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1.
Biosensors and Bioelectronics ; : 114663, 2022.
Article in English | ScienceDirect | ID: covidwho-2003888

ABSTRACT

The SARS-CoV-2 pandemic has highlighted the need for improved technologies to help control the spread of contagious pathogens. While rapid point-of-need testing plays a key role in strategies to rapidly identify and isolate infectious patients, current test approaches have significant shortcomings related to assay limitations and sample type. Direct quantification of viral shedding in exhaled particles may offer a better rapid testing approach, since SARS-CoV-2 is believed to spread mainly by aerosols. It assesses contagiousness directly, the sample is easy and comfortable to obtain, sampling can be standardized, and the limited sample volume lends itself to a fast and sensitive analysis. In view of these benefits, we developed and tested an approach where exhaled particles are efficiently sampled using inertial impaction in a micromachined silicon chip, followed by an RT-qPCR molecular assay to detect SARS-CoV-2 shedding. Our portable, silicon impactor allowed for the efficient capture (>85%) of respiratory particles down to 300 nm without the need for additional equipment. We demonstrate using both conventional off-chip and in-situ PCR directly on the silicon chip that sampling subjects’ breath in less than a minute yields sufficient viral RNA to detect infections as early as standard sampling methods. A longitudinal study revealed clear differences in the temporal dynamics of viral load for nasopharyngeal swab, saliva, breath, and antigen tests. Overall, after an infection, the breath-based test remains positive during the first week but is the first to consistently report a negative result, putatively signalling the end of contagiousness and further emphasizing the potential of this tool to help manage the spread of airborne respiratory infections.

2.
iScience ; 25(8): 104705, 2022 Aug 19.
Article in English | MEDLINE | ID: covidwho-1914523

ABSTRACT

Treatment with neutralizing monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to COVID-19 management. Unfortunately, SARS-CoV-2 variants escape several of these recently approved mAbs, highlighting the need for additional discovery and development. In a convalescent patient with COVID-19, we identified six mAbs, classified in four epitope groups, that potently neutralized SARS-CoV-2 D614G, beta, gamma, and delta infection in vitro, with three mAbs neutralizing omicron as well. In hamsters, mAbs 3E6 and 3B8 potently cured infection with SARS-CoV-2 Wuhan, beta, and delta when administered post-viral infection at 5 mg/kg. Even at 0.2 mg/kg, 3B8 still reduced viral titers. Intramuscular delivery of DNA-encoded 3B8 resulted in in vivo mAb production of median serum levels up to 90 µg/mL, and protected hamsters against delta infection. Overall, our data mark 3B8 as a promising candidate against COVID-19, and highlight advances in both the identification and gene-based delivery of potent human mAbs.

3.
Res Pract Thromb Haemost ; 6(3): e12683, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1772842

ABSTRACT

Background: Venous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID-19). The optimal dose of anticoagulation for thromboprophylaxis in COVID-19 is unknown. Aims: To report VTE incidence and bleeding before and after implementing a hospital-wide intensified thromboprophylactic protocol in patients with COVID-19. Methods: On March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti-Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID-19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible. Results: We included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed. Conclusion: In hospitalized patients with COVID-19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight-adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation.

5.
Cell ; 184(24): 5932-5949.e15, 2021 11 24.
Article in English | MEDLINE | ID: covidwho-1549679

ABSTRACT

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.


Subject(s)
Autopsy/methods , COVID-19/mortality , COVID-19/virology , Olfactory Bulb/virology , Olfactory Mucosa/virology , Respiratory Mucosa/virology , Aged , Anosmia , COVID-19/physiopathology , Endoscopy/methods , Female , Glucuronosyltransferase/biosynthesis , Humans , Immunohistochemistry , In Situ Hybridization , Male , Microscopy, Fluorescence , Middle Aged , Olfaction Disorders , Olfactory Receptor Neurons/metabolism , Respiratory System , SARS-CoV-2 , Smell
6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293320

ABSTRACT

Treatment with neutralizing monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to COVID-19 management. Unfortunately, SARS-CoV-2 variants can escape several of these recently approved mAbs, highlighting the need for additional discovery and development. In a convalescent COVID-19 patient, we identified six mAbs, classified in four epitope groups, that potently neutralized SARS-CoV-2 Wuhan, alpha, beta, gamma and delta infection in vitro. In hamsters, mAbs 3E6 and 3B8 potently cured infection with SARS-CoV-2 Wuhan, beta and delta when administered post-viral infection at 5 mg/kg. Even at 0.2 mg/kg, 3B8 still reduced viral titers. Intramuscular delivery of DNA-encoded 3B8 resulted in in vivo mAb production of median serum levels up to 90 ug/ml, and protected hamsters against delta infection. Overall, our data mark 3B8 as a promising candidate against COVID-19, and highlight advances in both the identification and gene-based delivery of potent human mAbs.

7.
Int J Cardiol Heart Vasc ; 37: 100912, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1506961

ABSTRACT

BACKGROUND: ECG abnormalities in COVID-19 have been widely reported, however data after discharge is limited. The aim was to describe ECG abnormalities on admission and following recovery of COVID-19, and their associated mortality. METHODS: All patients hospitalized in a tertiary care hospital between March 7th and July 1st 2020 with COVID-19 were included in a retrospective registry. The first ECG on admission was collected, together with an ECG after hospital discharge in the absence of acute pathology. Automated measures and clinical ECG interpretations were collected. Multivariate Cox regression analysis was performed to predict 1-year all-cause mortality. RESULTS: In total 420 patients were included, of which 83 patients (19.8%) died during the 1-year follow-up period. Repolarization abnormalities were present in 189 patients (45.0%). The extent of repolarization abnormalities was an independent predictor of 1-year all-cause mortality (HR per region 1.30, 95%CI 1.04-1.64) together with age (/year HR 1.06, 95%CI 1.04-1.08), heart rate (/bpm HR 1.02, 95%CI 1.01-1.03), neurological disorders (HR 2.41, 95%CI 1.47-3.93), active cancer (HR 2.75, 95%CI 1.57-4.82), CRP (per 10 mg/L HR 1.05, 95%CI 1.02-1.08) and eGFR (per 10 mg/L HR 0.90, 95%CI 0.83-0.98).In 245 patients (68.1%) an ECG post discharge was available. New repolarization abnormalities were more frequent in patients who died after discharge (4.7% versus 41.7%, p < 0.001) and 8 (3.3%) had new ventricular conduction defects, none of whom died during follow-up. CONCLUSIONS: The presence and extent of repolarization abnormalities predicted outcome in patients with COVID-19. New repolarization abnormalities after discharge were associated with post-discharge mortality.

9.
EBioMedicine ; 66: 103288, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1141720

ABSTRACT

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Itraconazole/pharmacology , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/etiology , COVID-19/transmission , Chlorocebus aethiops , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Itraconazole/administration & dosage , Itraconazole/pharmacokinetics , Itraconazole/therapeutic use , Male , Mesocricetus , Middle Aged , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Proof of Concept Study , SARS-CoV-2/drug effects , Treatment Outcome , Vero Cells
10.
ESMO Open ; 5(5): e000947, 2020 09.
Article in English | MEDLINE | ID: covidwho-796349

ABSTRACT

BACKGROUND: Cancer seems to have an independent adverse prognostic effect on COVID-19-related mortality, but uncertainty exists regarding its effect across different patient subgroups. We report a population-based analysis of patients hospitalised with COVID-19 with prior or current solid cancer versus those without cancer. METHODS: We analysed data of adult patients registered until 24 May 2020 in the Belgian nationwide database of Sciensano. The primary objective was in-hospital mortality within 30 days of COVID-19 diagnosis among patients with solid cancer versus patients without cancer. Severe event occurrence, a composite of intensive care unit admission, invasive ventilation and/or death, was a secondary objective. These endpoints were analysed across different patient subgroups. Multivariable logistic regression models were used to analyse the association between cancer and clinical characteristics (baseline analysis) and the effect of cancer on in-hospital mortality and on severe event occurrence, adjusting for clinical characteristics (in-hospital analysis). RESULTS: A total of 13 594 patients (of whom 1187 with solid cancer (8.7%)) were evaluable for the baseline analysis and 10 486 (892 with solid cancer (8.5%)) for the in-hospital analysis. Patients with cancer were older and presented with less symptoms/signs and lung imaging alterations. The 30-day in-hospital mortality was higher in patients with solid cancer compared with patients without cancer (31.7% vs 20.0%, respectively; adjusted OR (aOR) 1.34; 95% CI 1.13 to 1.58). The aOR was 3.84 (95% CI 1.94 to 7.59) among younger patients (<60 years) and 2.27 (95% CI 1.41 to 3.64) among patients without other comorbidities. Severe event occurrence was similar in both groups (36.7% vs 28.8%; aOR 1.10; 95% CI 0.95 to 1.29). CONCLUSIONS: This population-based analysis demonstrates that solid cancer is an independent adverse prognostic factor for in-hospital mortality among patients with COVID-19. This adverse effect was more pronounced among younger patients and those without other comorbidities. Patients with solid cancer should be prioritised in vaccination campaigns and in tailored containment measurements.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Hospital Mortality , Neoplasms/epidemiology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Adrenal Cortex Hormones/therapeutic use , Aged , Aged, 80 and over , Belgium/epidemiology , COVID-19 , Comorbidity , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/virology , Female , Hospitalization , Humans , Intensive Care Units , Lung/diagnostic imaging , Male , Middle Aged , Neoplasms/drug therapy , Pandemics , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/virology , Prognosis , Respiration, Artificial , Risk Factors , SARS-CoV-2
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