Publications by authors named "Pieter Vermeersch"

140 Publications

Comparison of the quantitative DiaSorin Liaison antigen test to RT-PCR for the diagnosis of COVID-19 in symptomatic and asymptomatic outpatients.

J Clin Microbiol 2021 Apr 13. Epub 2021 Apr 13.

Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium.

Background: We evaluated the quantitative DiaSorin Liaison SARS-CoV-2 antigen test in symptomatic and asymptomatic individuals consulting their general practioner (GP) during a period of stable intense virus circulation (213/100,000 habitants per day).

Methods: Left-over RT-PCR positive (n=204) and negative (n=210) nasopharyngeal samples were randomly selected among fresh routine samples collected from patients consulting their GP. Samples were tested on Liaison XL according to the manufacturer's instructions. Equivocal results were considered positive.

Results: Overall sensitivity and specificity of the Liaison antigen test compared to RT-PCR were 67.7% [95% confidence interval (CI): 60.9%-73.7%] and 100% [CI: 97.8%-100%]. Sensitivity in samples with a viral load ≥10, ≥10 and ≥10 copies/mL was 100% [CI: 96.3%-100.0%], 96.5% [CI: 91.8%-98.7%] and 87.4% [CI: 81.3%-91.5%], respectively. All samples ≤10 copies/mL were antigen negative. The ratio of antigen concentration to viral load in samples ≥10 copies/mL was comparable in symptomatic and asymptomatic individuals (=0.58). The proportion of RT-PCR positive participants with a high viral load (≥10 copies/mL) was not significantly higher in symptomatic than in asymptomatic participants (63.9% [CI: 54.9%-72.0%] vs. 51.9% [CI: 41.1%-62.6%], =0.11), but the proportion of participants with a low viral load (<10 copies/mL) was significantly higher in asymptomatic than in symptomatic RT-PCR positive participants (35.4% [CI: 25.8%-46.4%] vs. 14.3% [CI: 9.0%-21.8%], <0.01).

Conclusions: Sensitivity and specificity in samples with a viral load ≥10 copies/mL was 96.5% and 100%. The correlation of antigen concentration with viral load was comparable in symptomatic and asymptomatic individuals.
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http://dx.doi.org/10.1128/JCM.00374-21DOI Listing
April 2021

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

EBioMedicine 2021 Mar 19;66:103288. Epub 2021 Mar 19.

Department of Cardiovascular Sciences, UZ and KU Leuven, Belgium.

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.
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http://dx.doi.org/10.1016/j.ebiom.2021.103288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979145PMC
March 2021

Estimated half-life of SARS-CoV-2 anti-spike antibodies more than double the half-life of anti-nucleocapsid antibodies in healthcare workers.

Clin Infect Dis 2021 Mar 8. Epub 2021 Mar 8.

Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1093/cid/ciab219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989510PMC
March 2021

A patient with neonatal cholestasis.

J Mother Child 2021 Mar 9. Epub 2021 Mar 9.

Center for Metabolic Diseases, University Hospital Leuven, Leuven, Belgium.

The patient, a boy born in 1991, showed pronounced polyostotic fibrous dysplasia due to McCune-Albright syndrome, as well as Gilbert syndrome and Charcot-Marie-Tooth neuropathy caused by a mutation. In addition, the patient, his sister, mother and maternal grandfather had intermittently increased plasma arginine and lysine levels, most probably due to heterozygosity for a novel pathogenic variant.
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http://dx.doi.org/10.34763/jmotherandchild.20202404.d-20-00012DOI Listing
March 2021

Impact of Cardiac Resynchronization Therapy on Global and Cardiac Metabolism and Cardiac Mitochondrial Function.

J Card Fail 2021 Feb 24. Epub 2021 Feb 24.

Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; Department of Laboratory Medicine, KU Leuven, UZ Leuven, Leuven, Belgium; Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.

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http://dx.doi.org/10.1016/j.cardfail.2021.02.008DOI Listing
February 2021

Longitudinal follow-up of IgG anti-nucleocapsid antibodies in SARS-CoV-2 infected patients up to eight months after infection.

J Clin Virol 2021 03 18;136:104765. Epub 2021 Feb 18.

Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium. Electronic address:

Background: Most SARS-CoV-2 infected patients develop IgG antibodies within 2-3 weeks after symptom onset. Antibody levels have been shown to gradually decrease in the first months after infection, but few data are available at six months or later.

Methods: A retrospective multi-center study was performed using 652 samples of 236 PCR-confirmed SARS-CoV-2 infected patients from 2 Belgian University hospitals. Patients were included if at least two samples were available (range 2-7 samples); including at least one sample collected 30 days or later after first positive PCR (range 0-240 days). Of those 236 patients, 19.1 % were classified as mild/asymptomatic (mild) and 80.9 % as moderate to critical (severe). IgG anti-nucleocapsid antibodies (anti-N) were measured using the Abbott Architect immunoassay.

Results: 22.2 % of mild and 2.6 % of severe COVID-19 cases never seroconverted (p < 0.001). Of the mild patients who seroconverted 0-59 days after PCR; 18.8 %, 40.0 % and 61.1 % were seronegative in the windows 60-119 days, 120-179 days and 180-240 days after PCR, respectively. In severe patients, these numbers were 1.9 %, 10.8 % and 29.4 % respectively (p < 0.05 each). Antibody levels were significantly higher in severe patients compared to mild patients in each 60 day window (p < 0.001 each).

Conclusions: SARS-CoV-2 anti-N IgG antibody levels steadily decreased after 2 months up to 8 months post PCR. Of severe COVID-19 patients, 70.6 % remained positive up to eight months after infection. Antibody levels were significantly lower in mild SARS-CoV-2 infected patients and 61.1 % became seronegative within 6 months after the first positive PCR.
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http://dx.doi.org/10.1016/j.jcv.2021.104765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891078PMC
March 2021

Belgian rare diseases plan in clinical pathology: identification of key biochemical diagnostic tests and establishment of reference laboratories and financing conditions.

Orphanet J Rare Dis 2021 Feb 17;16(1):89. Epub 2021 Feb 17.

Department of Quality of Laboratories, Sciensano, Rue Juliette Wytsmanstraat 14, 1050, Brussels, Belgium.

Background: One objective of the Belgian Rare Diseases plan is to improve patients' management using phenotypic tests and, more specifically, the access to those tests by identifying the biochemical analyses used for rare diseases, developing new financing conditions and establishing reference laboratories.

Methods: A feasibility study was performed from May 2015 until August 2016 in order to select the financeable biochemical analyses, and, among them, those that should be performed by reference laboratories. This selection was based on an inventory of analyses used for rare diseases and a survey addressed to the Belgian laboratories of clinical pathology (investigating the annual analytical costs, volumes, turnaround times and the tests unavailable in Belgium and outsourced abroad). A proposal of financeable analyses, financing modalities, reference laboratories' scope and budget estimation was developed and submitted to the Belgian healthcare authorities. After its approval in December 2016, the implementation phase took place from January 2017 until December 2019.

Results: In 2019, new reimbursement conditions have been published for 46 analyses and eighteen reference laboratories have been recognized. Collaborations have also been developed with 5 foreign laboratories in order to organize the outsourcing and financing of 9 analyses unavailable in Belgium.

Conclusions: In the context of clinical pathology and rare diseases, this initiative enabled to identify unreimbursed analyses and to meet the most crucial financial needs. It also contributed to improve patients' management by establishing Belgian reference laboratories and foreign referral laboratories for highly-specific analyses and a permanent surveillance, quality and financing framework for those tests.
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http://dx.doi.org/10.1186/s13023-021-01728-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890854PMC
February 2021

How to meet ISO15189:2012 pre-analytical requirements in clinical laboratories? A consensus document by the EFLM WG-PRE.

Clin Chem Lab Med 2021 Jan 14. Epub 2021 Jan 14.

Department of Medical Laboratory Diagnostics, University Hospital Sveti Duh, Zagreb, Croatia.

The International Organization for Standardization (ISO) 15189:2012 standard aims to improve quality in medical laboratories through standardization of all key elements in the total testing process, including the pre-analytical phase. It is hence essential that accreditation bodies, assessing laboratories against ISO15189:2012, pay sufficient attention to auditing pre-analytical activities. However, there are significant differences in how technical auditors interpret the pre-analytical requirements described in ISO15189:2012. In this consensus document, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for Pre-analytical Phase (WG-PRE) sets out to review pre-analytical requirements contained in ISO15189:2012 and provide guidance for laboratories on how to meet these requirements. The target audience for this consensus document is laboratory professionals who wish to improve the quality of the pre-analytical phase in their laboratory. For each of the ISO requirements described in ISO15189:2012, members of EFLM WG-PRE agreed by consensus on minimal recommendations and best-in-class solutions. The minimal consensus recommendation was defined as the minimal specification which laboratories should implement in their quality management system to adequately address the pre-analytical requirement described in ISO15189:2012. The best-in-class solution describes the current state-of-the-art in fulfilling a particular pre-analytical requirement in ISO15189:2012. We fully acknowledge that not every laboratory has the means to implement these best-in-class solutions, but we hope to challenge laboratories in critically evaluating and improving their current procedures by providing this expanded guidance.
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http://dx.doi.org/10.1515/cclm-2020-1859DOI Listing
January 2021

The role of serotonin in the control of esophageal sensitivity assessed by multimodal stimulation in health.

Neurogastroenterol Motil 2021 03 6;33(3):e14057. Epub 2020 Dec 6.

Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium.

Background: Esophageal hypersensitivity is considered an important pathophysiological mechanism in refractory gastroesophageal reflux disease (GERD) patients. Serotonin (5-HT) plays an important role in the regulation of GI (gastrointestinal) secretion, motility and sensitivity. Previous studies found that altered 5-HT availability has no clear effects on esophageal/GI sensations. Our aim was therefore to investigate the role of 5-HT in esophageal sensitivity in healthy volunteers (HV).

Methods: Esophageal sensitivity to thermal, mechanical, electrical, and chemical stimuli was assessed in 3 different placebo-controlled studies. In the first study, the effect of citalopram (40 mg; 5-HT reuptake inhibitor; intravenous) was investigated (n = 14). In the second study, the effect of buspirone (20 mg; 5HT1A agonist; oral) was investigated (n = 10). In the third study, acute tryptophan depletion (ATD) was used to decrease 5-HT levels to investigate the effect of reduced 5-HT availability on esophageal sensitivity (n = 15).

Key Results: No difference was observed in esophageal sensitivity after the administration of citalopram or buspirone (all p > 0.06). In contrast, pain perception threshold to chemical stimulation was increased after ATD (p = 0.017, Cohen's d+ = 0.67). No effect was found on the first perception or pain tolerance threshold. ATD had no influence on esophageal sensitivity to thermal, mechanical, and electrical stimulation compared with placebo.

Conclusions And Inferences: ATD, which induces 5-HT depletion, significantly decreased pain perception threshold during chemical stimulation, without affecting sensitivity to mechanical, thermal, or electrical stimulation. These findings confirm the involvement of 5-HT in the control of esophageal acid sensitivity, but identifying the receptors involved requires more ligands and studies.
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http://dx.doi.org/10.1111/nmo.14057DOI Listing
March 2021

Recent progress in the LC-MS/MS analysis of oxidative stress biomarkers.

Electrophoresis 2021 Feb 28;42(4):402-428. Epub 2020 Dec 28.

Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven - University of Leuven, Leuven, Belgium.

The presence of a dynamic and balanced equilibrium between the production of reactive oxygen (ROS) and nitrogen (RNS) species and the in-house antioxidant defense mechanisms is characteristic for a healthy body. During oxidative stress (OS), this balance is switched to increased production of ROS and RNS, exceeding the capacity of physiological antioxidant systems. This can cause damage to biological molecules, leading to loss of function and even cell death. Nowadays, there is increasing scientific and clinical interest in OS and the associated parameters to measure the degree of OS in biofluids. An increasing number of reports using LC-MS/MS methods for the analysis of OS biomarkers can be found. Since bioanalysis is usually complicated by matrix effects, various types of cleanup procedures are used to effectively separate the biomarkers from the matrix. This is an essential part of the analysis to prepare a reproducible and homogenous solution suitable for injection onto the column. The present review gives a summary of the chromatographic methods used for the determination of OS biomarkers in both urine and plasma, serum, and whole blood samples. The first part mainly describes the biological background of the different OS biomarkers, while the second part reports examples of chromatographic methods for the analysis of different metabolites connected with OS in biofluids, covering a period from 2015 till early 2020. The selected examples mainly include LC-MS/MS methods for isoprostanes, oxidized proteins, oxidized lipoproteins, and DNA/RNA biomarkers. The last part explains the clinical relevance of this review.
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http://dx.doi.org/10.1002/elps.202000208DOI Listing
February 2021

Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis-Addicted Breast Tumor Growth.

Mol Cancer Ther 2021 01 17;20(1):50-63. Epub 2020 Nov 17.

Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.

Metabolic rewiring is a hallmark of cancer that supports tumor growth, survival, and chemotherapy resistance. Although normal cells often rely on extracellular serine and glycine supply, a significant subset of cancers becomes addicted to intracellular serine/glycine synthesis, offering an attractive drug target. Previously developed inhibitors of serine/glycine synthesis enzymes did not reach clinical trials due to unfavorable pharmacokinetic profiles, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. In this study, we aimed to develop therapies that can rapidly enter the clinical practice by focusing on drug repurposing, as their safety and cost-effectiveness have been optimized before. Using a yeast model system, we repurposed two compounds, sertraline and thimerosal, for their selective toxicity against serine/glycine synthesis-addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines. Isotope tracer metabolomics, computational docking, enzymatic assays, and drug-target interaction studies revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase and phosphoglycerate dehydrogenase, respectively. In addition, we demonstrated that sertraline's antiproliferative activity was further aggravated by mitochondrial inhibitors, such as the antimalarial artemether, by causing G-S cell-cycle arrest. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts. Collectively, this study provides molecular insights into the repurposed mode-of-action of the antidepressant sertraline and allows to delineate a hitherto unidentified group of cancers being particularly sensitive to treatment with sertraline. Furthermore, we highlight the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a novel treatment strategy for serine/glycine synthesis-addicted cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0480DOI Listing
January 2021

Immunoassays for anti-SARS-CoV-2 antibodies: recent insights.

Lancet Infect Dis 2020 Oct 30. Epub 2020 Oct 30.

Clinical Department of Laboratory Medicine and National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, 3000 Leuven, Belgium; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(20)30846-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833516PMC
October 2020

Added value of anti-SARS-CoV-2 antibody testing in a Flemish nursing home during an acute COVID-19 outbreak in April 2020.

Acta Clin Belg 2020 Oct 18:1-6. Epub 2020 Oct 18.

Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven , Leuven, Belgium.

Objectives: To examine the added value of anti-SARS-CoV-2 antibody testing in a nursing home during an acute COVID-19 outbreak. RT-PCR is the gold standard, but can be false-negative.

Methods: 119 residents and 93 staff members were tested with RT-PCR test and/or a rapid IgM/IgG test. Of these participants, 176 had both tests, 24 only RT-PCR, and 12 only IgM/IgG in the period April 14 to 16 April 2020.

Results: 40 (34%) residents and 11 (13%) staff were PCR-positive. Using a rapid IgM/IgG test, 17 (17%) residents and 18 (20%) staff were positive for IgM and/or IgG (IgM/IgG). Thirty-two PCR-positive residents had an IgM/IgG test: 9 (28%), 11 (34%), and 13 (41%) were positive for IgM, IgG, and IgM/IgG. Ten PCR-positive staff had an IgM/IgG test: 3 (30%), 6 (60%), and 6 (60%) were positive for IgM, IgG, and IgM/IgG. Additional IgM/IgG tests were performed in 9 residents 11 to 14 days after the positive RT-PCR test. Of those, 7 (78%) tested positive for IgM/IgG. When retested 3 weeks later, the 2 remaining residents also tested positive. Of the 134 PCR-negative participants who had an IgM/IgG test, 15 were positive for IgM/IgG (8% of the 200 participants tested with RT-PCR).

Conclusions: During an acute outbreak in a nursing home, 26% of residents and staff were PCR-positive. An additional 8% was diagnosed using IgM/IgG antibody testing. The use of RT-PCR alone as the sole diagnostic method for surveillance during an acute outbreak is insufficient to grab the full extent of the outbreak.
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http://dx.doi.org/10.1080/17843286.2020.1834285DOI Listing
October 2020

Non-Lethal Intoxication by Ingestion of 50 Castor Beans: Serial Measurement of Ricinine in Blood, Plasma, and Urine.

J Anal Toxicol 2020 Sep 30. Epub 2020 Sep 30.

Department of Laboratory Medicine, AZ Groeninge, Kortrijk, Belgium.

A 30-year-old woman presented to the emergency department 2 days after ingestion of 50 castor beans. Her symptoms on admission were vomiting, diarrhea, abdominal cramps, agitation and anxiety. Initial laboratory tests showed a slightly elevated C-reactive protein (CRP) and mild liver and kidney dysfunction The patient was transferred to the medium care unit of our hospital where she was observed for possible organ failure. During the next days the kidney function improved and liver function started to recover. Four days after admission, the patient was transferred to the psychiatric ward. Urine, serum, plasma and whole-blood samples were analyzed for ricinine using a quantitative LC-MS-MS method. Initial values on admission (serum and urine) were very high in comparison with previously reported cases. Based on these values, the patient was monitored closely in the following days. The patient made a full recovery and during the course of hospitalization, concentrations of ricinine in plasma/serum, blood and urine gradually declined. The presence of ricinine in a patient's blood or plasma is proof of castor bean, hence, ricin exposure. However, based on this case and previous reported cases in literature, we can conclude that no clear correlation can be established between ricinine blood, plasma or urine levels and the severity of the intoxication. Clinicians should be aware of the potential danger of a ricin intoxication and patients should be monitored closely for several days due to the unpredictable outcome of the intoxication.
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http://dx.doi.org/10.1093/jat/bkaa139DOI Listing
September 2020

Aspiration Pneumonia After External Dacryocystorhinostomy Under Local Anesthesia Without Sedation: A Case Report.

Ophthalmic Plast Reconstr Surg 2020 Sep 25. Epub 2020 Sep 25.

Department of Ophthalmology.

Amid the global coronavirus disease 2019 (COVID-19) outbreak, an 89-year-old male with chronic kidney disease presented with acute dacryocystitis and a persistent dry cough. After a course of antibiotics, external dacryocystorhinostomy was performed under local anesthesia without sedation. During planned hemodialysis in the early hours after the procedure, the patient developed nausea and hematemesis followed by severe dyspnea and hypoxemia. The patient was diagnosed with aspiration pneumonia, a previously unreported complication in lacrimal surgery.
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http://dx.doi.org/10.1097/IOP.0000000000001836DOI Listing
September 2020

Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain.

Clin Infect Dis 2020 Sep 5. Epub 2020 Sep 5.

KU Leuven, Rega Institute Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Leuven, Belgium.

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http://dx.doi.org/10.1093/cid/ciaa1330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499557PMC
September 2020

Antibody response against SARS-CoV-2 spike protein and nucleoprotein evaluated by four automated immunoassays and three ELISAs.

Clin Microbiol Infect 2020 Nov 31;26(11):1557.e1-1557.e7. Epub 2020 Jul 31.

Clinical Department of Laboratory Medicine and National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium. Electronic address:

Objectives: The aim was to determine the antibody response against SARS-CoV-2 spike protein and nucleoprotein using four automated immunoassays and three ELISAs for the detection of total Ig antibodies (Roche) or IgG (Abbott, Diasorin, Snibe, Euroimmun, Mikrogen) in COVID-19 patients.

Methods: Sensitivity and dynamic trend to seropositivity were evaluated in 233 samples from 114 patients with moderate, severe or critical COVID-19 confirmed with PCR on nasopharyngeal swab. Specificity was evaluated in 113 samples collected before January 2020, including 24 samples from patients with non-SARS coronavirus infection.

Results: Sensitivity for all assays was 100% (95% confidence interval 83.7-100) 3 weeks after onset of symptoms. Specificity varied between 94.7% (88.7-97.8) and 100% (96.1-100). Calculated at the cut-offs that corresponded to a specificity of 95% and 97.5%, Roche had the highest sensitivity (85.0% (79.8-89.0) and 81.1% (76.6-85.7), p < 0.05 except vs. Abbott). Seroconversion occurred on average 2 days earlier for Roche total Ig anti-N and the three IgG anti-N assays (Abbott, Mikrogen, Euroimmun) than for the two IgG anti-S assays (Diasorin, Euroimmun) (≥50% seroconversion day 9-10 vs. day 11-12 and p < 0.05 for percent seropositive patients day 9-10 to 17-18). There was no significant difference in the IgG antibody time to seroconversion between critical and non-critical patients.

Discussion: Seroconversion occurred within 3 weeks after onset of symptoms with all assays and on average 2 days earlier for assays detecting IgG or total Ig anti-N than for IgG anti-S. The specificity of assays detecting anti-N was comparable to anti-S and excellent in a challenging control population.
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http://dx.doi.org/10.1016/j.cmi.2020.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834107PMC
November 2020

The new IVD Regulation 2017/746: a case study at a large university hospital laboratory in Belgium demonstrates the need for clarification on the degrees of freedom laboratories have to use lab-developed tests to improve patient care.

Clin Chem Lab Med 2020 Jul 21;59(1):101-106. Epub 2020 Jul 21.

Biomedical Quality Assurance Research Unit, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.

Objectives: The new European In Vitro Diagnostic (IVD) Regulation 2017/746 (IVDR) restricts the use of lab-developed tests (LDT) after 26th May 2022. There are no data on the impact of the IVDR on laboratories in the European Union.

Methods: Laboratory tests performed in UZ Leuven were divided in four groups: core laboratory, immunology, special chemistry, and molecular microbiology testing. Each test was classified as Conformité Européenne (CE)-IVD, modified/off-label CE-IVD, commercial Research Use Only (RUO) or LDT. Each matrix was considered a separate test.

Results: We found that 97.6% of the more than 11.5 million results/year were generated with a CE-IVD method. Of the 922 different laboratory tests, however, only 41.8% were CE-IVD, 10.8% modified/off-label CE-IVD, 0.3% RUO, and 47.1% LDT. Off-label CE-IVD was mainly used to test alternative matrices not covered by the claim of the manufacturer (e.g., pleural or peritoneal fluid). LDTs were mainly used for special chemistry, flow cytometry, and molecular testing. Excluding flow cytometry, the main reasons for the use of 377 LDTs were lack of a CE-IVD method (71.9%), analytical requirements (14.3%), and the fact the LDT was in use before CE-IVD available (11.9%).

Conclusions: While the large majority of results (97.6%) were generated with a CE-IVD method, only 41.8% of laboratory tests were CE-IVD. There is currently no alternative on the market for 71.5% of the 537 LDTs performed in our laboratory which do not fall within the scope of the current IVD directive (IVDD). Compliance with the IVDR will require a major investment of time and effort.
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http://dx.doi.org/10.1515/cclm-2020-0804DOI Listing
July 2020

Comparison of the diagnostic performance with whole blood and plasma of four rapid antibody tests for SARS-CoV-2.

Clin Chem Lab Med 2020 09;58(10):e197-e199

Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1515/cclm-2020-0817DOI Listing
September 2020

A case of severe pseudohyperkalaemia due to muscle contraction.

Biochem Med (Zagreb) 2020 Jun;30(2):021004

Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.

Introduction: Severe hyperkalaemia is a serious medical condition requiring immediate medical attention. Before medical treatment is started, pseudohyperkalaemia has to be ruled out.

Case Description: A 10-month old infant presented to the emergency department with fever and coughing since 1 week. Routine venous blood testing revealed a severe hyperkalaemia of 6.9 mmol/L without any indication of haemolysis. Reanalysis of the plasma sample confirmed the hyperkalaemia (7.1 mmol/L). Based on these results, the clinical pathologist suggested to perform a venous blood gas analysis and electrocardiogram (ECG) which revealed a normal potassium of 3.7 mmol/L and normal ECG, ruling out a potentially life-treating hyperkalaemia. The child was diagnosed with pneumonia. The paediatrician had difficulty to perform the first venous blood collection due to excessive movement of the infant during venipuncture. The muscle contractions of the child in combination with venous stasis most probably led to a local increase of potassium in the sampled limbs. The second sample collected under optimal preanalytical circumstances had a normal potassium. Since muscle contraction typically does not cause severe hyperkalaemia, other causes of pseudohyperkalaemia were excluded. K-EDTA contamination and familial hyperkalaemia were ruled out and the patient did not have extreme leucocytosis or thrombocytosis. By exclusion a diagnosis of pseudohyperkalaemia due to intense muscle movement and venous stasis was made.

Conclusion: This case suggests that intense muscle contraction and venous stasis can cause severe pseudohyperkalemia without hemolysis. Once true hyperkalemia has been ruled out, a laboratory work-up can help identify the cause of pseudohyperkalaemia.
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http://dx.doi.org/10.11613/BM.2020.021004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271752PMC
June 2020

Women in sports: The applicability of reference intervals for 6 commercially available testosterone immunoassays (HemSter Study).

Clin Biochem 2020 Oct 10;84:55-62. Epub 2020 Jun 10.

Department of Medical Laboratory Diagnostics, University Hospital "Sveti Duh", Zagreb, Croatia; Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.

Background: Testosterone levels in female athletes are increased due to their physical activity and correlate with their exercise volume. We therefore hypothesized that the reference intervals (RIs) derived from the general population are not applicable for female athletes. The aim of this study was to evaluate the applicability of the given RIs for 6 commercially available testosterone immunoassays in a group of female athletes.

Methods: Our study included 121 female athletes from various sporting disciplines (water polo, handball, volleyball, football, and basketball). The physical activity score was assessed by the Short Form of the International Physical Activity Questionnaire. Total testosterone was measured in serum samples by the reference LC-MS/MS method and six different immunoassays (Abbott Architect 2 Generation Testosterone, Beckman Coulter Access Testosterone, Roche Elecsys Testosterone II, Siemens Atellica® IM Testosterone II (TSTII), Siemens IMMULITE 2000 Total Testosterone, and Snibe MAGLUMI™ Testosterone).

Results: There were statistically significant differences in age (P = 0.042), weight (P = 0.001), height (P < 0.001), and BMI (P < 0.001) between athletes across different sports. Their quantitative measurements of physical activity and testosterone concentration did not differ significantly between subgroups of various sports, P = 0.167 and P = 0.181, respectively. All immunoassays had a positive absolute and relative bias, in comparison with the LC-MS/MS. The manufacturer's RI was not verified for Abbott Architect, Beckman Coulter Access, and Roche Elecsys Testosterone methods, with the highest percentage of athletes above RI for Beckman Coulter (30%).

Conclusions: We demonstrated that the upper reference limit provided was too low for some young female athletes. Clinical laboratories should consider implementation of the new proposed RIs.
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http://dx.doi.org/10.1016/j.clinbiochem.2020.06.006DOI Listing
October 2020

Optimization of serologic diagnosis of celiac disease in the pediatric setting.

Autoimmun Rev 2020 May 12;19(5):102513. Epub 2020 Mar 12.

Department of Laboratory Medicine, University Hospital Leuven, Leuven, Belgium; Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium. Electronic address:

Background: The clinical presentation of celiac disease (CD) varies between children. The objective of this study was to document the pre-test probability for CD based on symptoms and routine laboratory test and to evaluate the performance of two IgA anti-tissue transglutaminase (tTG) assays. We critically reviewed the concept of using multiples of the manufacturer's upper limit of normal (ULN), as proposed in the ESPGHAN guidelines (if IgA tTG is >10 times ULN, no biopsy is needed).

Methods: The retrospective study included 91 children with newly diagnosed CD and 605 controls (<16 years). All underwent upper endoscopy with small bowel biopsies. Four laboratory parameters and 16 symptoms were registered. All patients were tested for IgA anti-tTG antibodies with assays from Inova Diagnostics and Thermo Fisher Scientific.

Results: Some combinations of clinical symptoms and laboratory parameters had a high pre-test probability for CD, such as (combinations of) anorexia, failure to thrive, low ferritin level and elevated AST. The diagnostic performance of both IgA anti-tTG assays was excellent and comparable (no difference in ROC curve area under the curve). At a threshold that corresponds to a specificity of 100% (5 times ULN for Inova Diagnostics and 2 times ULN for Thermo Fisher), the sensitivity was 82% for both assays. At the 10 times ULN threshold, the sensitivity differed between the assays (77% vs. 57%), indicating that such threshold does not completely align interpretation across companies.

Conclusions: Our study showed that some combinations of symptoms and aberrant laboratory parameters had a high pre-test probability. The use of the ESPGHAN non-biopsy approach could reduce small bowel biopsies, but thresholds for IgA-tTG levels are not aligned across assays and should be based on predefined likelihood ratios or specificity.
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http://dx.doi.org/10.1016/j.autrev.2020.102513DOI Listing
May 2020

UPLC-MS/MS method for determination of retinol and α-tocopherol in serum using a simple sample pretreatment and UniSpray as ionization technique to reduce matrix effects.

Clin Chem Lab Med 2020 04;58(5):769-779

Clinical Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium.

Background Our goal was to develop a simple, rapid and precise ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of retinol and α-tocopherol in serum. Currently published LC-MS/MS methods either require complex extraction procedures (liquid-liquid or solid-phase) or do not meet desirable specifications for imprecision in serum (coefficient of variation [CV] <6.8% and 6.9%, respectively). Methods Sample preparation consisted of a simple protein precipitation with ethanol and acetonitrile. Stable isotope-labeled internal standards (IS) and a homemade calibration curve were used for quantification. The analysis was performed using an Acquity I-class Xevo TQ XS LC-MS/MS. Chromatographic runtime was 6.0 min using a reversed phase gradient elution. UniSpray (US) as an ionization technique was compared to electrospray ionization (ESI). Analytical validation included matrix effect, recovery and trueness compared to National Institute of Standards and Technology (NIST) standards and United Kingdom National External Quality Assessment Service (UK NEQAS) samples. Results Intra- and inter-run CVs were <4.9% for retinol and <1.7% for α-tocopherol, both complying with desirable specifications for imprecision. Bias compared to NIST standards was <3.1% for both compounds. The method was linear over the entire tested range. The lower limit of quantification (LLOQ) with US was lower than with ESI for both retinol (0.022 vs. 0.043 mg/L) and α-tocopherol (0.22 vs. 0.87 mg/L). Matrix effects were not significant (<15%) for retinol. However, for α-tocopherol matrix effects of on average 54.0% were noted using ESI, but not with US. Conclusions We developed a fast, precise and accurate UPLC-MS/MS method for the determination of retinol and α-tocopherol in human serum using a single-step sample pretreatment. Ionization using US eliminated the matrix effects for α-tocopherol.
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http://dx.doi.org/10.1515/cclm-2019-1237DOI Listing
April 2020

Clinicians' and laboratory medicine specialists' views on laboratory demand management: a survey in nine European countries.

Diagnosis (Berl) 2021 02 28;8(1):111-119. Epub 2020 Jan 28.

Section of Clinical Biochemistry, University of Verona, Verona, Italy.

Background: Laboratory tests are an essential aspect of current medical practice and their use has grown exponentially. Several studies however have demonstrated inappropriate use of laboratory testing. This inappropriateness can lead to delayed or wrong diagnosis, negatively impacting patient safety and an increase in health care expenditure. The aim of the present small-scale survey was to obtain information on the current status of demand management in European laboratories, as well as the opinions of laboratory and clinical professionals in this regard.

Methods: Two surveys were developed, one for laboratory specialists and one for clinicians, covering information on current use, knowledge and opinions on the possible impact of different demand management strategies on patient outcome and health care costs. Additionally, we asked for the current state and willingness on collaboration of laboratory specialists and clinicians.

Results: One hundred and fifty responses, 72 laboratory specialists and 78 clinicians, from nine countries were received. Developing local ordering protocols/profiles in collaboration with clinicians was the most used strategy (80.3% of laboratories). Of clinicians, 85.6% considered measures to ensure appropriate use of tests necessary and 100% were interested in advice/information about their indication. Of the laboratory specialists 97.2% were either already participating or willing to participate in multidisciplinary groups on the appropriateness of test demand as were 60.3% of clinicians, and 85.9% of clinicians were interested in attending activities about laboratory test demand management.

Conclusions: The results of our survey show that tools to improve the appropriate use of laboratory tests are already regularly used today. Laboratory medicine specialists as well as clinicians are willing to undertake additional shared activities aimed at improving patient-centered laboratory diagnostic workup.
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http://dx.doi.org/10.1515/dx-2019-0081DOI Listing
February 2021

High anion gap metabolic acidosis caused by D-lactate: mind the time of blood collection.

Biochem Med (Zagreb) 2020 Feb 15;30(1):011001. Epub 2019 Dec 15.

Clinical Department of Laboratory Medicine, UZ Leuven, Leuven, Belgium.

Introduction: D-lactic acidosis is an uncommon cause of high anion gap acidosis.

Materials And Methods: A 35-year old woman was admitted to the emergency room with somnolence, drowsiness, dizziness, incoherent speech and drunk appearance. Her past medical history included a Roux-en-Y bypass. Point-of-care venous blood analysis revealed a high anion gap acidosis. Based on the clinical presentation, routine laboratory results and negative toxicology screening, D-lactate and 5-oxoprolinuria were considered as the most likely causes of the high anion gap acidosis. Urine organic acid analysis revealed increased lactate, but no 5-oxoproline. Plasma D-lactate was < 1.0 mmol/L and could not confirm D-lactic acidosis.

What Happened: Further investigation revealed that the blood sample for D-lactate was drawn 12 hours after admission, which might explain the false-negative result. Data regarding the half-life of D-lactate are, however, scarce. During a second admission, one month later, D-lactic acidosis could be confirmed with an anion gap of 40.7 mmol/L and a D-lactate of 21.0 mmol/L measured in a sample collected at the time of admission.

Main Lesson: The time of blood collection is of utmost importance to establish the diagnosis of D-lactic acidosis due to the fast clearance of D-lactate in the human body.
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http://dx.doi.org/10.11613/BM.2020.011001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904971PMC
February 2020

An unconscious man with profound drug-induced hypoglycaemia.

Biochem Med (Zagreb) 2020 Feb 15;30(1):010802. Epub 2019 Dec 15.

Laboratory Medicine, University Hospitals Leuven; Department of cardiovascular Medicine, University of Leuven, Leuven, Belgium.

Introduction: Hypoglycaemia has been reported as an unusual complication of tramadol use and in a few cases of tramadol poisoning, but the exact mechanism is not known.

Case Description: An ambulance crew was dispatched to an unconscious 46-year old man. A glucometer point-of-care measurement revealed a profound hypoglycaemia (1.9 mmol/L). Treatment with intravenous glucose was started and the patient was transported to the hospital. The patient had several episodes of pulseless electrical activity requiring cardiopulmonary resuscitation in the ambulance and upon arrival in the hospital. Despite continuous glucose infusion the hypoglycaemia was difficult to correct during the next few hours and the patient developed hypokalaemia. Further investigation to identify the cause of hypoglycaemia revealed that insulin and C-peptide were inappropriately raised. A toxicological investigation revealed the presence of tramadol and its metabolites in lethal concentrations. Also acetaminophen, ibuprofen and lormetazepam were present. Ethanol screening was negative (< 0.1 g/L) and no sulfonylurea were detected. The patient developed multiple organ failure, but eventually recovered.

What Happened: The hypoglycaemia was caused by inappropriate stimulation of insulin secretion in a patient intoxicated with tramadol. The sudden hypokalaemia was caused by a massive intracellular shift of potassium in response to the hyperinsulinemia, triggered by the intravenous administration of glucose.

Main Lesson: To our knowledge, we are the first to document a significant rise in endogenous insulin production in a hypoglycaemic patient presenting with tramadol intoxication. Our observation suggests that hyperinsulinemia could be the cause of the hypoglycaemia associated with tramadol use.
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http://dx.doi.org/10.11613/BM.2020.010802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904963PMC
February 2020