Publications by authors named "Jean-Luc Murk"

42 Publications

Self-testing for the detection of SARS-CoV-2 infection with rapid antigen tests for people with suspected COVID-19 in the community.

Clin Microbiol Infect 2021 Aug 4. Epub 2021 Aug 4.

Department of Infection Control, Amphia Hospital, Breda, the Netherlands; Microvida Laboratory for Medical Microbiology, Amphia Hospital, Breda, the Netherlands; Microvida Laboratory for Medical Microbiology and Immunology, Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands; Amphia Academy Infectious Disease Foundation, Amphia Hospital, Breda, the Netherlands; Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands.

Objectives: To evaluate the performance of nasal mid-turbinate self-testing using rapid antigen detection tests (RDT) for persons with suspected coronavirus disease 2019 (COVID-19) in the community. Self-testing for COVID-19 infection with lateral flow assay severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RDT, provides rapid results and could enable frequent and extensive testing in the community, thereby improving the control of SARS-CoV-2.

Methods: Participants visiting a municipal SARS-CoV-2 testing centre, received self-testing kits containing either the BD Veritor System (BD-RDT) or Roche SARS-CoV-2 antigen detection test (Roche-RDT). Oro-nasopharyngeal swabs were collected from the participants for quantitative RT-PCR (qRT-PCR) testing. As a proxy for contagiousness, viral culture was performed on a selection of qRT-PCR positive samples to determine the Ct-value at which the chance of a positive culture dropped below 0.5 (Ct-value cut-off). Sensitivity and specificity of self-testing were compared to qRT-PCR with a Ct-value below the Ct value cut-off. Determinants independently associated with a false-negative self-test result were determined.

Results: A total of 3201 participants were included (BD-RDT n = 1595; Roche-RDT n = 1606). Sensitivity and specificity of self-testing compared with the qRT-PCR results with a Ct-value below the Ct-value cut-off were 78.4% (95% CI 73.2%-83.5%) and 99.4% (95% CI 99.1%-99.7%), respectively. A higher age was independently associated with a false-negative self-testing result with an odds ratio of 1.024 (95% CI 1.003-1.044).

Conclusions: Self-testing using currently available RDT has a high specificity and relatively high sensitivity to identify individuals with a high probability of contagiousness.
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http://dx.doi.org/10.1016/j.cmi.2021.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336990PMC
August 2021

Increasing the Efficiency of a National Laboratory Response to COVID-19: a Nationwide Multicenter Evaluation of 47 Commercial SARS-CoV-2 Immunoassays by 41 Laboratories.

J Clin Microbiol 2021 08 18;59(9):e0076721. Epub 2021 Aug 18.

Centre for Infectious Disease Control, WHO COVID-19 Reference Laboratory, National Institute for Public Health and the Environmentgrid.31147.30, Bilthoven, the Netherlands.

In response to the worldwide pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the subsequent antibody tests that flooded the market, a nationwide collaborative approach in the Netherlands was employed. Forty-one Dutch laboratories joined forces and shared their evaluation data to allow for the evaluation of a quantity of serological assays for SARS-CoV-2 that exceeds the capacity of each individual laboratory. As of April 2020, these performance data had been aggregated and shared in regularly updated reports with other laboratories, Dutch government, public health organizations, and the public. This frequently updated overview of assay performance increased the efficiency of our national laboratory response, supporting laboratories in their choice and implementation of assays. Aggregated performance data for 47 immunoassays for SARS-CoV-2 showed that none of the evaluated immunoassays that detect only IgM or IgA met the diagnostic criteria, indicating that they are not suitable for diagnosing acute infections. For the detection of IgG, only the Biozek Corona virus COVID rapid test, Euroimmun SARS-CoV-2 IgG, and Wantai SARS-CoV-2 antibody (Ab) ELISA met predefined performance criteria in hospitalized patients where samples were collected 14 days post-onset of symptoms (DPO), while for patients with mild or asymptomatic infections, only the Wantai SARS-CoV-2 Ab ELISA met the predefined performance criteria if samples were collected 14 days postonset. Here, we describe this unique nationwide collaboration during the onset of the COVID-19 pandemic; the collected data and their results are an example of what can be accomplished when forces are joined during a public health crisis.
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http://dx.doi.org/10.1128/JCM.00767-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373020PMC
August 2021

Test, trace, isolate: evidence for declining SARS-CoV-2 PCR sensitivity in a clinical cohort.

Diagn Microbiol Infect Dis 2021 Oct 21;101(2):115392. Epub 2021 Apr 21.

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Electronic address:

Real-time reverse transcription-polymerase chain reaction (RT-PCR) on upper respiratory tract (URT) samples is the primary method to diagnose SARS-CoV-2 infections and guide public health measures, with a supportive role for serology. We reinforce previous findings on limited sensitivity of PCR testing, and solidify this fact by statistically utilizing a firm basis of multiple tests per individual. We integrate stratifications with respect to several patient characteristics such as severity of disease and time since onset of symptoms. Bayesian statistical modelling was used to retrospectively determine the sensitivity of RT-PCR using SARS-CoV-2 serology in 644 COVID-19-suspected patients with varying degrees of disease severity and duration. The sensitivity of RT-PCR ranged between 80% - 95%; increasing with disease severity, it decreased rapidly over time in mild COVID-19 cases. Negative URT RT-PCR results should be interpreted in the context of clinical characteristics, especially with regard to containment of viral transmission based on 'test, trace and isolate'. Keywords: SARS-CoV-2, RT-PCR, serology, sensitivity, public health.
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http://dx.doi.org/10.1016/j.diagmicrobio.2021.115392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059257PMC
October 2021

Neutralising Antibodies against Enterovirus and Parechovirus in IVIG Reflect General Circulation: A Tool for Sero-Surveillance.

Viruses 2021 May 29;13(6). Epub 2021 May 29.

Department of Medical Microbiology, Amsterdam University Medical Centres, Locatie AMC, 1105 AZ Amsterdam, The Netherlands.

Non-polio enteroviruses (NPEV) and parechoviruses (PeV) are widespread pathogens that cause significant morbidity. Surveillance is based on culturing or genotyping of virus strains found in clinical samples. Sero-surveillance, by measuring neutralising antibodies (nAb) through virus neutralisation assays (VNA), could provide additional information as it offers a more comprehensive overview of exposure to circulating types in the general population. In our study we evaluated Intravenous immunoglobulins (IVIG) to generate sero-surveillance data. We performed VNA of nineteen NPEV and PeV with Dutch IVIG batches from two different time points (2010 and 2017) and an IVIG batch from Vietnam (2011). We compared our findings with geno- and sero-surveillance data and evaluated changes over time and between the two countries. Our findings show a good correlation with what is known from geno-surveillance data. The highest nAb titres were found against strains from , while we did not observe nAb titres against strains belonging to . In conclusion, we demonstrated that sero-surveillance by means of IVIG can be used to obtain insight into circulation of EV and PeV genotypes. This is of particular interest for public health, to evaluate changes over time and population susceptibility to emerging genotypes.
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http://dx.doi.org/10.3390/v13061028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228535PMC
May 2021

Molecular Epidemiology and Evolutionary Trajectory of Emerging Echovirus 30, Europe.

Emerg Infect Dis 2021 06;27(6):1616-1626

In 2018, an upsurge in echovirus 30 (E30) infections was reported in Europe. We conducted a large-scale epidemiologic and evolutionary study of 1,329 E30 strains collected in 22 countries in Europe during 2016-2018. Most E30 cases affected persons 0-4 years of age (29%) and 25-34 years of age (27%). Sequences were divided into 6 genetic clades (G1-G6). Most (53%) sequences belonged to G1, followed by G6 (23%), G2 (17%), G4 (4%), G3 (0.3%), and G5 (0.2%). Each clade encompassed unique individual recombinant forms; G1 and G4 displayed >2 unique recombinant forms. Rapid turnover of new clades and recombinant forms occurred over time. Clades G1 and G6 dominated in 2018, suggesting the E30 upsurge was caused by emergence of 2 distinct clades circulating in Europe. Investigation into the mechanisms behind the rapid turnover of E30 is crucial for clarifying the epidemiology and evolution of these enterovirus infections.
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http://dx.doi.org/10.3201/eid2706.203096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153861PMC
June 2021

The clinical relevance of IgM and IgA anti-pneumococcal polysaccharide ELISA assays in patients with suspected antibody deficiency.

Clin Exp Immunol 2021 Aug 1;205(2):213-221. Epub 2021 Jun 1.

Department of Tranzo, Tilburg University, Tilburg, the Netherlands.

Unlike immunoglobulin (Ig)G pneumococcal polysaccharide (PnPS)-antibodies, PnPS IgA and IgM-antibodies are not routinely determined for the assessment of immunocompetence. It is not yet known whether an isolated inability to mount a normal IgM or IgA-PnPS response should be considered a relevant primary antibody deficiency (PAD). We studied the clinical relevance of anti-PnPS IgM and IgA-assays in patients with suspected primary immunodeficiency in a large teaching hospital in 's-Hertogenbosch, the Netherlands. Serotype-specific-PnPS IgG assays were performed; subsequently, 23-valent-PnPS IgG assays (anti-PnPS IgG assays), and later anti-PnPS IgA and IgM assays, were performed in archived material (240 patients; 304 samples). Eleven of 65 pre- and six of 10 post-immunization samples from good responders to PnPS serotype-specific IgG testing had decreased anti-PnPS IgA and/or IgM titres. Of these, three pre- and no post-immunization samples were from patients previously classified as 'no PAD'. Determination of anti-PnPS IgA and IgM in addition to anti-PnPS IgG did not reduce the need for serotype-specific PnPS IgG testing to assess immunocompetence [receiver operating characteristic (ROC) analysis of post-immunization samples: anti-PnPS IgA + IgG area under the curve (AUC) = 0.80, 95% confidence interval (CI) = 0.63-0.97; anti-PnPS IgM + IgG AUC 0.80, 95% CI = 0.62-0.98; anti-PnPS IgA + IgG + IgM AUC = 0.71, 95% CI = 0.51-0.91; anti-PnPS IgG AUC = 0.93, 95% CI = 0.85-1.00]. Our data show that patients classified as having an intact antibody response based on measurement of serotype-specific PnPS IgG can still display impaired anti-PnPS IgM and IgA responses, and that the additional measurement of anti-PnPS IgA and IgM could not reduce the need for serotype-specific IgG testing. Future studies are needed to investigate the clinical relevance of potential 'specific IgA or IgM antibody deficiency' in patients with recurrent airway infections in whom no PAD could be diagnosed according to the current definitions.
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http://dx.doi.org/10.1111/cei.13605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274160PMC
August 2021

Varicella zoster-associated acute retinal necrosis and central nervous system complications in natalizumab treated MS patients.

Mult Scler Relat Disord 2021 May 10;50:102838. Epub 2021 Feb 10.

Department of Neurology, MS Center Amsterdam, Amsterdam UMC - location VUmc, Amsterdam, the Netherlands.

There is not much awareness of varicella zoster virus (VZV) associated central nervous system (CNS) infections under treatment with natalizumab. Here we describe two natalizumab treated MS patients who developed acute retinal necrosis combined with CNS vasculitis caused by VZV. In natalizumab treated patients, visual symptoms atypical of optic neuritis should be promptly evaluated by an ophthalmologist. Currently, a total of 12 cases of natalizumab-associated VZV CNS or retinal infections are reported in literature. Our two cases and overview of currently available data provide information on prognosis and treatment decisions of this rare but devastating complication.
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http://dx.doi.org/10.1016/j.msard.2021.102838DOI Listing
May 2021

Evidence for Independent Hepatitis E Virus Replication in the Brain.

Neurol Neuroimmunol Neuroinflamm 2021 03 5;8(2). Epub 2021 Jan 5.

From the Microvida (E.P.M.d.D., J.J.V., J.-L.M.), Department of Internal Medicine (A.E.B.), and Department of Neurology (N.E.S.), Elisabeth-TweeSteden Hospital, Tilburg; and Microvida (J.P.K., S.D.P.), Bravis Hospital, Roosendaal, The Netherlands.

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http://dx.doi.org/10.1212/NXI.0000000000000939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862082PMC
March 2021

Development of a SARS-CoV-2 Total Antibody Assay and the Dynamics of Antibody Response over Time in Hospitalized and Nonhospitalized Patients with COVID-19.

J Immunol 2020 12 30;205(12):3491-3499. Epub 2020 Oct 30.

Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, 1066 CX Amsterdam, the Netherlands;

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infections often cause only mild disease that may evoke relatively low Ab titers compared with patients admitted to hospitals. Generally, total Ab bridging assays combine good sensitivity with high specificity. Therefore, we developed sensitive total Ab bridging assays for detection of SARS-CoV-2 Abs to the receptor-binding domain (RBD) and nucleocapsid protein in addition to conventional isotype-specific assays. Ab kinetics was assessed in PCR-confirmed, hospitalized coronavirus disease 2019 (COVID-19) patients ( = 41) and three populations of patients with COVID-19 symptoms not requiring hospital admission: PCR-confirmed convalescent plasmapheresis donors ( = 182), PCR-confirmed hospital care workers ( = 47), and a group of longitudinally sampled symptomatic individuals highly suspect of COVID-19 ( = 14). In nonhospitalized patients, the Ab response to RBD is weaker but follows similar kinetics, as has been observed in hospitalized patients. Across populations, the RBD bridging assay identified most patients correctly as seropositive. In 11/14 of the COVID-19-suspect cases, seroconversion in the RBD bridging assay could be demonstrated before day 12; nucleocapsid protein Abs emerged less consistently. Furthermore, we demonstrated the feasibility of finger-prick sampling for Ab detection against SARS-CoV-2 using these assays. In conclusion, the developed bridging assays reliably detect SARS-CoV-2 Abs in hospitalized and nonhospitalized patients and are therefore well suited to conduct seroprevalence studies.
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http://dx.doi.org/10.4049/jimmunol.2000767DOI Listing
December 2020

Accurate serology for SARS-CoV-2 and common human coronaviruses using a multiplex approach.

Emerg Microbes Infect 2020 Dec;9(1):1965-1973

Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Serology is a crucial part of the public health response to the ongoing SARS-CoV-2 pandemic. Here, we describe the development, validation and clinical evaluation of a protein micro-array as a quantitative multiplex immunoassay that can identify S and N-directed SARS-CoV-2 IgG antibodies with high specificity and sensitivity and distinguish them from all currently circulating human coronaviruses. The method specificity was 100% for SARS-CoV-2 S1 and 96% for N antigen based on extensive syndromic (n=230 cases) and population panel (n=94) testing that also confirmed the high prevalence of seasonal human coronaviruses. To assess its potential role for both SARS-CoV-2 patient diagnostics and population studies, we evaluated a large heterogeneous COVID-19 cohort (n=330) and found an overall sensitivity of 89% (≥ 21 days post onset symptoms (dps)), ranging from 86% to 96% depending on severity of disease. For a subset of these patients longitudinal samples were provided up to 56 dps. Mild cases showed absent or delayed, and lower SARS-CoV-2 antibody responses. Overall, we present the development and extensive clinical validation of a multiplex coronavirus serological assay for syndromic testing, to answer research questions regarding to antibody responses, to support SARS-CoV-2 diagnostics and to evaluate epidemiological developments efficiently and with high-throughput.
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http://dx.doi.org/10.1080/22221751.2020.1813636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284965PMC
December 2020

Differences in Antibody Kinetics and Functionality Between Severe and Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infections.

J Infect Dis 2020 09;222(8):1265-1269

World Health Organization COVID-19 Reference Laboratory, Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.

We determined and compared the humoral immune response in patients with severe (hospitalized) and mild (nonhospitalized) coronavirus disease 2019 (COVID-19). Patients with severe disease (n = 38) develop a robust antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including immunoglobulin G and immunoglobulin A antibodies. The geometric mean 50% virus neutralization titer is 1:240. SARS-CoV-2 infection was found in hospital personnel (n = 24), who developed mild symptoms necessitating leave of absence and self-isolation, but not hospitalization; 75% developed antibodies, but with low/absent virus neutralization (60% with titers <1:20). While severe COVID-19 patients develop a strong antibody response, mild SARS-CoV-2 infections induce a modest antibody response. Long-term monitoring will show whether these responses predict protection against future infections.
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http://dx.doi.org/10.1093/infdis/jiaa463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454692PMC
September 2020

[COVID-19: patient zero in the Netherlands].

Ned Tijdschr Geneeskd 2020 07 2;164. Epub 2020 Jul 2.

Elisabeth-TweeSteden ziekenhuis, Tilburg.

Background: Since December 2019, the world is captivated by SARS-CoV-2, a new coronavirus that shows a lot of similaritieswith previous coronaviruses such as SARS and MERS. Although it was initially seen mainly in China and the surrounding countries, now it also reached Europe, where a large region in northern Italy, in particular, encountered many infections.

Case Description: Here we describe the first Dutch patient with COVID-19, a 56-year-old man whose infection appeared to be related to a trip to Northern Italy one week before presentation. In the days that followed, the brother of the patient with whom he had traveled, his wife and daughter also tested positive.

Conclusion: At the moment much is still unclear and it is particularly important to quickly identify patients with an increased risk of complications and to prevent unrestrained spread in the Netherlands.
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July 2020

[The first 100 COVID-19 patients admitted to the Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands].

Ned Tijdschr Geneeskd 2020 Apr 2;164. Epub 2020 Apr 2.

Elisabeth-Tweesteden Ziekenhuis, afd. Intensive Care Geneeskunde, Tilburg.

Here we describe the characteristics of the first 100 laboratory confirmed COVID-19 patients admitted to the Elisabeth-Tweesteden Hospital (Tilburg, The Netherlands). The median age was 72 years, 67% was male, approximately 80% had co-morbidity, approximately 50% of which consisted of hypertension, cardiac and or pulmonary conditions and 25% diabetes. At admission 61% of patients had fever and about 50% presented at day 6 or more after onset of symptoms. At the time of writing 38 patients were discharged, 19 admitted to the intensive care unit (ICU) and 20 patients had died. The median age of ICU patients was 67 years and 63% had co-morbidity. The median time to discharge or to death was 6 and 5.5 days, respectively.
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April 2020

Rapid assessment of regional SARS-CoV-2 community transmission through a convenience sample of healthcare workers, the Netherlands, March 2020.

Euro Surveill 2020 03;25(12)

Amphia hospital, Breda, the Netherlands.

To rapidly assess possible community transmission in Noord-Brabant, the Netherlands, healthcare workers (HCW) with mild respiratory complaints and without epidemiological link (contact with confirmed case or visited areas with active circulation) were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within 2 days, 1,097 HCW in nine hospitals were tested; 45 (4.1%) were positive. Of six hospitals with positive HCW, two accounted for 38 positive HCW. The results informed local and national risk management.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.12.2000334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118342PMC
March 2020

Focusing on Good Responders to Pneumococcal Polysaccharide Vaccination in General Hospital Patients Suspected for Immunodeficiency. A Decision Tree Based on the 23-Valent Pneumococcal IgG Assay.

Front Immunol 2019 5;10:2496. Epub 2019 Nov 5.

Department of Tranzo, Tilburg University, Tilburg, Netherlands.

Recently, the 23-valent IgG-assay was suggested as screening assay to identify responders to pneumococcal polysaccharide (PnPS)-vaccination with the serotype-specific assay as a second-line test. However, in a low pre-test probability general hospital setting predicting responders could be more valuable to reduce the number of samples needing serotyping. Serotype-specific PnPS antibody-assays were performed for suspected immunodeficiency in two Dutch general hospitals (Jeroen Bosch Hospital, 's-Hertogenbosch; Elisabeth Tweesteden Hospital, Tilburg). 23-Valent PnPS antibody-assays were subsequently performed in archived material. Data were analyzed using receiver operating characteristic curves (AUC) and agreement indices (ICC). Sera of 284 patients (348 samples) were included; 23-valent IgG-titres and the corresponding sum of PnPS-serotype specific antibodies showed moderate correlation (ICC = 0.63). In 232 conjugated-pneumococcal-vaccine-naïve patients (270 samples), a random 23-valent IgG-titer could discriminate between samples with and without ≥7/11, ≥7/13, or ≥6/9 pneumococcal serotypes when both cut-off values 0.35 and 1.0 μg/ml were used (AUC 0.86 and 0.92, respectively). All patients with a pre-immunization-titer ≥38.2 μg/ml and/or post-immunization-titer ≥96.1 μg/ml and none with a post-immunization-titer ≤38.5 μg/ml exhibited a good response to PnPS vaccination. Using these breakpoints as screening test to predict responders, only 24% of patients would require further serotyping, as opposed to 68% if breakpoints to predict responders would have been used. In a low pre-test probability setting, the 23-valent IgG-assay proved to be a reliable screening test for good responders in conjugated-pneumococcal-vaccine-naïve patients, reducing the overall number of patient samples needing further serotyping, thus reducing overall costs of pneumococcal vaccination response assessment.
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http://dx.doi.org/10.3389/fimmu.2019.02496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848064PMC
November 2020

Tubuloids derived from human adult kidney and urine for personalized disease modeling.

Nat Biotechnol 2019 03 4;37(3):303-313. Epub 2019 Mar 4.

Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands.

Adult stem cell-derived organoids are three-dimensional epithelial structures that recapitulate fundamental aspects of their organ of origin. We describe conditions for the long-term growth of primary kidney tubular epithelial organoids, or 'tubuloids'. The cultures are established from human and mouse kidney tissue and can be expanded for at least 20 passages (>6 months) while retaining a normal number of chromosomes. In addition, cultures can be established from human urine. Human tubuloids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. We apply tubuloids to model infectious, malignant and hereditary kidney diseases in a personalized fashion. BK virus infection of tubuloids recapitulates in vivo phenomena. Tubuloids are established from Wilms tumors. Kidney tubuloids derived from the urine of a subject with cystic fibrosis allow ex vivo assessment of treatment efficacy. Finally, tubuloids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active (trans-)epithelial transport function.
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http://dx.doi.org/10.1038/s41587-019-0048-8DOI Listing
March 2019

Pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza.

Antivir Ther 2018 ;23(5):457-461

Intensive Care, University Medical Center Utrecht, Utrecht, the Netherlands.

Favipiravir is a novel antiviral drug approved for influenza treatment in Japan. Little is known about favipiravir pharmacokinetics in critically ill patients. Here, we report a patient with influenza treated with favipiravir and undergoing continuous venovenous haemofiltration (CVVH) on the Intensive Care Unit of a tertiary hospital in the Netherlands. Pharmacokinetic analyses showed increased clearance and decreased plasma levels compared to healthy volunteers. CVVH has no clinically relevant contribution to total clearance. Despite susceptibility to favipiravir, the influenza virus was not cleared. A multi-disciplinary approach is needed to ensure optimal favipiravir treatment in critically ill patients.
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http://dx.doi.org/10.3851/IMP3210DOI Listing
September 2019

Nitazoxanide May Modify the Course of Progressive Multifocal Leukoencephalopathy.

J Clin Immunol 2018 01 20;38(1):4-6. Epub 2017 Nov 20.

Immunodeficiency Unit, Inflammation Center and Center for Rare Diseases, Children's Hospital, Helsinki University and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1007/s10875-017-0463-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086546PMC
January 2018

Infection with a respiratory virus before hematopoietic cell transplantation is associated with alloimmune-mediated lung syndromes.

J Allergy Clin Immunol 2018 02 15;141(2):697-703.e8. Epub 2017 Jul 15.

Blood and Marrow Transplantation Program, Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands; U-DANCE Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Alloimmune-mediated lung syndromes (allo-LSs) are life-threatening complications after hematopoietic cell transplantation (HCT). Respiratory virus (RV) has been suggested to play a role in the pathogenesis.

Objective: We studied the relation between RV DNA/RNA detection in the upper/lower airways before HCT and the occurrence of allo-LSs.

Methods: We retrospectively analyzed all HCT recipients between 2004 and 2014, in whom real-time PCR for RV was performed in nasopharyngeal aspirates (NPAs) and bronchoalveolar lavage (BAL) fluid before HCT. The main outcome of interest was the presence of an allo-LS, which was defined as idiopathic pneumonia syndrome or bronchiolitis obliterans syndrome. Other outcomes were overall survival and treatment-related mortality. We used Cox proportional hazard models, logistic regression models, and Fine-Gray competing risk regression for analyses.

Results: One hundred seventy-nine children (median age, 6.8 years) were included. RVs were found in 61% (41% in BAL fluid/NPAs and 20% in NPAs only). Rhinovirus was the most frequently detected RV (42%). Allo-LSs occurred in 13%. RV positivity in BAL fluid was a predictor for allo-LSs (hazard ratio, 3.8; 95% CI, 1.4-10.7; P = .01), whereas RV positivity in NPAs only was not. No other predictors were found. Grade II to IV acute graft-versus-host disease related to steroid treatment shows a trend toward a protective effect (odds ratio, 0.16; 95% CI, 0.0-1.3; P = .08). Allo-LSs significantly increased treatment-related mortality (52% ± 10% in allo-LSs and 20% ± 4% in non-allo-LSs, P = .007).

Conclusions: These results show that pre-HCT BAL fluid RV positivity was a predictor for allo-LSs. Screening for RVs before HCT might identify patients at risk for allo-LSs. This could have implications for prevention and treatment and might subsequently influence the outcomes of HCT.
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http://dx.doi.org/10.1016/j.jaci.2017.03.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125836PMC
February 2018

Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases.

J Neurol 2017 Jun 23;264(6):1155-1164. Epub 2017 May 23.

Laboratory of Medical Microbiology and Immunology, St. Elisabeth Hospital Tilburg, Tilburg, The Netherlands.

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6-110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6-72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.
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http://dx.doi.org/10.1007/s00415-017-8509-9DOI Listing
June 2017

Acute influenza virus-associated encephalitis and encephalopathy in adults: a challenging diagnosis.

JMM Case Rep 2016 Dec 19;3(6):e005076. Epub 2016 Dec 19.

Department of Medical Microbiology, University Medical Center Utrecht , Heidelberglaan 100, 3584 CX Utrecht , The Netherlands.

: Acute influenza-associated encephalopathy/encephalitis (IAE) in adults is a rare but well-known complication of influenza virus infection. The diagnosis is difficult to make due to the absence of distinctive clinical symptoms and validated diagnostic criteria. We present an illustrative case and a case review on acute IAE in adults. : We performed a Medline search of the English literature using the terms influenz*, encephal* and adult, and constructed a database of detailed descriptions of patients with influenza virus infection with influenza-like symptoms at the onset of neurological symptoms. : A total of 44 patients were included. Confusion and seizures were the most prevalent neurological symptoms, present in 12 (27 %) and 10 (23 %) patients, respectively. Magnetic resonance imaging (MRI) was performed in 21 patients and anomalies were found in 13 (62 %), with lesions located throughout the brain. Influenza virus RNA was detected in cerebrospinal fluid (CSF) in 5 (16 %) of 32 patients. Eight (18 %) of the forty-four patients died. The benefits of antiviral and immunomodulatory therapy have not been well studied. : Our results show that many different neurological symptoms can be present in patients with acute onset IAE. Therefore, the diagnosis should be considered in patients with fever and neurological symptoms, especially during the influenza season. Laboratory diagnosis consists of demonstration of influenza virus RNA in brain tissue, CSF or respiratory samples, and demonstration of intrathecal antibody production against influenza virus. The presence of brain lesions in MRI and influenza virus in CSF appear to be of prognostic value.
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http://dx.doi.org/10.1099/jmmcr.0.005076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343125PMC
December 2016

Progressive multifocal leukoencephalopathy and black fungus in a patient with rheumatoid arthritis without severe lymphocytopenia.

JMM Case Rep 2016 Aug 30;3(4):e005053. Epub 2016 Aug 30.

Department of Internal Medicine and infectious Diseases, University Medical Centre Utrecht, the Netherlands.

Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating brain infection caused by JC polyomavirus (JCV), primarily seen in patients with severely compromised cellular immunity. Clinical presentation varies depending on the affected white matter. PML prognosis is variable and effective treatments are lacking.

Case Presentation: A 75-year-old Chinese woman with type 2 diabetes mellitus, chronic kidney disease and rheumatoid arthritis, treated with low-dose methotrexate and prednisolone for 2.5 years, developed a infection of her left arm. After 6 months of treating this rare black fungus infection with voriconazole, surgery and immunosuppression discontinuation, she presented with progressive afebrile encephalopathy with right-sided hemiparesis. There were no signs of inflammation or metabolic abnormalities. Brain magnetic resonance imaging revealed diffuse frontal white matter lesions and a cerebrospinal fluid PCR confirmed PML due to JC virus. Severe lymphopenia was never present, and at PML diagnosis, CD4 and CD8 T-cell counts were 454 mm and 277 mm. CD8 T-cells were able to respond to JCV VP1 peptide stimulation with TNFα secretion. Peripheral B-cell count was only 8 mm. Mirtazapine and Maraviroc were started, but unfortunately, she rapidly deteriorated and died 5 weeks after PML diagnosis.

Conclusion: Although peripheral lymphocyte counts were never low and CD4 T-cell count was close to normal, the persistent black fungus infection was a hallmark of severely compromised cellular immunity. The unexpected extremely low absolute B-cell count might suggest a protective role for B-cells. The paradoxical, clinical PML onset months after immunosuppressive discontinuation suggests that it was only discovered in the context of an immune reconstitution inflammatory syndrome.
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http://dx.doi.org/10.1099/jmmcr.0.005053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330243PMC
August 2016

Congenital Cytomegalovirus Infection in the Absence of Maternal Cytomegalovirus-IgM Antibodies.

Fetal Diagn Ther 2017 4;42(2):144-149. Epub 2017 Mar 4.

Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Congenital cytomegalovirus (cCMV) infections are the most prevalent intrauterine infections worldwide and are the result of maternal primary or non-primary infections. Early maternal primary infections are thought to carry the highest risk of fetal developmental abnormalities as seen by ultrasound; however, non-primary infections may prove equally detrimental.

Methods/results: This case series presents 5 cases with fetal abnormalities detected in the second and third trimester, in which cCMV infection was ruled out due to negative maternal CMV-IgM.

Discussion: This series highlights the possible pitfalls in serology interpretation and fetal diagnosis necessary for appropriate parental counseling. Once fetal abnormalities have been confirmed and cCMV is suspected, maternal CMV serostatus and fetal infection should be determined. Maternal CMV serology may be ambiguous; therefore, caution should be exercised when interpreting the results.
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http://dx.doi.org/10.1159/000456615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637361PMC
May 2018

Reply to the letter to the editor "Is colchicine really harmful in viral myocarditis?"

Int J Cardiol 2017 02 26;229:43. Epub 2016 Nov 26.

Department of Pathology, VU University Medical Center, Postbox 7057, 1007 MB Amsterdam, The Netherlands; Institute for Cardiovascular Research of the Vrije Universiteit (ICaR-VU), VU University Medical Center, De Postbox 7057, 1007 MB Amsterdam, The Netherlands; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, Postbox 9892, 1006 AN Amsterdam, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2016.11.292DOI Listing
February 2017

Drug-associated progressive multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid analysis of 326 cases.

J Neurol 2016 Oct 11;263(10):2004-21. Epub 2016 Jul 11.

Department of Radiology and Nuclear Medicine, VU Medical Center, Amsterdam, The Netherlands.

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037162PMC
http://dx.doi.org/10.1007/s00415-016-8217-xDOI Listing
October 2016

Colchicine aggravates coxsackievirus B3 infection in mice.

Int J Cardiol 2016 Aug 19;216:58-65. Epub 2016 Apr 19.

Department of Pathology, VU University Medical Center, Postbox 7057, 1007, MB, Amsterdam, The Netherlands; Institute for Cardiovascular Research of the Vrije Universiteit (ICaR-VU), VU University Medical Center, De Postbox 7057, 1007, MB, Amsterdam, The Netherlands; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, Postbox 9892, 1006, AN, Amsterdam, The Netherlands. Electronic address:

Background: There is a clinical need for immunosuppressive therapy that can treat myocarditis patients in the presence of an active viral infection. In this study we therefore investigated the effects of colchicine, an immunosuppressive drug which has been used successfully as treatment for pericarditis patients, in a mouse model of coxsackievirus B3(CVB3)-induced myocarditis.

Methods: Four groups of C3H mice were included: control mice (n=8), mice infected with CVB3 (1×10(5) PFU, n=10), mice with colchicine administration (2mg/kg i.p, n=5) and mice with combined CVB3 infection and colchicine administration (n=10). After three days, the heart, pancreas and spleen were harvested and evaluated using (immuno)histochemical analysis and CVB3 qPCR.

Results: Mice were terminated at day 3 post-virus infection as colchicine treatment rapidly resulted in severe illness and mortality in CVB3-infected mice. Colchicine significantly decreased the number of macrophages in the heart in CVB3-infected mice (p<0.01) but significantly increased the number of neutrophils (p<0.01). In the pancreas, colchicine caused complete destruction of the acini in the CVB3-infected mice and also significantly decreased macrophage (p<0.01) and increased neutrophil numbers (p<0.01). In the spleen, colchicine treatment of CVB3-infected mice induced massive apoptosis in the white pulp and significantly inhibited the virus-induced increase of megakaryocytes in the spleen (p<0.001). Finally, we observed that colchicine significantly increased CVB3 levels in both the pancreas and the heart.

Conclusions: Colchicine treatment in CVB3-induced myocarditis has a detrimental effect as it causes complete destruction of the exocrine pancreas and enhances viral load in both heart and pancreas.
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http://dx.doi.org/10.1016/j.ijcard.2016.04.144DOI Listing
August 2016

Epidemiology of Guillain-Barré Syndrome in Aruba.

Am J Trop Med Hyg 2016 06 28;94(6):1380-4. Epub 2016 Mar 28.

Department of Medical Microbiology and Infection Control, VU University Medical Centre (VUMC), Amsterdam, The Netherlands; Department of Neurology, Dr Horacio E. Oduber Hospital, Oranjestad, Aruba; Department of Internal Medicine, Dr Horacio E. Oduber Hospital, Oranjestad, Aruba; Department of Microbiology, Landslaboratorium, Oranjestad, Aruba; Department of Virology, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands; Institute of Tropical Medicine, Antwerp, Belgium.

The epidemiology of Guillain-Barré syndrome (GBS) in tropical areas is different compared with developed countries. We investigated the epidemiology of GBS on the Caribbean island of Aruba. Data were collected retrospectively from all 36 patients hospitalized with GBS between 2003 and 2011 in Aruba. We observed a seasonal distribution of GBS cases with a peak in February. The incidence rate (IR) fluctuated heavily between individual years. The overall IR was 3.93/100,000, which is higher than that observed in developed countries. Serological studies indicated a possible relation of GBS cases with dengue virus infections. We also observed a relation between the annual number of dengue cases in Aruba and the number of GBS cases in the same year. We conclude that the epidemiology of GBS in tropical areas can be different from temperate climate regions and that dengue may be a trigger for developing GBS.
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http://dx.doi.org/10.4269/ajtmh.15-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889761PMC
June 2016
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