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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. At this point, projects which share data openly or which explicitly promise to share data on request are included in this section. In the near future, only projects that either share data openly or have at least a metadata-only record with a clear data access procedure will be included.

Last updated: 2021-04-13

Project Last updated Available data
Messner CB, Demichev V, Bloomfield N, Yu JSL, White M, [...], Ralser M
Nat Biotechnol
10.1038/s41587-021-00860-4
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.
2021-03-25
Beridze G, Triolo F, Grande G, Fratiglioni L, Calderón-Larrañaga A
medRxiv
10.1101/2021.03.16.21253750
2021-03-20 Data available through the the Swedish National study on Aging and Care in Kungsholmen
Patel H, Ashton NJ, Dobson RJB, Andersson LM, Yilmaz A, [...], Zetterberg H
Sci Rep 11 (1) 6357
10.1038/s41598-021-85877-0
The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/ . Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.
2021-03-18
Cotugno N, Ruggiero A, Bonfante F, Petrara MR, Zicari S, [...], Palma P
Cell Rep 34 (11) 108852
10.1016/j.celrep.2021.108852
As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4 +CD40L+ T cells and Spike-specific B cells were associated with the anti-SARS-CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT+ patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.
2021-03-16
Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, [...], Steves CJ
Nat Med
10.1038/s41591-021-01292-y
Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called 'long COVID', are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app 1. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.
2021-03-10
Dillner J, Elfström KM, Blomqvist J, Eklund C, Lagheden C, [...], Conneryd Lundgren K
Sci Rep 11 (1) 5160
10.1038/s41598-021-84356-w
The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. We invited all employees (n = 15,300) at work at the Karolinska University Hospital, Stockholm, Sweden to participate in a study examining SARS-Cov-2 antibodies in relation to registered sick leave. For consenting 12,928 healthy hospital employees antibodies to SARS-CoV-2 could be determined and compared to participant sick leave records. Subjects with viral serum antibodies were not at excess risk for future sick leave (adjusted odds ratio (OR) controlling for age and sex: 0.85 [95% confidence interval (CI) (0.85 (0.43-1.68)]. By contrast, subjects with antibodies had an excess risk for sick leave in the weeks prior to testing [adjusted OR in multivariate analysis: 3.34 (2.98-3.74)]. Thus, presence of viral antibodies marks past disease and protection against excess risk of future disease. Knowledge of whether exposed subjects have had disease in the past or are at risk for future disease is essential for planning of control measures.Trial registration: First registered on 02/06/20, ClinicalTrials.gov NCT04411576.
2021-03-04 Available on request
Vlachos J, Hertegård E, B Svaleryd H
Proc Natl Acad Sci U S A 118 (9)
10.1073/pnas.2020834118
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.
2021-03-02
  • Analysis code
  • Data available from Statistics Sweden, the Public Health Agency, the National Board of Health and Welfare
Manisty C, Treibel TA, Jensen M, Semper A, Joy G, [...], Moon JC
EBioMedicine 65 103259
10.1016/j.ebiom.2021.103259
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
Ledberg A
Front Public Health 9 579948
10.3389/fpubh.2021.579948
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).
Sherina N, Piralla A, Du L, Wan H, Kumagai-Braesch M, [...], Pan-Hammarström Q
Med (N Y)
10.1016/j.medj.2021.02.001
Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody levels and specific memory B- and T-cell responses in convalescent coronavirus disease-2019 (COVID-19) patients. Altogether 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain antibody levels over a period of eight months. In addition, level of SARS-CoV-2 neutralizing antibodies, specific memory B- and T-cell responses were tested in a subset of samples. Anti-SARS-CoV-2 antibodies were present in 85% of the samples collected within 4 weeks after onset of symptoms in COVID-19 patients. Levels of specific IgM/IgA antibodies declined after 1 month while levels of specific IgG antibodies and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG antibodies were still present, though at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B- and T-cell responses developed with time and were persistent in all patients followed up till 6-8 months. Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 might persist for at least 6-8 months, regardless of disease severity. Development of medium or long-term protective immunity through vaccination might thus be possible. EU-ATAC consortium, the Italian Ministry of Health and SciLife/KAW.
2021-02-10 Demographic and clinical characteristics of the COVID-19 patients (N=122 Italian, N=12 Swedish)
Chen X, Saccon E, Appelberg KS, Mikaeloff F, Rodriguez JE, [...], Gupta S
medRxiv
10.1101/2021.02.04.429738
2021-02-04 Bioinformatics analysis code
Lourda M, Dzidic M, Hertwig L, Bergsten H, Palma Medina LM, [...], None
medRxiv
https://doi.org/10.1101/2021.01.27.21250591
2021-01-31 Karolinska KI/K Covid19 Immune atlas
Falck-Jones S, Vangeti S, Yu M, Falck-Jones R, Cagigi A, [...], Smed-Sorensen A
J Clin Invest 131 (6)
10.1172/JCI144734
The immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFNγ production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.
2021-01-28 Available on request
Alekseenko A, Barrett D, Pareja-Sanchez Y, Howard R, Strandback E, [...], Pelechano V
Sci Rep 11 (1) 1820
10.1038/s41598-020-80352-8
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.
2021-01-21
Persson BD, John L, Rafie K, Strebl M, Frängsmyr L, [...], Arnberg N
Proc Natl Acad Sci U S A 118 (3)
10.1073/pnas.2020732118
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
Langegård U, Kiani K, Nielsen SJ, Svensson P
BMC Nurs 20 (1) 23
10.1186/s12912-021-00542-1
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
Björkman A, Engström M, Winblad U, Holmström IK
BMC Nurs 20 (1)
10.1186/s12912-021-00540-3
2021-01-14 Available on request
Iravani B, Peter MG, Arshamian A, Olsson MJ, Hummel T, [...], Lundström JN
bioRxiv
10.1101/2021.01.11.426175
2021-01-13 Available on request
Koenig PA, Das H, Liu H, Kümmerer BM, Gohr FN, [...], Schmidt FI
Science 371 (6530) eabe6230
10.1126/science.abe6230
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.
2021-01-12
Sallam M, Dababseh D, Eid H, Al-Mahzoum K, Al-Haidar A, [...], Mahafzah A
Vaccines 9 (1) 42
10.3390/vaccines9010042
2021-01-12 Available on request
Kermani NZ, None , Song WJ, Badi Y, Versi A, [...], Chung KF
Respir Res 22 (1) 101876
10.1186/s12931-020-01605-8
Bats are reservoirs for a large number of viruses which have potential to cause major human disease outbreaks, including the current coronavirus disease 2019 (COVID-19) pandemic. Major efforts are underway to understand bat immune response to viruses, whereas much less is known about their immune responses to bacteria. In this study, MR1-restricted T (MR1T) cells were detected through the use of MR1 tetramers in circulation and tissues of Pteropus alecto (Pa) bats. Pa MR1T cells exhibited weak responses to MR1-presented microbial metabolites at resting state. However, following priming with MR1-presented agonist they proliferated, upregulated critical transcription factors and cytolytic proteins, and gained transient expression of Th1/17-related cytokines and antibacterial cytotoxicity. Collectively, these findings show that the Pa bat immune system encompasses an abundant and functionally conserved population of MR1T cells with mucosal-associated invariant T-like characteristics, suggesting that MR1 and MR1T cells also play a significant role in bat immune defense.
2021-01-07 Available on request
Spangler D, Blomberg H, Smekal D
Scand J Trauma Resusc Emerg Med 29 (1) 3
10.1186/s13049-020-00826-6
The novel coronavirus disease 2019 (Covid-19) pandemic has affected prehospital care systems across the world, but the prehospital presentation of affected patients and the extent to which prehospital care providers are able to identify them is not well characterized. In this study, we describe the presentation of Covid-19 patients in a Swedish prehospital care system, and asses the predictive value of Covid-19 suspicion as documented by dispatch and ambulance nurses. Data for all patients with dispatch, ambulance, and hospital records between January 1-August 31, 2020 were extracted. A descriptive statistical analysis of patients with and without hospital-confirmed Covid-19 was performed. In a subset of records beginning from April 14, we assessed the sensitivity and specificity of documented Covid-19 suspicion in dispatch and ambulance patient care records. A total of 11,894 prehospital records were included, of which 481 had a primary hospital diagnosis code related to-, or positive test results for Covid-19. Covid-19-positive patients had considerably worse outcomes than patients with negative test results, with 30-day mortality rates of 24% vs 11%, but lower levels of prehospital acuity (e.g. emergent transport rates of 14% vs 22%). About half (46%) of Covid-19-positive patients presented to dispatchers with primary complaints typically associated with Covid-19. Six thousand seven hundred seventy-six records were included in the assessment of predictive value. Sensitivity was 76% (95% CI 71-80) and 82% (78-86) for dispatch and ambulance suspicion respectively, while specificities were 86% (85-87) and 78% (77-79). While prehospital suspicion was strongly indicative of hospital-confirmed Covid-19, based on the sensitivity identified in this study, prehospital suspicion should not be relied upon as a single factor to rule out the need for isolation precautions. The data provided may be used to develop improved guidelines for identifying Covid-19 patients in the prehospital setting.
2021-01-06 Available on request
Havervall S, Jernbom Falk A, Klingstrom J, Ng H, Greilert Norin N, [...], Thalin C
medRxiv
10.1101/2021.01.03.21249162
2021-01-04 Available on request
Meijenfeldt FA, Havervall S, Adelmeijer J, Lundström A, Magnusson M, [...], Lisman T
Am J Hematol
10.1002/ajh.26085
2021-01-04 Available on request
Ahlström B, Frithiof R, Hultström M, Larsson I, Strandberg G, [...], Lipcsey M
Acta Anaesthesiol Scand 65 (4) 525-533
10.1111/aas.13781
Abstract Background: Several studies have recently addressed factors associated with severe Coronavirus disease 2019 (COVID-19); however, some medications and comorbidities have yet to be evaluated in a large matched cohort. We therefore explored the role of relevant comorbidities and medications in relation to the risk of intensive care unit (ICU) admission and mortality. Methods: All ICU COVID-19 patients in Sweden until 27 May 2020 were matched to population controls on age and sex to assess the risk of ICU admission. Cases were identified, comorbidities and medications were retrieved from high-quality registries. Three conditional logistic regression models were used for risk of ICU admission and three Cox proportional hazards models for risk of ICU mortality, one with comorbidities, one with medications and finally with both models combined, respectively. Results: We included 1981 patients and 7924 controls. Hypertension, type 2 diabetes mellitus, chronic renal failure, asthma, obesity, being a solid organ transplant recipient and immunosuppressant medications were independent risk factors of ICU admission and oral anticoagulants were protective. Stroke, asthma, chronic obstructive pulmonary disease and treatment with renin-angiotensin-aldosterone inhibitors (RAASi) were independent risk factors of ICU mortality in the pre-specified primary analyses; treatment with statins was protective. However, after adjusting for the use of continuous renal replacement therapy, RAASi were no longer an independent risk factor. Conclusion: In our cohort oral anticoagulants were protective of ICU admission and statins was protective of ICU death. Several comorbidities and ongoing RAASi treatment were independent risk factors of ICU admission and ICU mortality. This article is protected by
2021-01-04 Available on request
Pettke A, Tampere M, Pronk R, Wallner O, Falk A, [...], Puumalainen MR
Viruses 13 (1) 37
10.3390/v13010037
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
Virhammar J, Nääs A, Fällmar D, Cunningham JL, Klang A, [...], Rostami E
European Journal of Neurology
10.1111/ene.14703
Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19), and biomarkers of central nervous system (CNS) injury are reported to be increased in plasma but not extensively studied in cerebrospinal fluid (CSF). This study examined CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain [NfL] protein, glial fibrillary acidic protein [GFAp], and total tau), was performed and compared to neurological features and disease severity. Neurological symptoms included altered mental status (42%), headache (42%), and central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis, and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL protein, total tau, and GFAp were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL protein correlated with disease severity, time in intensive care, and level of consciousness. NfL protein in CSF was higher in patients with central neurological symptoms. Although limited by the small sample size, our data suggest that levels of NfL protein, GFAp, and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF workup where pathological findings are scarce. NfL protein, in particular, is associated with central neurological symptoms and disease severity.
2020-12-28
  • Provided in the article: patient characteristics and biomarkers in cerebrospinal fluid for 19 patients
  • Available on request
Dopico XC, Muschiol S, Christian M, Hanke L, Sheward DJ, [...], Karlsson Hedestam GB
medRxiv
10.1101/2020.12.24.20248821
2020-12-26
Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, [...], OHDSI-COVID-19 consortium
Rheumatology (Oxford)
10.1093/rheumatology/keaa771
Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA. We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%. A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis. HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation. Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.
2020-12-25 Data aggregated by data source
2020-12-22 Available on request
Beneria A, Arnedo M, Contreras S, Pérez-Carrasco M, Garcia-Ruiz I, [...], Rius JB
BMC Med Educ 20 (1) 515
10.1186/s12909-020-02427-4
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
10.1101/2020.12.15.20248279
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.
2020-12-16
Kennedy B, Martinell M, Hammar U, van Zoest V, Kristiansson RS, [...], Fall T
medRxiv
10.1101/2020.12.15.20248247
2020-12-16 Available on request
Gossen J, Albani S, Hanke A, Joseph BP, Bergh C, [...], Rossetti G
bioRxiv
10.1101/2020.12.14.422634
The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unfortunately, unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ~30,000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ~200 virtual screenings of compound libraries on selected protein structures, we redefine the protein’s druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.
2020-12-15 Simulation results for Sars-CoV2 3C-like main protease: TRAPP analysis of the binding site flexibility and results of the docking study
Dillner J, Elfström KM, Blomqvist J, Engstrand L, Uhlén M, [...], Lundgren KC
medRxiv
10.1101/2020.12.13.20248122
2020-12-14 Available on request
Godman B, Haque M, Islam S, Iqbal S, Urmi UL, [...], Sefah I
Front Public Health 8 585832
10.3389/fpubh.2020.585832
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
2020-12-12
Tampere M, Pettke A, Salata C, Wallner O, Koolmeister T, [...], Puumalainen MR
Viruses 12 (12) 1423
10.3390/v12121423
2020-12-10
Mondino E, Di Baldassarre G, Mård J, Ridolfi E, Rusca M
Sci Data 7 (1) 434
10.1038/s41597-020-00778-7
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)
Robertson J, Gostner JM, Nilsson S, Andersson L, Fuchs D, [...], Gisslen M
Infect Dis . 2020 Dec 10;20(1):942. Dec 10; 20 (1) 942
10.1186/s12879-020-05671-7
Background The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is rapidly spreading worldwide. There is limited information about prognostic markers that could help clinicians to identify COVID-19 patients with a poor prognosis. Serum levels of the immune activation marker neopterin has shown to be of prognostic value in patients with SARS. The aim of this study was to investigate whether serum neopterin is associated with the severity of COVID-19. Methods We included 34 patients with confirmed COVID-19 between March 3 and March 30, 2020. Fifteen patients had mild disease and did not require hospitalization, whereas 19 patients developed severe COVID-19 requiring intensive care. Concentrations of serum neopterin, tryptophan, and kynurenine were measured at and repeatedly after inclusion. Results We found a more than two-fold higher mean concentration of neopterin in severely ill patients (mean value 42.0 nmol/L (SD 18.2)) compared to patients with mild symptoms (16.9 nmol/L (SD 11.0)). All of the severe cases had elevated neopterin concentrations (>9.1 nmol/L) at the initial sampling with values ranging from 17.2 to 86.7 nmol/L. In comparison, 10 of 15 patients with mild disease had neopterin levels above 9.1 nmol/L, with concentrations in the range from 4.9 to 31.6 nmol/L. Neopterin levels gradually decreased during the course of COVID-19, but severe cases maintained elevated levels for a longer period. Moreover, lower levels of tryptophan and higher levels of kynurenine, indicating an increased tryptophan catabolism, were seen in the group with severe cases. Conclusions In conclusion, we found that serum neopterin levels are associated with the severity of COVID-19. Our findings suggest that neopterin could be used as a prognostic marker, but further studies are needed to elucidate how it can be used in clinical praxis.
2020-12-10 Available on request
Cagigi A, Yu M, Falck-Jones S, Vangeti S, Österberg B, [...], Smed-Sörensen A
medRxiv
10.1101/2020.11.25.20238592
2020-12-06 Available on request
Hofman P, Ilié M, Chamorey E, Brest P, Schiappa R, [...], Calabrese F
ESMO Open 6 (1) 100024
10.1016/j.esmoop.2020.100024
This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.
2020-12-02 Available on request
Mohammad MA, Koul S, Gale CP, Alfredsson J, James S, [...], Erlinge D
J Intern Med
10.1111/joim.13206
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
10.1007/s10875-020-00928-x
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
Nyman E, Lindh M, Lövfors W, Simonsson C, Persson A, [...], Cedersund G
CPT Pharmacometrics Syst. Pharmacol. 9 (12) 707-717
10.1002/psp4.12568
2020-12-00 Experimental data and data analysis code
Morales DR, Conover MM, You SC, Pratt N, Kostka K, [...], Suchard MA
The Lancet Digital Health
10.1016/s2589-7500(20)30289-2
2020-12-00 Data aggregated by data source
Mohammad MA, Koul S, Olivecrona GK, Gӧtberg M, Tydén P, [...], Erlinge D
Heart 106 (23) 1812-1818
10.1136/heartjnl-2020-317685
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
Pakpour AH, Al Mamun F, Hosen I, Griffiths MD, Mamun MA
Data Brief 33 106621
10.1016/j.dib.2020.106621
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.
2020-12-00
Appelberg S, Gupta S, Svensson Akusjärvi S, Ambikan AT, Mikaeloff F, [...], Neogi U
Emerg Microbes Infect 9 (1) 1748-1760
10.1080/22221751.2020.1799723
How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.
2020-12-00
Kirschenbaum D, Imbach LL, Jane Rushing E, Frauenknecht KBM, Gascho R T D, [...], Frontzek K
Neuropathol Appl Neurobiol
10.1111/nan.12677
Coronavirus disease 19 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2), has become a worldwide pandemic (1). Symptoms of COVID-19 vary widely and range from asymptomatic disease to severe pneumonia and multiorgan failure (2). A severe disease course is more likely in older patients and patients with pre-existing respiratory and cardiovascular conditions (2). Patients with severe Sars-CoV-2 infection may present with ischaemic stroke (3, 4) or even fatal intracerebral haemorrhage (5). To date, little is known about the neuropathological sequelae of COVID-19. The largest published autopsy series of COVID-19 neuropathology reported microthrombi and acute haemorrhagic infarction in a significant number of patients (6), while another more recent study found evidence of lymphocytic encephalitis and meningitis (7). Endotheliitis of the brain and extraneural organs has been shown in Sars-CoV infected patients (8). Similarly, it is a recurrent feature in the lungs and other peripheral organs of Sars-CoV-2 infected patients (9) but has not yet been reported in the central nervous system. We speculated that cerebrovascular pathology in COVID-19 patients could be a direct consequence of hitherto unidentified cerebral endotheliitis caused by Sars-CoV-2.
2020-11-29 Provided in the article: Clinical and pathological characteristics of four patients
Fellman D, Ritakallio L, Waris O, Jylkkä J, Laine M
Front Psychol 11 576466
10.3389/fpsyg.2020.576466
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 www.prolific.co. 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
10.3389/fpubh.2020.571364
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
10.1186/s13054-020-03375-7
A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates. The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding. In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible. Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500-4500 IU tinzaparin or 2500-5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin). Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis. Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission. Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis. A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis. Baseline characteristics did not differ between groups. For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02. The hazard ratio of death was 0.33 (95% confidence intervals 0.13-0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43-1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis. There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04. Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses. Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered.
2020-11-23 Available on request due to privacy restrictions
Ludvigsson JF
Acta Paediatr
10.1111/apa.15673
Persistent symptoms in adults after COVID-19 are emerging and the term long COVID is increasingly appearing in the literature. However, paediatric data are scarce . This paper contains a case report of five Swedish children and the long-term symptoms reported by their parents. It also includes a systematic literature review of the MEDLINE, EMBASE and Web of Science databases and the medRxiv/bioRxiv preprint servers up to 2 November 2020. The five children with potential long covid had a median age of 12 years (range 9-15) and four were girls. They had symptoms for 6-8 months after their clinical diagnoses of COVID-19. None were hospitalised at diagnosis, but one was later admitted for peri-myocarditis. All five children had fatigue, dyspnoea, heart palpitations or chest pain and four had headaches, difficulties concentrating, muscle weakness, dizziness and sore throats. Some had improved after 6-8 months, but they all suffered from fatigue and none had fully returned to school. The systematic review identified 179 publications and 19 of these were deemed relevant and read in detail. None contained any information on long COVID in children. Children may experience similar long COVID symptoms to adults and females may be more affected.
2020-11-17 Provided in the article: clinical data reported by parents of five children with long-term effects of COVID-19
Zeng HL, Dichio V, Rodríguez Horta E, Thorell K, Aurell E
Proc Natl Acad Sci USA 202012331
10.1073/pnas.2012331117
2020-11-17 Supplementary material
Elofsson A, Bryant P
medRxiv
10.1101/2020.07.03.20145649
In response to the pandemic development of the novel coronavirus (SARS-CoV-2), governments worldwide have implemented strategies of suppression by non-pharmaceutical interventions (NPIs). Such NPIs include social distancing, school closures, limiting international travel and complete lockdown. Worldwide the NPIs enforced to limit the spread of COVID-19 are now being lifted. Understanding how the risk increases when NPIs are lifted is important for decision making. Treating NPIs equally across countries and regions limits the possibility for modelling differences in epidemic response, as the response to the NPIs influences can vary between regions and this can affect the epidemic outcome, so do the strength and speed of lifting these. Our solution to this is to measure mobility changes from mobile phone data and their impacts on the basic reproductive number. We model the epidemic in all US states to compare the difference in outcome if NPIs are lifted or retained. We show that keeping NPIs just a few weeks longer has a substantial impact on the epidemic outcome.
2020-11-17 Analysis code and data
Susek KH, Gran C, Ljunggren HG, Alici E, Nahi H
Eur J Haematol. 105 (6) 751-754
10.1111/ejh.13502
COVID‐19 has emerged as a global pandemic. Cancer patients have been reported to be at higher risk for adverse outcome of COVID‐19. Studies are ongoing to decipher the risk factors and risk groups among cancer patients as well as strategies to refine treatment approaches. Here, we report eight patients with multiple myeloma that underwent immunomodulatory therapies with daratumumab or lenalidomide‐based combination treatments and one patient with smoldering multiple myeloma, all of which presented with symptomatic COVID‐19. We report that patients that succumbed to COVID‐19 presented with either progressive tumor disease under daratumumab treatment or were in remission under lenalidomide‐dexamethasone treatment.
2020-11-17 Provided in the article: Characteristics, treatments, COVID-19-related outcomes, additional laboratory and clinical data for 9 patients
Elofsson A, Bryant P
medRxiv
10.1101/2020.10.19.20215046
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 for modelling the spread of COVID-19 on a dynamic social network with spread reduction according to Google mobility changes
Stebbing J, Sánchez Nievas G, Falcone M, Youhanna S, Richardson P, [...], Lauschke VM
Sci Adv 7 (1)
10.1126/sciadv.abe4724
Using AI we identified baricitinib as possessing anti-viral and anti-cytokine efficacy. We now show a 71% (95% CI 0.15-0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age 81 years). A further 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold. RNA-Seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and super-resolution microscopy, baricitinib exerts activity rapidly through the inhibition of host proteins (numb associated kinases), uniquely amongst anti-virals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivizes further randomized controlled trials.
2020-11-13
Kharlamova N, Dunn N, Bedri SK, Jerling S, Almgren M, [...], Fogdell-Hahn A
medRxiv
10.1101/2020.11.13.20231076
Objectives 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 the tests give false positive results. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays with samples from patients with chronic inflammatory diseases collected before April 2019, thus defined as negative. Methods 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 RF +/- systemic lupus erythematosus (SLE, n=10), were tested with 17 commercially available lateral flow assays (LFA), two ELISA kits and one in-house developed multiplex bead-based assay. Results Six LFA and the in-house IgG assay gave the correct negative results for all samples. However, the majority of assays (n=13), gave false positive signal with samples from patients with RA and SLE. This was most notable in RF positive RA samples. MS samples did not give any false positive in any of the assays. Conclusion The majority of the verified serological assays were sensitive to interfering antibodies in samples from patients with chronic inflammatory diseases and therefore may have poor specificity in this context. For these patients, the risk of false positivity should be considered when interpreting results of the SARS-CoV-2 serological assays.
2020-11-13 Available on request
Saguti F, Magnil E, Enache L, Churqui MP, Johansson A, [...], Norder H
Water Res 189 116620
10.1016/j.watres.2020.116620
SARS-CoV-2 was discovered among humans in Wuhan, China in late 2019, and then spread rapidly, causing a global pandemic. The virus was found to be transmitted mainly by respiratory droplets from infected persons or by direct contact. It was also shown to be excreted in feces, why we investigated whether the virus could be detected in wastewater and if so, to which extent its levels reflects its spread in society. Samples of wastewater from the city of Gothenburg, and surrounding municipalities in Sweden were collected daily from mid-February until June 2020 at the Rya wastewater treatment plant. Flow proportional samples of wastewater were collected to ensure that comparable amounts were obtained for analysis. Daily samples were pooled into weekly samples. Virus was concentrated on a filter and analyzed by RT-qPCR. The amount of SARS-CoV-2 varied with peaks approximately every four week, preceding variations in number of newly hospitalized patients by 19-21 days. At that time virus testing for COVID-19 was limited to patients with severe symptoms. Local differences in viral spread was shown by analyzing weekly composite samples of wastewater from five sampling sites for four weeks. The highest amount of virus was found from the central, eastern, and northern parts of the city. SARS-CoV-2 was also found in the treated effluent wastewater from the WWTP discharged into the recipient, the Göta River, although with a reduction of 4-log 10. The viral peaks with regular temporal intervals indicated that SARS-CoV-2 may have a cluster spread, probably reflecting that the majority of infected persons only spread the disease during a few days. Our results are important for both the planning of hospital care and to rapidly identify and intervene against local spread of the virus.
2020-11-10 Provided in the article: amount of SARS-CoV-2 in wastewater in Gothenburg per week between February and June 2020
Wacker A, Weigand JE, Akabayov SR, Altincekic N, Bains JK, [...], Zetzsche H
Nucleic Acids Res 48 (22) 12415-12435
10.1093/nar/gkaa1013
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.
2020-11-10
Al-Tammemi AB, Akour A, Alfalah L
Front Psychol 11 562213
10.3389/fpsyg.2020.562213
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
Asif S, Frithiof R, Lipcsey M, Kristensen B, Alving K, [...], Hultström M
Crit Care 24 (1) 639
10.1186/s13054-020-03362-y
2020-11-06 Available on request
García M, Kokkinou E, Carrasco García A, Parrot T, Palma Medina LM, [...], Group tKKCS
Clin Transl Immunol 9 (12)
10.1002/cti2.1224
Objectives The role of innate lymphoid cells (ILCs) in coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unknown. Understanding the immune response in COVID-19 could contribute to unravel the pathogenesis and identification of treatment targets. To describe the phenotypic landscape of circulating ILCs in COVID-19 patients and to identify ILC phenotypes correlated to serum biomarkers, clinical markers, and laboratory parameters relevant in COVID-19. Methods Blood samples collected from moderately (n=11) and severely ill (n=12) COVID-19 patients as well as healthy control donors (n=16), were analyzed with 18-parameter flow cytometry. Using supervised and unsupervised approaches, we examined the ILC activation status and homing profile. Clinical and laboratory parameters were obtained from all COVID-19 patients and serum biomarkers were analyzed with multiplex immunoassays. Results ILCs were largely depleted from the circulation of COVID-19 patients compared with healthy controls. Remaining circulating ILCs from patients revealed increased frequencies of ILC2 in moderate COVID-19, with a concomitant decrease of ILC precursors (ILCp), as compared with controls. ILC2 and ILCp showed an activated phenotype with increased CD69 expression, whereas expression levels of the chemokine receptors CXCR3 and CCR4 were significantly altered in ILC2 and ILCp, and ILC1, respectively. The activated ILC profile of COVID-19 patients was associated with soluble inflammatory markers, while frequencies of ILC subsets were correlated with laboratory parameters that reflect the disease severity. Conclusion This study provides insights into the potential role of ILCs in immune responses against SARS-CoV-2, particularly linked to the severity of COVID-19.
2020-11-04 Karolinska KI/K Covid19 Immune atlas
Lundberg OHM, Lengquist M, Spångfors M, Annborn M, Bergmann D, [...], Friberg H
Crit Care 24 (1) 636
10.1186/s13054-020-03351-1
Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis. In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis. Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better. Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.
2020-11-04 Available on request
Custódio TF, Das H, Sheward DJ, Hanke L, Pazicky S, [...], Löw C
Nat Commun 11 (1)
10.1038/s41467-020-19204-y
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.
2020-11-04
Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, [...], OHDSI-COVID-19 consortium
Lancet Rheumatol 2 (11) e698-e711
10.1016/S2665-9913(20)30276-9
Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4. The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]). Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.
2020-11-00 Data aggregated by data source
Pellert M, Lasser J, Metzler H, Garcia D
Front Big Data 3 32
10.3389/fdata.2020.00032
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 derstandard.at, 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 http://www.mpellert.at/covid19_monitor_austria/. Our work is part of a web archive of resources on COVID-19 collected by the Austrian National Library.
2020-10-26 http://www.mpellert.at/covid19_monitor_austria/.
Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H, [...], Casanova J
Science 370 (6515)
10.1126/science.abd4585
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.
2020-10-23
Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, [...], Casanova J
Science 370 (6515) eabd4570
10.1126/science.abd4570
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.
2020-10-23
Marklund E, Leach S, Axelsson H, Nyström K, Norder H, [...], Gisslén M
PLoS One 15 (10) e0241104
10.1371/journal.pone.0241104
To accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset. SARS-CoV-2-specific IgG antibody levels were quantified using two clinically validated and widely used commercial serological assays (Architect, Abbott Laboratories and iFlash 1800, YHLO), detecting antibodies against the spike and nucleocapsid proteins. Forty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P = 0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset. Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys.
2020-10-21 Raw data
Castro Dopico X, Hanke L, Sheward DJ, Muschiol S, Aleman S, [...], Karlsson Hedestam GB
medRxiv
10.1101/2020.07.17.20155937
Serology is critical for understanding pathogen-specific immune responses, but is fraught with difficulty, not least because the strength of antibody (Ab) response varies greatly between individuals and mild infections generally generate lower Ab titers (1-3). We used robust IgM, IgG and IgA Ab tests to evaluate anti-SARS-CoV-2 responses in individuals PCR+ for virus RNA (n=105) representing different categories of disease severity, including mild cases. All PCR+ individuals in the study became IgG-positive against pre-fusion trimers of the virus spike (S) glycoprotein, but titers varied greatly. Elevated IgA, IL-6 and neutralizing responses were present in intensive care patients. Additionally, blood donors and pregnant women (n=2,900) sampled throughout the first wave of the pandemic in Stockholm, Sweden, further demonstrated that anti-S IgG titers differed several orders of magnitude between individuals, with an increase of low titer values present in the population at later time points (4,5). To improve upon current methods to identify low titers and extend the utility of individual measures (6,7), we used our PCR+ individual data to train machine learning algorithms to assign likelihood of past infection. Using these tools that assigned probability to individual responses against S and the receptor binding domain (RBD), we report SARS-CoV-2-specific IgG in 13.7% of healthy donors five months after the peak of spring COVID-19 deaths, when mortality and ICU occupancy in the country due to the virus were at low levels. These data further our understanding of antibody responses to the virus and provide solutions to problems in serology data analysis.
2020-10-19 Inferring seroprevalence from ELISA data, without choosing a cutoff
Almskog LM, Wikman A, Svensson J, Wanecek M, Bottai M, [...], Ågren A
J Thromb Thrombolysis
10.1007/s11239-020-02312-3
High prevalence of thrombotic events in severely ill COVID-19 patients have been reported. Pulmonary embolism as well as microembolization of vital organs may in these individuals be direct causes of death. The identification of patients at high risk of developing thrombosis may lead to targeted, more effective prophylactic treatment. The primary aim of this study was to test whether rotational thromboelastometry (ROTEM) at admission indicates hypercoagulopathy and predicts the disease severity, assessed as care level, in COVID-19 patients. The study was designed as a prospective, observational study where COVID-19 patients over 18 years admitted to hospital were eligible for inclusion. Patients were divided into two groups depending on care level: (1) regular wards or (2) wards with specialized ventilation support. Conventional coagulation tests, blood type and ROTEM were taken at admission. 60 patients were included; age 61 (median), 67% men, many with comorbidities (e.g. hypertension, diabetes). The ROTEM variables Maximum Clot Firmness (EXTEM-/FIBTEM-MCF) were higher in COVID-19 patients compared with in healthy controls (p < 0.001) and higher in severely ill patients compared with in patients at regular wards (p < 0.05). Our results suggest that hypercoagulopathy is present early in patients with mild to moderate disease, and more pronounced in severe COVID-19 pneumonia. Non-O blood types were not overrepresented in COVID-19 positive patients. ROTEM variables showed hypercoagulopathy at admission and this pattern was more pronounced in patients with increased disease severity. If this feature is to be used to predict the risk of thromboembolic complications further studies are warranted.
2020-10-17 Raw data
Rudberg A, Havervall S, Månberg A, Jernbom Falk A, Aguilera K, [...], Thålin C
Nat Commun 11 (1) 5064
10.1038/s41467-020-18848-0
SARS-CoV-2 may pose an occupational health risk to healthcare workers. Here, we report the seroprevalence of SARS-CoV-2 antibodies, self-reported symptoms and occupational exposure to SARS-CoV-2 among healthcare workers at a large acute care hospital in Sweden. The seroprevalence of IgG antibodies against SARS-CoV-2 was 19.1% among the 2149 healthcare workers recruited between April 14th and May 8th 2020, which was higher than the reported regional seroprevalence during the same time period. Symptoms associated with seroprevalence were anosmia (odds ratio (OR) 28.4, 95% CI 20.6-39.5) and ageusia (OR 19.2, 95% CI 14.3-26.1). Seroprevalence was also associated with patient contact (OR 2.9, 95% CI 1.9-4.5) and covid-19 patient contact (OR 3.3, 95% CI 2.2-5.3). These findings imply an occupational risk for SARS-CoV-2 infection among healthcare workers. Continued measures are warranted to assure healthcare workers safety and reduce transmission from healthcare workers to patients and to the community.
2020-10-08 Data available upon request and collaboration inquiries welcome.
Rogstam A, Nyblom M, Christensen S, Sele C, Talibov VO, [...], Kozielski F
Int J Mol Sci 21 (19)
10.3390/ijms21197375
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.
2020-10-06
Edén A, Kanberg N, Gostner J, Fuchs D, Hagberg L, [...], Gisslén M
Neurology 96 (2) e294-e300
10.1212/WNL.0000000000010977
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
Sekine T, Perez-Potti A, Rivera-Ballesteros O, Strålin K, Gorin J, [...], Buggert M
Cell 183 (1) 158-168.e14
10.1016/j.cell.2020.08.017
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.
2020-10-01
Calderón-Larrañaga A, Vetrano DL, Rizzuto D, Bellander T, Fratiglioni L, [...], Dekhtyar S
BMJ Glob Health 5 (10)
10.1136/bmjgh-2020-003595
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)
Frithiof R, Bergqvist A, Järhult JD, Lipcsey M, Hultström M
Crit Care 24 (1) 587
10.1186/s13054-020-03302-w
2020-09-29 Available on request
Parrot T, Gorin J, Ponzetta A, Maleki KT, Kammann T, [...], Sandberg JK
Sci Immunol 5 (51)
10.1126/sciimmunol.abe1670
Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69 high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis.
2020-09-28 Karolinska KI/K Covid19 Immune atlas
Hellman U, Karlsson MG, Engström-Laurent A, Cajander S, Dorofte L, [...], Blomberg A
J Biol Chem 295 (45) 15418-15422
10.1074/jbc.AC120.015967
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
10.1038/s41467-020-18611-5
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.
2020-09-23
Kanberg N, Ashton NJ, Andersson LM, Yilmaz A, Lindh M, [...], Gisslén M
Neurology 95 (12) e1754-e1759
10.1212/WNL.0000000000010111
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
Frithiof R, Rostami E, Kumlien E, Virhammar J, Fällmar D, [...], Punga AR
Research square
10.21203/rs.3.rs-78038/v1
2020-09-22 Available on request
Akaberi D, Krambrich J, Ling J, Luni C, Hedenstierna G, [...], Lundkvist Å
Redox Biology 37 101734
10.1016/j.redox.2020.101734
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
Dillner J, Elfström M, Blomqvist J, Eklund C, Lagheden C, [...], Conneryd Lundgren K
medRxiv
10.1101/2020.09.14.20194308
Background: The extent that antibodies to SARS-CoV-2 may protect against future virus-associated disease is unknown. Method: We analyzed 12928 healthy hospital employees for SARS-CoV-2 antibodies and compared results to participant sick leave records (Clinical trial registration: ClinicalTrials.gov NCT04411576). Results: Subjects with viral serum antibodies were not at excess risk for future sick leave (Odds Ratio (OR): 0.85 (95% Confidence Interval (CI) (0.85 (0.43-1.68)). By contrast, subjects with antibodies had an excess risk for sick leave in the past weeks (OR: 3.34 (2.98-3.74)). Conclusion: Presence of viral antibodies marks past disease and protection against excess risk of future disease.
2020-09-18 Pseudonymised, individual-level data available on request.
Bryant P, Elofsson A
PeerJ 8 e9879
10.7717/peerj.9879
As governments across Europe have issued non-pharmaceutical interventions (NPIs) such as social distancing and school closing, the mobility patterns in these countries have changed. Most states have implemented similar NPIs at similar time points. However, it is likely different countries and populations respond differently to the NPIs and that these differences cause mobility patterns and thereby the epidemic development to change. We build a Bayesian model that estimates the number of deaths on a given day dependent on changes in the basic reproductive number, R0, due to differences in mobility patterns. We utilise mobility data from Google mobility reports using five different categories: retail and recreation, grocery and pharmacy, transit stations, workplace and residential. The importance of each mobility category for predicting changes in R0 is estimated through the model. The changes in mobility have a considerable overlap with the introduction of governmental NPIs, highlighting the importance of government action for population behavioural change. The shift in mobility in all categories shows high correlations with the death rates 1 month later. Reduction of movement within the grocery and pharmacy sector is estimated to account for most of the decrease in R0. Our model predicts 3-week epidemic forecasts, using real-time observations of changes in mobility patterns, which can provide governments with direct feedback on the effects of their NPIs. The model predicts the changes in a majority of the countries accurately but overestimates the impact of NPIs in Sweden and Denmark and underestimates them in France and Belgium. We also note that the exponential nature of all epidemiological models based on the basic reproductive number, R0 cause small errors to have extensive effects on the predicted outcome.
2020-09-15 Modelling code and data
Ling J, Hickman RA, Li J, Lu X, Lindahl JF, [...], Järhult JD
Viruses 12 (9)
10.3390/v12091026
During the COVID-19 pandemic, the virus evolved, and we therefore aimed to provide an insight into which genetic variants were enriched, and how they spread in Sweden. We analyzed 348 Swedish SARS-CoV-2 sequences freely available from GISAID obtained from 7 February 2020 until 14 May 2020. We identified 14 variant sites ≥5% frequency in the population. Among those sites, the D936Y substitution in the viral Spike protein was under positive selection. The variant sites can distinguish 11 mutational profiles in Sweden. Nine of the profiles appeared in Stockholm in March 2020. Mutational profiles 3 (B.1.1) and 6 (B.1), which contain the D936Y mutation, became the predominant profiles over time, spreading from Stockholm to other Swedish regions during April and the beginning of May. Furthermore, Bayesian phylogenetic analysis indicated that SARS-CoV-2 could have emerged in Sweden on 27 December 2019, and community transmission started on February 1st with an evolutionary rate of 1.5425 × 10 -3 substitutions per year. Our study provides novel knowledge on the spatio-temporal dynamics of Swedish SARS-CoV-2 variants during the early pandemic. Characterization of these viral variants can provide precious insights on viral pathogenesis and can be valuable for diagnostic and drug development approaches.
2020-09-14 Spatial temporal appearance of each variant and their mutation profile and clade information; Other supplementary materials.
Glans H, Gredmark-Russ S, Olausson M, Falck-Jones S, Varnaite R, [...], Brave A
medRxiv
10.1101/2020.09.11.20191940
To understand the risk of transmission of SARS-CoV-2 in hospitalized COVID-19 patients we simultaneously assessed the presence of SARS-CoV-2 RNA, live infectious virus in the airways, and virus-specific IgG and neutralizing antibodies in sera in 36 hospitalized COVID-19 patients. SARS-CoV-2 could be cultured from four patients, all with low or undetectable antibody response. Our data suggests that the level of SARS-CoV-2 antibodies may correlate to risk for shedding live SARS-CoV-2 virus in hospitalized COVID-19 patients.
2020-09-13 Available on request
Bortz RH, Florez C, Laudermilch E, Wirchnianski AS, Lasso G, [...], Chandran K
medRxiv
10.1101/2020.09.10.20192187
The COVID-19 global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to place an immense burden on societies and healthcare systems. A key component of COVID-19 control efforts is serologic testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test makes it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.
2020-09-11 Available on request
Virhammar J, Kumlien E, Fällmar D, Frithiof R, Jackmann S, [...], Rostami E
Neurology 95 (10) 445-449
10.1212/wnl.0000000000010250
Here, we report a case of COVID-19–related acute necrotizing encephalopathy where SARS-CoV-2 RNA was found in CSF 19 days after symptom onset after testing negative twice. Although monocytes and protein levels in CSF were only marginally increased, and our patient never experienced a hyperinflammatory state, her neurologic function deteriorated into coma. MRI of the brain showed pathologic signal symmetrically in central thalami, subinsular regions, medial temporal lobes, and brain stem. Extremely high concentrations of the neuronal injury markers neurofilament light and tau, as well as an astrocytic activation marker, glial fibrillary acidic protein, were measured in CSF. Neuronal rescue proteins and other pathways were elevated in the in-depth proteomics analysis. The patient received IV immunoglobulins and plasma exchange. Her neurologic status improved, and she was extubated 4 weeks after symptom onset. This case report highlights the neurotropism of SARS-CoV-2 in selected patients and emphasizes the importance of repeated lumbar punctures and CSF analyses in patients with suspected COVID-19 and neurologic symptoms.
2020-09-08 Proteomic data
Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, [...], Brodin P
Cell 183 (4) 968-981.e7
10.1016/j.cell.2020.09.016
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.
2020-09-06
Larsson E, Brattström O, Agvald-Öhman C, Grip J, Campoccia Jalde F, [...], Karolinska Intensive Care COVID-19 Study Group
Acta Anaesthesiol Scand 65 (1) 76-81
10.1111/aas.13694
Information on characteristics and outcomes of intensive care unit (ICU) patients with COVID-19 remains limited. We examined characteristics, clinical course and early outcomes of patients with COVID-19 admitted to ICU. We included all 260 patients with COVID-19 admitted to nine ICUs at the Karolinska University Hospital (Stockholm, Sweden) between 9 March and 20 April 2020. Primary outcome was in-hospital mortality among patients with definite outcomes (discharged from ICU or death), as of 30 April 2020 (study end point). Secondary outcomes included ICU length of stay, the proportion of patients receiving mechanical ventilation and renal replacement therapy, and hospital discharge destination. Of 260 ICU patients with COVID-19, 208 (80.0%) were men, the median age was 59 (IQR 51-65) years, 154 (59.2%) had at least one comorbidity, and the median duration of symptoms preceding ICU admission was 11 (IQR 8-14) days. Sixty-two (23.8%) patients remained in ICU at study end point. Among the 198 patients with definite outcomes, ICU length of stay was 12 (IQR, 6-18) days, 163 (82.3%) received mechanical ventilation, 28 (14.1%) received renal replacement therapy, 60 (30.3%) died, 62 (31.3%) were discharged home, 47 (23.7%) were discharged to ward, and 29 (14.6%) were discharged to another health care facility. On multivariable logistic regression analysis, older age and admission from the emergency department was associated with higher mortality. This study presents detailed data on clinical characteristics and early outcomes of consecutive patients with COVID-19 admitted to ICU in a large tertiary hospital in Sweden.
2020-09-06 Available on request
Hanke L, Vidakovics Perez L, Sheward DJ, Das H, Schulte T, [...], McInerney GM
Nat Commun 11 (1) 4420
10.1038/s41467-020-18174-5
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.
2020-09-04
Morgantini LA, Naha U, Wang H, Francavilla S, Acar Ö, [...], Weine SM
PLoS One 15 (9) e0238217
10.1371/journal.pone.0238217
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
10.1016/j.envres.2020.109890
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
Soratto TAT, Darban H, Bjerkner A, Coorens M, Albert J, [...], Andersson B
Microbiol Resour Announc 9 (35)
10.1128/mra.00934-20
2020-08-27 ENA PRJEB39632: SARS-CoV-2 genomes from late April in Stockholm, Sweden
Rodriguez L, Pekkarinen PT, Lakshmikanth T, Tan Z, Consiglio CR, [...], Brodin P
Cell Rep Med 1 (5) 100078
10.1016/j.xcrm.2020.100078
Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.
2020-08-25
Maucourant C, Filipovic I, Ponzetta A, Aleman S, Cornillet M, [...], Karolinska COVID-19 Study Group
Sci Immunol 5 (50)
10.1126/sciimmunol.abd6832
Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56 bright NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease.
2020-08-21
Hultström M, Persson B, Eriksson O, Lipcsey M, Frithiof R, [...], Nilsson B
Crit Care 24 (1) 496
10.1186/s13054-020-03223-8
No abstract available
2020-08-12 Available on request
Huckriede J, Anderberg SB, Morales A, Vries Fd, Hultström M, [...], Nicolaes GAF
Research square
10.21203/rs.3.rs-52432/v1
2020-08-05 Available on request
Lindahl JF, Hoffman T, Esmaeilzadeh M, Olsen B, Winter R, [...], Lundkvist Å
Infect Ecol Epidemiol 10 (1) 1789036
10.1080/20008686.2020.1789036
The COVID-19 pandemic is growing and spread in the Swedish elderly care system during April 2020. The increasing number of employees on sick-leave due to COVID-19 created severe logistic problems. Some elderly care homes therefore started to screen their personnel to secure the safety of the elderly and to avoid unnecessary quarantine of potentially immune employees. Secondary data from a screening with a COVID-19 rapid test for detection of SARS-CoV-2-specific IgM and IgG of 1,005 employees in 22 elderly care homes in Stockholm, Sweden, were analyzed. Seropositive employees were found in 21 out of the 22 care homes. In total, 23% (231/1,005) of the employees tested positive for antibodies against SARS-CoV-2, and 14.3% (144/1,005) were found positive for IgM (either alone or combined with IgG), indicating recent or present infection. Of those that tested seropositive, 46.5% did not report any clinical symptoms, indicating pre- or asymptomatic infections. Reported symptoms with the highest correlation with seropositivity were fever and loss of smell and taste. These results suggest that antibody testing of employees in elderly care homes is valuable for surveillance of disease development and a crucial screening tool in the effort to decrease the death toll in this pandemic.
2020-08-05 Serological responses of 1,005 employees to SARS-CoV-2 at 22 different elderly care homes in Stockholm
Böhmer MM, Buchholz U, Corman VM, Hoch M, Katz K, [...], Zapf A
Lancet Infect Dis 20 (8) 920-928
10.1016/S1473-3099(20)30314-5
In December, 2019, the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, causing COVID-19, a respiratory disease presenting with fever, cough, and often pneumonia. WHO has set the strategic objective to interrupt spread of SARS-CoV-2 worldwide. An outbreak in Bavaria, Germany, starting at the end of January, 2020, provided the opportunity to study transmission events, incubation period, and secondary attack rates. A case was defined as a person with SARS-CoV-2 infection confirmed by RT-PCR. Case interviews were done to describe timing of onset and nature of symptoms and to identify and classify contacts as high risk (had cumulative face-to-face contact with a confirmed case for ≥15 min, direct contact with secretions or body fluids of a patient with confirmed COVID-19, or, in the case of health-care workers, had worked within 2 m of a patient with confirmed COVID-19 without personal protective equipment) or low risk (all other contacts). High-risk contacts were ordered to stay at home in quarantine for 14 days and were actively followed up and monitored for symptoms, and low-risk contacts were tested upon self-reporting of symptoms. We defined fever and cough as specific symptoms, and defined a prodromal phase as the presence of non-specific symptoms for at least 1 day before the onset of specific symptoms. Whole genome sequencing was used to confirm epidemiological links and clarify transmission events where contact histories were ambiguous; integration with epidemiological data enabled precise reconstruction of exposure events and incubation periods. Secondary attack rates were calculated as the number of cases divided by the number of contacts, using Fisher's exact test for the 95% CIs. Patient 0 was a Chinese resident who visited Germany for professional reasons. 16 subsequent cases, often with mild and non-specific symptoms, emerged in four transmission generations. Signature mutations in the viral genome occurred upon foundation of generation 2, as well as in one case pertaining to generation 4. The median incubation period was 4·0 days (IQR 2·3-4·3) and the median serial interval was 4·0 days (3·0-5·0). Transmission events were likely to have occurred presymptomatically for one case (possibly five more), at the day of symptom onset for four cases (possibly five more), and the remainder after the day of symptom onset or unknown. One or two cases resulted from contact with a case during the prodromal phase. Secondary attack rates were 75·0% (95% CI 19·0-99·0; three of four people) among members of a household cluster in common isolation, 10·0% (1·2-32·0; two of 20) among household contacts only together until isolation of the patient, and 5·1% (2·6-8·9; 11 of 217) among non-household, high-risk contacts. Although patients in our study presented with predominately mild, non-specific symptoms, infectiousness before or on the day of symptom onset was substantial. Additionally, the incubation period was often very short and false-negative tests occurred. These results suggest that although the outbreak was controlled, successful long-term and global containment of COVID-19 could be difficult to achieve. All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.
2020-08-00
Hultström M, von Seth M, Frithiof R
J Hypertens 38 (8) 1613-1614
10.1097/HJH.0000000000002531
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
10.1038/s41467-021-21085-8
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.
2020-07-29
Roxhed N, Bendes A, Dale M, Mattsson C, Hanke L, [...], Schwenk JM
medRxiv
10.1101/2020.07.01.20143966
The COVID-19 pandemic has posed a tremendous challenge for the global community. We established a translational approach combining home blood sampling by finger-pricking with multiplexed serology to assess the exposure to the SARS-CoV-2 virus in a general population. The developed procedure determines the immune response in multiplexed assays against several spike (S, here denoted SPK), receptor binding domain (RBD) and nucleocapsid (NCP) proteins in eluates from dried capillary blood. The seroprevalence was then determined in two study sets by mailing 1000 blood sampling kits to random households in urban Stockholm during early and late April 2020, respectively. After receiving 55% (1097/2000) of the cards back within three weeks, 80% (878/1097) were suitable for the analyses of IgG and IgM titers. The data revealed diverse pattern of immune response, thus seroprevalence was dependent on the antigen, immunoglobulin class, stringency to include different antigens, as well as the required analytical performance. Applying unsupervised dimensionality reduction to the combined IgG and IgM data, 4.4% (19/435; 95% CI: 2.4%-6.3%) and 6.3% (28/443; 95% CI: 4.1%-8.6%) of the samples clustered with convalescent controls. Using overlapping scores from at least two SPK antigens, prevalence rates reached 10.1% (44/435; 95% CI: 7.3%-12.9%) in study set 1 and 10.8% (48/443; 95% CI: 7.9%-13.7%). Measuring the immune response against several SARS-CoV-2 proteins in a multiplexed workflow can provide valuable insights about the serological diversity and improve the certainty of the classification. Combining such assays with home-sampling of blood presents a viable strategy for individual-level diagnostics and towards an unbiased assessment of the seroprevalence in a population and may serve to improve our understanding about the diversity of COVID-19 etiology.
2020-07-02 Available on request
Altay O, Mohammadi E, Lam S, Turkez H, Boren J, [...], Mardinoglu A
iScience 23 (7) 101303
10.1016/j.isci.2020.101303
The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2.
2020-07-00 Supplementary information
Patel H, Ashton NJ, Dobson RJ, Anderson LM, Yilmaz A, [...], Zetterberg H
Sci Rep 11 (1)
https://doi.org/10.1038/s41598-021-85877-0
The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in the majority of individuals leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. The purpose of this study is to explore the proteomic differences between mild, severe and critical COVID-19 positive patients. Blood protein profiling was performed on 59 COVID-19 mild (n=26), severe (n=9) or critical (n=24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/. Our results demonstrate that dynamic changes in blood proteins that associate with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic target.
2020-06-23
Qiao XM, Xu XF, Zi H, Liu GX, Li BH, [...], Wang X
Front Med (Lausanne) 7 349
10.3389/fmed.2020.00349
Background: The frequent emergence of the re-positive patients with COVID-19 is a potential threat worldwide. This study aimed to describe data from admission to follow-up for patients with COVID-19 and analyze the possible causes for re-positive nucleic acid tests to provide more scientific basis for reducing the numbers of re-positive patients after discharge. Methods: We retrospectively recorded 15 patients with COVID-19 admitted to the Xianyang Central Hospital, China. The baseline, exposure histories, clinical syndromes, laboratory characteristics, nucleic acid, and follow-up tests were analyzed, and the radiological characteristics of re-positive patient at different periods were compared. Results: Eight (53.33%) patients had the history of travel to Wuhan, four (26.67%) patients had close contact with confirmed patients, and one (6.67%) patient had close contact with suspected patients. After treatment, all patients had two consecutively negative nucleic acid tests and were discharged from hospital. All patients were followed up for more than 14 days, and the average time from discharge to the first follow-up was 14.67 ± 3.31 days (from 9 to 22 days). Most patients showed no clinical symptoms and negative nucleic acid tests, while one patient had an itchy throat, her CT scan showed a light density shadow in the right lower lobe of the lung, and the nucleic acid was once again positive. The second follow-up of the other 14 patients (except the re-positive one) was conducted 20.80 ± 7.78 days (from 13 to 30 days) after discharge, and all of them had negative nucleic acid tests. The positive patient was immediately readmitted and received a new round of treatment. Her family members and colleagues remained healthy until now. Conclusions: The quality of nucleic acid testing reagents should be enhanced, and the training of nucleic acid sampling operators should be strengthened to reduce the false-negative results in the nucleic acid of SARS-CoV-2; the clinical specimens of throat and nasopharynx swabs can be collected at the same time; IgM- and IgG-specific antibodies of SARS-CoV-2 should be carried out for discharged patients; the radiological characteristics should be evaluated strictly; and the discharge standard can be specified according to the baseline and severity of disease of patients.
2020-06-23 All data provided in the article
Jia JS, Lu X, Yuan Y, Xu G, Jia J, [...], Christakis NA
Nature 582 (7812) 389-394
10.1038/s41586-020-2284-y
Sudden, large-scale and diffuse human migration can amplify localized outbreaks of disease into widespread epidemics 1-4. Rapid and accurate tracking of aggregate population flows may therefore be epidemiologically informative. Here we use 11,478,484 counts of mobile phone data from individuals leaving or transiting through the prefecture of Wuhan between 1 January and 24 January 2020 as they moved to 296 prefectures throughout mainland China. First, we document the efficacy of quarantine in ceasing movement. Second, we show that the distribution of population outflow from Wuhan accurately predicts the relative frequency and geographical distribution of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) until 19 February 2020, across mainland China. Third, we develop a spatio-temporal 'risk source' model that leverages population flow data (which operationalize the risk that emanates from epidemic epicentres) not only to forecast the distribution of confirmed cases, but also to identify regions that have a high risk of transmission at an early stage. Fourth, we use this risk source model to statistically derive the geographical spread of COVID-19 and the growth pattern based on the population outflow from Wuhan; the model yields a benchmark trend and an index for assessing the risk of community transmission of COVID-19 over time for different locations. This approach can be used by policy-makers in any nation with available data to make rapid and accurate risk assessments and to plan the allocation of limited resources ahead of ongoing outbreaks.
2020-06-00 Population outflow data from Wuhan from January 1-24, 2020; COVID-19 case counts as of February 19 and other data for 296 prefectures in mainland China
Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, [...], Penninger JM
Cell 181 (4) 905-913.e7
10.1016/j.cell.2020.04.004
We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
2020-05-14
Sakib N, Bhuiyan AKMI, Hossain S, Al Mamun F, Hosen I, [...], Mamun MA
Int J Ment Health Addict 1-12
10.1007/s11469-020-00289-x
The recently developed Fear of COVID-19 Scale (FCV-19S) is a seven-item uni-dimensional scale that assesses the severity of fears of COVID-19. Given the rapid increase of COVID-19 cases in Bangladesh, we aimed to translate and validate the FCV-19S in Bangla. The forward-backward translation method was used to translate the English version of the questionnaire into Bangla. The reliability and validity properties of the Bangla FCV-19S were rigorously psychometrically evaluated (utilizing both confirmatory factor analysis and Rasch analysis) in relation to socio-demographic variables, national lockdown variables, and response to the Bangla Health Patient Questionnaire. The sample comprised 8550 Bangladeshi participants. The Cronbach α value for the Bangla FCV-19S was 0.871 indicating very good internal reliability. The results of the confirmatory factor analysis showed that the uni-dimensional factor structure of the FCV-19S fitted well with the data. The FCV-19S was significantly correlated with the nine-item Bangla Patient Health Questionnaire (PHQ-90) (r = 0.406, p < 0.001). FCV-19S scores were significantly associated with higher worries concerning lockdown. Measurement invariance of the FCV-19S showed no differences with respect to age or gender. The Bangla version of FCV-19S is a valid and reliable tool with robust psychometric properties which will be useful for researchers carrying out studies among the Bangla speaking population in assessing the psychological impact of fear from COVID-19 infection during this pandemic.
2020-05-11 Available on request
Gao J, Liu JQ, Wen HJ, Liu H, Hu WD, [...], Wang XJ
Respir Res 21 (1) 96
10.1186/s12931-020-01363-7
The novel coronavirus disease (COVID-19) outbreak started in December 2019 in Wuhan, China, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The CT image is used to assess the disease progress, whereas the continued two times of negative results from SARS-CoV-2 nucleic acid detection had been considered as a criterion for ending antiviral treatment. We compared the two COVID-19 cases with similar backgrounds and CT image repeated intervals under treatment. Our report highlighted the unsynchronized expression in the changes of CT image and nucleic acid detection in COVID-19, and lasting positive nucleic acid test result in patients recovered from pneumonia. It may be contributed to recognize the disease and improve prevention.
2020-04-22 Provided in the article: CT images for 2 patients over 12 days