Publications by authors named "Bitten Aagaard"

8 Publications

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Estimation of SARS-CoV-2 infection fatality rate by age and comorbidity status using antibody screening of blood donors during the COVID-19 epidemic in Denmark.

J Infect Dis 2021 Nov 12. Epub 2021 Nov 12.

Department of Clinical Immunology, Aarhus University Hospital, Aarhus N, Denmark.

Background: Studies presenting the SARS-CoV-2 infection fatality rate (IFR) for healthy individuals are warranted. Here we estimate the IFR by age and comorbidity status using data from a large serosurvey among Danish blood donors and nationwide data on COVID-19 mortality.

Methods: Danish blood donors aged 17 to 69 years donating blood between October 2020 and February 2021 were tested with a commercial SARS-CoV-2 total antibody assay. IFR was estimated for weeks 11 to 42, 2020 and for week 43, 2020 to week 6, 2021, representing the first two waves of the COVID-19 epidemic in Denmark.

Results: In total, 84,944 blood donors were tested for antibodies. The seroprevalence was 2% in October 2020 and 7% in February 2021. Among 3,898,039 Danish residents aged 17 to 69 years, 249 deaths were recorded. The IFR was low for people younger than 51 years without comorbidity during the two waves (combined IFR = 3.36 per 100,000 infections). The IFR was below 3‰ for people aged 61 to 69 years without comorbidity. IFR increased with age and comorbidity but declined from the first to the second wave.

Conclusions: In this nationwide study, the IFR was very low among people younger than 51 years without comorbidity.
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http://dx.doi.org/10.1093/infdis/jiab566DOI Listing
November 2021

The new donor vigilance system in Denmark reveals regional differences in adverse reactions supposedly caused by variation in the registration.

Vox Sang 2021 Sep 15. Epub 2021 Sep 15.

Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.

Background And Objectives: In recent years, there has been an increased focus among blood bank professionals on the health and safety of blood donors. In 2019, the Danish Haemovigilance Committee designed a national donor vigilance system to improve the registration of adverse reactions (AR) in blood donors. The new donor vigilance system was implemented on 1 January 2020 and we here present the results from the first year of registration.

Materials And Methods: AR categories, severity level and imputability score were defined based on the definitions from the International Society of Blood Transfusion, AABB and the European Commission directive 2005/61/EC, respectively.

Results: Across all severity levels, AR in Danish blood donors were found to be rare (1498 per 100,000 donations). Only 0.2% of the registered reactions were classified as serious (2.7 per 100,000 donations). Large regional differences were seen in the registration of citrate reactions and haematomas.

Conclusion: Significant differences across regions in what to categorize as an AR were persistent even when including a severity score in the reporting. The Danish Haemovigilance Committee will commence a national work to align the definitions but suggests that this matter is raised to an international level as part of the current work to agree upon definitions for assessment of donor AR.
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http://dx.doi.org/10.1111/vox.13202DOI Listing
September 2021

Characterization of Fitness and Convalescent Antibody Neutralization of SARS-CoV-2 Cluster 5 Variant Emerging in Mink at Danish Farms.

Front Microbiol 2021 25;12:698944. Epub 2021 Jun 25.

Virus and Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen, Denmark.

In addition to humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit to animals that include hamsters, cats, dogs, mink, ferrets, tigers, lions, cynomolgus macaques, rhesus macaques, and treeshrew. Among these, mink are particularly susceptible. Indeed, 10 countries in Europe and North America reported SARS-CoV-2 infection among mink on fur farms. In Denmark, SARS-CoV-2 spread rapidly among mink farms and spilled-over back into humans, acquiring mutations/deletions with unknown consequences for virulence and antigenicity. Here we describe a mink-associated SARS-CoV-2 variant (Cluster 5) characterized by 11 amino acid substitutions and four amino acid deletions relative to Wuhan-Hu-1. Temporal virus titration, together with genomic and subgenomic viral RNA quantitation, demonstrated a modest fitness attenuation of the Cluster 5 virus in the Vero-E6 cell line. Potential alterations in antigenicity conferred by amino acid changes in the spike protein that include three substitutions (Y453F, I692V, and M1229I) and a loss of two amino acid residues 69 and 70 (ΔH69/V70), were evaluated in a virus microneutralization assay. Compared to a reference strain, the Cluster 5 variant showed reduced neutralization in a proportion of convalescent human COVID-19 samples. The findings underscore the need for active surveillance SARS-CoV-2 infection and virus evolution in susceptible animal hosts.
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http://dx.doi.org/10.3389/fmicb.2021.698944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267889PMC
June 2021

Comparison of 16 Serological SARS-CoV-2 Immunoassays in 16 Clinical Laboratories.

J Clin Microbiol 2021 04 20;59(5). Epub 2021 Apr 20.

Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.

Serological assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to support clinical diagnosis and epidemiological investigations. Recently, assays for large-scale detection of total antibodies (Ab), immunoglobulin G (IgG), and IgM against SARS-CoV-2 antigens have been developed, but there are limited data on the diagnostic accuracy of these assays. This study was a Danish national collaboration and evaluated 15 commercial and one in-house anti-SARS-CoV-2 assays in 16 laboratories. Sensitivity was evaluated using 150 samples from individuals with asymptomatic, mild, or moderate COVID-19, nonhospitalized or hospitalized, confirmed by nucleic acid amplification tests (NAAT); samples were collected 13 to 73 days either from symptom onset or from positive NAAT (patients without symptoms). Specificity and cross-reactivity were evaluated in samples collected prior to the SARS-CoV-2 epidemic from >586 blood donors and patients with autoimmune diseases, cytomegalovirus or Epstein-Barr virus infections, and acute viral infections. A specificity of ≥99% was achieved by all total-Ab and IgG assays except one, DiaSorin Liaison XL IgG (97.2%). Sensitivities in descending order were Wantai ELISA total Ab (96.7%), CUH-NOVO in-house ELISA total Ab (96.0%), Ortho Vitros total Ab (95.3%), YHLO iFlash IgG (94.0%), Ortho Vitros IgG (93.3%), Siemens Atellica total Ab (93.2%), Roche Elecsys total Ab (92.7%), Abbott Architect IgG (90.0%), Abbott Alinity IgG (median 88.0%), DiaSorin Liaison XL IgG (median 84.6%), Siemens Vista total Ab (81.0%), Euroimmun/ELISA IgG (78.0%), and Snibe Maglumi IgG (median 78.0%). However, confidence intervals overlapped for several assays. The IgM results were variable, with the Wantai IgM ELISA showing the highest sensitivity (82.7%) and specificity (99%). The rate of seropositivity increased with time from symptom onset and symptom severity.
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http://dx.doi.org/10.1128/JCM.02596-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091860PMC
April 2021

Reduced prevalence of SARS-CoV-2 infection in ABO blood group O.

Blood Adv 2020 10;4(20):4990-4993

Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.

Identification of risk factors for contracting and developing serious illness following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of paramount interest. Here, we performed a retrospective cohort analysis of all Danish individuals tested for SARS-CoV-2 between 27 February 2020 and 30 July 2020, with a known ABO and RhD blood group, to determine the influence of common blood groups on virus susceptibility. Distribution of blood groups was compared with data from nontested individuals. Participants (29% of whom were male) included 473 654 individuals tested for SARS-CoV-2 using real-time polymerase chain reaction (7422 positive and 466 232 negative) and 2 204 742 nontested individuals, accounting for ∼38% of the total Danish population. Hospitalization and death from COVID-19, age, cardiovascular comorbidities, and job status were also collected for confirmed infected cases. ABO blood groups varied significantly between patients and the reference group, with only 38.41% (95% confidence interval [CI], 37.30-39.50) of the patients belonging to blood group O compared with 41.70% (95% CI, 41.60-41.80) in the controls, corresponding to a relative risk of 0.87 (95% CI, 0.83-0.91) for acquiring COVID-19. This study identifies ABO blood group as a risk factor for SARS-CoV-2 infection but not for hospitalization or death from COVID-19.
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http://dx.doi.org/10.1182/bloodadvances.2020002657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594382PMC
October 2020

Epidemiology of hepatitis E virus infection in a cohort of 4023 immunocompromised patients.

Int J Infect Dis 2020 Feb 20;91:188-195. Epub 2019 Nov 20.

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark.

Objectives: The prevalence of active, chronic, and former hepatitis E virus (HEV) infections was investigated in a cohort of immunocompromised patients. The association with transfusion transmitted HEV was evaluated, and the HEV seroprevalence was compared with that in healthy blood donors.

Study Design And Methods: Serum samples from 4023 immunocompromised patients at Rigshospitalet, Denmark were retrospectively tested for HEV RNA and anti-HEV IgG. HEV RNA-positive patients were followed up by HEV testing, clinical symptoms, and transfusion history. Factors associated with anti-HEV were explored by multivariable logistic regression analysis. Samples from 1226 blood donors were retrospectively tested for anti-HEV IgG.

Results: HEV RNA was detected in six patients (0.15%) with no indications of chronic HEV infection. HEV RNA prevalence rates among recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation (SOT) were 0.58% and 0.21%, respectively. Transfusion transmitted infections were refuted, and transfusion history was not associated with anti-HEV positivity. The difference in HEV seroprevalence between patients (22.0%) and blood donors (10.9%) decreased when adjusting for age and sex (odds ratio 1.20, 95% confidence interval 0.97-1.48).

Conclusions: HEV viremia among allo-HSCT and SOT recipients suggests that clinicians should be aware of this diagnosis. The lack of association of blood transfusion with anti-HEV positivity supports food-borne transmission as the main transmission route of HEV common to both patients and blood donors.
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http://dx.doi.org/10.1016/j.ijid.2019.11.014DOI Listing
February 2020

Premedication with corticosteroids does not impact the pharmacokinetics of infliximab in inflammatory bowel disease irrespective of azathioprine cotreatment.

Eur J Gastroenterol Hepatol 2019 Aug;31(8):964-967

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Objective: Loss of infliximab (IFX) effect is a clinical challenge in the management of patients with Crohn's disease (CD), but this can potentially be reduced with azathioprine (AZA) or with corticosteroids (CS). We aimed to study whether CS premedication with or without cotreatment with AZA could reduce antibody formation and affect the IFX elimination rate.

Patients And Methods: A cross-sectional observational study was conducted at two centers with CD patients receiving maintenance IFX therapy for 12-18 months. In addition to IFX, patients received either CS premedication or not, with or without concominant AZA.

Results: Fifty-seven patients were included in the study. Thirty-one patients received premedication with CSs, and 11 (35.5%) of these also received AZA, whereas this was the case for 22 of 26 (84.6%) patients in the non-CS group. No difference in IFX trough level (P=0.10) or halftime elimination (P=0.31) was observed with or without CS premedication. Concomitant AZA was associated with significantly longer mean half-life of IFX (P=0.04). Total IFX antibody concentrations were 15.8 and 12.9 with and without CS, respectively, in those not receiving AZA versus 4.3 and 6.1 AU/ml with and without CS, respectively, in those receiving AZA (P=0.004). Premedication with CS did not have any effect on the frequency of antibody formation (P=0.28).

Conclusion: In patients with CD and in maintenance IFX therapy, premedication with CS did not influence antibody formation, IFX trough levels or IFX halftime elimination, irrespective of concomitant AZA use. However, the use of AZA was associated with higher IFX trough levels and lower total IFX antibody concentrations.
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http://dx.doi.org/10.1097/MEG.0000000000001440DOI Listing
August 2019

Pulmonary effects of immediate versus deferred antiretroviral therapy in HIV-positive individuals: a nested substudy within the multicentre, international, randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial.

Lancet Respir Med 2016 12 20;4(12):980-989. Epub 2016 Oct 20.

University of Minnesota, Minneapolis, MN, USA.

Background: Observational data have been conflicted regarding the potential role of HIV antiretroviral therapy (ART) as a causative factor for, or protective factor against, COPD. We therefore aimed to investigate the effect of immediate versus deferred ART on decline in lung function in HIV-positive individuals.

Methods: We did a nested substudy within the randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial at 80 sites in multiple settings in 20 high-income and low-to-middle-income countries. Participants were HIV-1 infected individuals aged at least 25 years, naive to ART, with CD4 T-cell counts of more than 500 per μL, not receiving treatment for asthma, and without recent respiratory infections (baseline COPD was not an exclusion criterion). Participants were randomly assigned to receive ART (an approved drug combination derived from US Department of Health and Human Services guidelines) either immediately, or deferred until CD4 T-cell counts decreased to 350 per μL or AIDS developed. The randomisation was determined by participation in the parent START study, and was not specific to the substudy. Because of the nature of our study, site investigators and participants were not masked to the treatment group assignment; however, the assessors who reviewed the outcomes were masked to the treatment group. The primary outcome was the annual rate of decline in lung function, expressed as the FEV slope in mL/year; spirometry was done annually during follow-up for up to 5 years. We analysed data on an intention-to-treat basis, and planned separate analyses in smokers and non-smokers because of the known effects of smoking on FEV decline. The substudy was registered at ClinicalTrials.gov number NCT01797367.

Findings: Between March 11, 2010, and Aug 23, 2013, we enrolled 1026 participants to our substudy, who were then randomly assigned to either immediate (n=518) or deferred (n=508) ART. Median baseline characteristics included age 36 years (IQR 30-44), CD4 T-cell count 648 per μL (583-767), and HIV plasma viral load 4·2 log copies per mL (3·5-4·7). 29% were female and 28% were current smokers. Median follow-up time was 2·0 years (IQR 1·9-3·0). We noted no differences in FEV slopes between the immediate and deferred ART groups either in smokers (difference of -3·3 mL/year, 95% CI -38·8 to 32·2; p=0·86) or in non-smokers (difference of -5·6 mL/year, -29·4 to 18·3; p=0·65) or in pooled analyses adjusted for smoking status at each study visit (difference of -5·2 mL/year, -25·1 to 14·6; p=0·61).

Interpretation: The timing of ART initiation has no major short-term effect on rate of lung function decline in HIV-positive individuals who are naive to ART, with CD4 T-cell counts of more than 500 per μL. In light of updated WHO recommendations that all HIV-positive individuals should be treated with ART, regardless of their CD4 T-cell count, our results suggest an absence of significant pulmonary harm with such an approach.

Funding: US National Heart Lung and Blood Institute, US National Institute of Allergy and Infectious Diseases, Division of AIDS, Agence Nationale de Recherches sur le SIDA et les Hipatites Virales (France), Australian National Health and Medical Research Council, Danish National Research Foundation, European AIDS Treatment Network, German Ministry of Education and Research, UK Medical Research Council and National Institute for Health Research, and US Veterans Health Administration Office of Research and Development.
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http://dx.doi.org/10.1016/S2213-2600(16)30319-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5279910PMC
December 2016
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