger. The changes lasted for remarkably long periods of time (up to 12 weeks). We have also discussed these and more patterns and connect them to the emergence of collective emotions. The interactive dashboard showcasing our data is available online at Our work is part of a web archive of resources on COVID-19 collected by the Austrian National Library.
Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, [...], Casanova J
Science 370 (6515) eabd4570
Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H, [...], Casanova J
Science 370 (6515)
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
Marklund E, Leach S, Axelsson H, Nyström K, Norder H, [...], Gisslén M
PLoS One 15 (10) e0241104
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.
Castro Dopico X, Hanke L, Sheward DJ, Muschiol S, Aleman S, [...], Karlsson Hedestam GB
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
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
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.
Burn E, You SC, Sena AG, Kostka K, Abedtash H, [...], Ryan P
Nat Commun 11 (1) 5009
Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.
Rogstam A, Nyblom M, Christensen S, Sele C, Talibov VO, [...], Kozielski F
Int J Mol Sci 21 (19)
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), causing Coronavirus Disease 19 (COVID-19), emerged at the end of 2019 and quickly spread to cause a global pandemic with severe socio-economic consequences. The early sequencing of its RNA genome revealed its high similarity to SARS, likely to have originated from bats. The SARS-CoV-2 non-structural protein 10 (nsp10) displays high sequence similarity with its SARS homologue, which binds to and stimulates the 3'-to-5' exoribonuclease and the 2'-O-methlytransferase activities of nsps 14 and 16, respectively. Here, we report the biophysical characterization and 1.6 Å resolution structure of the unbound form of nsp10 from SARS-CoV-2 and compare it to the structures of its SARS homologue and the complex-bound form with nsp16 from SARS-CoV-2. The crystal structure and solution behaviour of nsp10 will not only form the basis for understanding the role of SARS-CoV-2 nsp10 as a central player of the viral RNA capping apparatus, but will also serve as a basis for the development of inhibitors of nsp10, interfering with crucial functions of the replication-transcription complex and virus replication.
Sekine T, Perez-Potti A, Rivera-Ballesteros O, Strålin K, Gorin J, [...], Buggert M
Cell 183 (1) 158-168.e14
SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.
Edén A, Kanberg N, Gostner J, Fuchs D, Hagberg L, [...], Gisslén M
Neurology 96 (2) e294-e300
To explore whether hospitalized patients with SARS-CoV-2 and neurologic symptoms have evidence of CNS infection, inflammation and injury using CSF biomarker measurements. We assessed CSF SARS-CoV-2 RNA along with CSF biomarkers of intrathecal inflammation (CSF white blood cell count, neopterin, β 2-microglobulin (β2M) and immunoglobulin G-index), blood-brain-barrier (BBB) integrity (albumin ratio), and axonal injury (CSF neurofilament light chain protein [NfL]) in 6 patients with moderate to severe COVID-19 and neurologic symptoms who had undergone a diagnostic lumbar puncture. Neurologic symptoms and signs included features of encephalopathies (4/6), suspected meningitis (1/6) and dysgeusia (1/6). SARS-CoV-2 infection was confirmed by rtPCR analysis of nasopharyngeal swabs. SARS-CoV-2 RNA was detected in the plasma of 2 patients (Cycle threshold [Ct] value 35.0-37.0) and in CSF at low levels (Ct 37.2, 38.0, 39.0) in 3 patients in one but not in a second rtPCR assay. CSF neopterin (median, 43.0 nmol/L) and β 2-microglobulin (median, 3.1 mg/L) were increased in all. Median IgG-index (0.39), albumin ratio (5.35) and CSF white blood cell count (<3 cells/µL) were normal in all, while CSF NfL was elevated in 2 patients. Our results on patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections, and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection.
2020-10-01 Researchers can apply for access to anonymized data
Calderón-Larrañaga A, Vetrano DL, Rizzuto D, Bellander T, Fratiglioni L, [...], Dekhtyar S
BMJ Glob Health 5 (10)
We aimed to describe the distribution of excess mortality (EM) during the first weeks of the COVID-19 outbreak in the Stockholm Region, Sweden, according to age, sex and sociodemographic context. Weekly all-cause mortality data were obtained from Statistics Sweden for the period 1 January 2015 to 17 May 2020. EM during the first 20 weeks of 2020 was estimated by comparing observed mortality rates with expected mortality rates during the five previous years (N=2 379 792). EM variation by socioeconomic status (tertiles of income, education, Swedish-born, gainful employment) and age distribution (share of 70+-year-old persons) was explored based on Demographic Statistics Area (DeSO) data. EM was first detected during the week of 23-29 March 2020. During the peak week of the epidemic (6-12 April 2020), an EM of 150% was observed (152% in 80+-year-old women; 183% in 80+-year-old men). During the same week, the highest EM was observed for DeSOs with lowest income (171%), lowest education (162%), lowest share of Swedish-born (178%) and lowest share of gainfully employed residents (174%). EM was further increased in areas with higher versus lower proportion of younger people (magnitude of increase: 1.2-1.7 times depending on socioeconomic measure). Living in areas characterised by lower socioeconomic status and younger populations was linked to excess mortality during the COVID-19 pandemic in the Stockholm Region. These conditions might have facilitated viral spread. Our findings highlight the well-documented vulnerability linked to increasing age and sociodemographic context for COVID-19-related death.
2020-10-00 Available on request (provided by Statistics Sweden, SCB)
Zeberg H, Pääbo S
Nature 587 (7835) 610-612
A recent genetic association study 1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative)2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe.
Parrot T, Gorin J, Ponzetta A, Maleki KT, Kammann T, [...], Sandberg JK
Sci Immunol 5 (51)
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.
Hellman U, Karlsson MG, Engström-Laurent A, Cajander S, Dorofte L, [...], Blomberg A
J Biol Chem 295 (45) 15418-15422
Severe corona virus disease 2019 (Covid-19) is characterized by inflammation of the lungs with increasing respiratory impairment. In fatal Covid-19, lungs at autopsy have been filled with a clear liquid jelly. However, the nature of this finding has not yet been determined.The aim of the study was to demonstrate if the lungs of fatal Covid-19 contain hyaluronan as it is associated with inflammation and acute respiratory distress syndrome (ARDS) and may have the appearance of liquid jelly.Lung tissue obtained at autopsy from three deceased Covid-19 patients was processed for hyaluronan histochemistry using a direct staining method and compared with staining in normal lung tissue.Stainings confirmed that hyaluronan is obstructing alveoli with presence in exudate and plugs, as well as in thickened perialveolar interstitium. In contrast, normal lungs only showed hyaluronan in intact alveolar walls and perivascular tissue. This is the first study to confirm prominent hyaluronan exudates in the alveolar spaces of Covid-19 lungs, supporting the notion that the macromolecule is involved in ARDS caused by SARS-CoV-2. The present finding may open up for new treatment options in severe Covid-19, aiming at reducing the presence and production of hyaluronan in the lungs.
2020-09-25 Provided in the article: color light micrographs of autopsy lung tissue from the three Covid-19 cases
Smyrlaki I, Ekman M, Lentini A, Rufino de Sousa N, Papanicolaou N, [...], Reinius B
Nat Commun 11 (1) 4812
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is commonly diagnosed by reverse transcription polymerase chain reaction (RT-PCR) to detect viral RNA in patient samples, but RNA extraction constitutes a major bottleneck in current testing. Methodological simplification could increase diagnostic availability and efficiency, benefitting patient care and infection control. Here, we describe methods circumventing RNA extraction in COVID-19 testing by performing RT-PCR directly on heat-inactivated or lysed samples. Our data, including benchmarking using 597 clinical patient samples and a standardised diagnostic system, demonstrate that direct RT-PCR is viable option to extraction-based tests. Using controlled amounts of active SARS-CoV-2, we confirm effectiveness of heat inactivation by plaque assay and evaluate various generic buffers as transport medium for direct RT-PCR. Significant savings in time and cost are achieved through RNA-extraction-free protocols that are directly compatible with established PCR-based testing pipelines. This could aid expansion of COVID-19 testing.
Kanberg N, Ashton NJ, Andersson LM, Yilmaz A, Lindh M, [...], Gisslén M
Neurology 95 (12) e1754-e1759
To test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury. We recruited 47 patients with mild (n = 20), moderate (n = 9), or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort. The patients with severe COVID-19 had higher plasma concentrations of GFAp ( p = 0.001) and NfL (p < 0.001) than controls, while GFAp was also increased in patients with moderate disease (p = 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (p < 0.01), while NfL showed a sustained increase from first to last follow-up (p < 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury. We show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19-related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients.
2020-09-22 Researchers can apply for access to anonymized data
Akaberi D, Krambrich J, Ling J, Luni C, Hedenstierna G, [...], Lundkvist Å
Redox Biology 37 101734
The ongoing SARS-CoV-2 pandemic is a global public health emergency posing a high burden on nations' health care systems and economies. Despite the great effort put in the development of vaccines and specific treatments, no prophylaxis or effective therapeutics are currently available. Nitric oxide (NO) is a broad-spectrum antimicrobial and a potent vasodilator that has proved to be effective in reducing SARS-CoV replication and hypoxia in patients with severe acute respiratory syndrome. Given the potential of NO as treatment for SARS-CoV-2 infection, we have evaluated the in vitro antiviral effect of NO on SARS-CoV-2 replication. The NO-donor S-nitroso-N-acetylpenicillamine (SNAP) had a dose dependent inhibitory effect on SARS-CoV-2 replication, while the non S-nitrosated NAP was not active, as expected. Although the viral replication was not completely abolished (at 200 μM and 400 μM), SNAP delayed or completely prevented the development of viral cytopathic effect in treated cells, and the observed protective effect correlated with the level of inhibition of the viral replication. The capacity of the NO released from SNAP to covalently bind and inhibit SARS-CoV-2 3CL recombinant protease in vitro was also tested. The observed reduction in SARS-CoV-2 protease activity was consistent with S-nitrosation of the enzyme active site cysteine.
2020-09-21 Supplementary data
Bryant P, Elofsson A
PeerJ 8 e9879
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)
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.
Bortz RH, Florez C, Laudermilch E, Wirchnianski AS, Lasso G, [...], Chandran K
mSphere 6 (2)
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
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
Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, [...], Brodin P
Cell 183 (4) 968-981.e7
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.
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
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
Hanke L, Vidakovics Perez L, Sheward DJ, Das H, Schulte T, [...], McInerney GM
Nat Commun 11 (1) 4420
SARS-CoV-2 enters host cells through an interaction between the spike glycoprotein and the angiotensin converting enzyme 2 (ACE2) receptor. Directly preventing this interaction presents an attractive possibility for suppressing SARS-CoV-2 replication. Here, we report the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. Ty1 binds the RBD with high affinity, occluding ACE2. A cryo-electron microscopy structure of the bound complex at 2.9 Å resolution reveals that Ty1 binds to an epitope on the RBD accessible in both the 'up' and 'down' conformations, sterically hindering RBD-ACE2 binding. While fusion to an Fc domain renders Ty1 extremely potent, Ty1 neutralizes SARS-CoV-2 spike pseudovirus as a 12.8 kDa nanobody, which can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Ty1 is therefore an excellent candidate as an intervention against COVID-19.
Morgantini LA, Naha U, Wang H, Francavilla S, Acar Ö, [...], Weine SM
PLoS One 15 (9) e0238217
2020-09-03 Individual-level data on exposure, perception, and workload collected from 2,707 healthcare professionals from 60 countries
Ioannidis JPA, Axfors C, Contopoulos-Ioannidis DG
Environ Res 188 109890
To provide estimates of the relative rate of COVID-19 death in people <65 years old versus older individuals in the general population, the absolute risk of COVID-19 death at the population level during the first epidemic wave, and the proportion of COVID-19 deaths in non-elderly people without underlying diseases in epicenters of the pandemic. Cross-sectional survey of countries and US states with at least 800 COVID-19 deaths as of April 24, 2020 and with information on the number of deaths in people with age <65. Data were available for 14 countries (Belgium, Canada, France, Germany, India, Ireland, Italy, Mexico, Netherlands, Portugal, Spain, Sweden, Switzerland, UK) and 13 US states (California, Connecticut, Florida, Georgia, Illinois, Indiana, Louisiana, Maryland, Massachusetts, Michigan, New Jersey, New York, Pennsylvania). We also examined available data on COVID-19 deaths in people with age <65 and no underlying diseases. Proportion of COVID-19 deaths in people <65 years old; relative mortality rate of COVID-19 death in people <65 versus ≥65 years old; absolute risk of COVID-19 death in people <65 and in those ≥80 years old in the general population as of June 17, 2020; absolute COVID-19 mortality rate expressed as equivalent of mortality rate from driving a motor vehicle. Individuals with age <65 account for 4.5-11.2% of all COVID-19 deaths in European countries and Canada, 8.3-22.7% in the US locations, and were the majority in India and Mexico. People <65 years old had 30- to 100-fold lower risk of COVID-19 death than those ≥65 years old in 11 European countries and Canada, 16- to 52-fold lower risk in US locations, and less than 10-fold in India and Mexico. The absolute risk of COVID-19 death as of June 17, 2020 for people <65 years old in high-income countries ranged from 10 (Germany) to 349 per million (New Jersey) and it was 5 per million in India and 96 per million in Mexico. The absolute risk of COVID-19 death for people ≥80 years old ranged from 0.6 (Florida) to 17.5 per thousand (Connecticut). The COVID-19 mortality rate in people <65 years old during the period of fatalities from the epidemic was equivalent to the mortality rate from driving between 4 and 82 miles per day for 13 countries and 5 states, and was higher (equivalent to the mortality rate from driving 106-483 miles per day) for 8 other states and the UK. People <65 years old without underlying predisposing conditions accounted for only 0.7-3.6% of all COVID-19 deaths in France, Italy, Netherlands, Sweden, Georgia, and New York City and 17.7% in Mexico. People <65 years old have very small risks of COVID-19 death even in pandemic epicenters and deaths for people <65 years without underlying predisposing conditions are remarkably uncommon. Strategies focusing specifically on protecting high-risk elderly individuals should be considered in managing the pandemic.
2020-09-00 Number of COVID-19 deaths contributed by specific age group and population characteristics for 14 countries and 13 US states
Rodriguez L, Pekkarinen PT, Lakshmikanth T, Tan Z, Consiglio CR, [...], Brodin P
Cell Rep Med 1 (5) 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.
Maucourant C, Filipovic I, Ponzetta A, Aleman S, Cornillet M, [...], Karolinska COVID-19 Study Group
Sci Immunol 5 (50)
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.
Ying K, Zhai R, Pyrkov TV, Mariotti M, Fedichev PO, [...], Gladyshev VN
2020-08-07 Supplementary information contains information on publicly available data sources used, instruments used, data on loci associated with risk factors, and genetic correlations between lifespan-related traits and COVID-19
Lindahl JF, Hoffman T, Esmaeilzadeh M, Olsen B, Winter R, [...], Lundkvist Å
Infect Ecol Epidemiol 10 (1) 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
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.
Hultström M, von Seth M, Frithiof R
J Hypertens 38 (8) 1613-1614
No abstract available
2020-08-00 Provided in the article: biochemistry of patients in intensive care (N=9)
Pang J, Xu F, Aondio G, Li Y, Fumagalli A, [...], Cao Y
Nat Commun 12 (1) 814
On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O 2 ratio (PaO2/FiO2) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO2/FiO2 ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.
Su Y, Chen D, Lausted C, Yuan D, Choi J, [...], None
2020-07-28 pseudonymized RNA sequencing data available upon request from corresponding author (Due to potential risk of de-identification)
Qiao XM, Xu XF, Zi H, Liu GX, Li BH, [...], Wang X
Front Med (Lausanne) 7 349
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
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
Gao J, Liu JQ, Wen HJ, Liu H, Hu WD, [...], Wang XJ
Respir Res 21 (1) 96
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