Publications by authors named "Annemiek A van der Eijk"

69 Publications

Herpes Zoster in Solid Organ Transplantation: Incidence and Risk Factors.

Front Immunol 2021 18;12:645718. Epub 2021 Mar 18.

Department of Internal Medicine-Nephrology and Transplantation, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands.

Background: Studies on herpes zoster (HZ) incidence in solid organ transplant (SOT) recipients report widely varying numbers. We investigated HZ incidence, severity, and risk factors in recipients of four different SOTs, with a follow-up time of 6-14 years.

Methods: Records of 1,033 transplant recipients after first heart (HTx: n = 211), lung (LuTx: n = 121), liver (LiTx: n = 258) and kidney (KTx: n = 443) transplantation between 2000 and 2014 were analyzed for VZV-PCR, clinical signs of HZ, and complications.

Results: HZ was diagnosed in 108 of 1,033 patients (10.5%): 36 HTx, 17 LuTx, 15 LiTx, and 40 KTx recipients. Overall HZ incidence rate after HTx (30.7 cases/1,000 person-years (PY)), LuTx (38.8 cases/1,000 PY), LiTx (22.7 cases/1,000 PY) and KTx (14.5 cases/1,000 PY) was significantly higher than in the general 50-70 year population. Multivariable analysis demonstrated age ≥50 years at transplantation (p = 0.038, RR 1.536), type of organ transplant (overall p = 0.002; LuTx p = 0.393; RR 1.314; LiTx p = 0.011, RR 0.444; KTx p = 0.034, RR 0.575), CMV prophylaxis (p = 0.043, RR 0.631) and type of anti-rejection therapy (overall p = 0.020; methylprednisolone p = 0.008, RR 0.475; r-ATG p = 0.64, RR1.194) as significant risk factors. Complications occurred in 33 of 108 (31%) patients (39% of HTx, 47% of LuTx, 20% of LiTx, 20% of KTx): post-herpetic neuralgia, disseminated disease, and cranial nerve involvement.

Conclusion: HZ incidence and severity in SOT recipients are most pronounced after heart and lung transplantation, in older patients, and when CMV prophylaxis is lacking.
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http://dx.doi.org/10.3389/fimmu.2021.645718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012754PMC
March 2021

Towards a sensitive and accurate interpretation of molecular testing for SARS-CoV-2: a rapid review of 264 studies.

Euro Surveill 2021 03;26(10)

Global Outbreak Alert and Response Network (GOARN), Geneva, Switzerland.

BackgroundSensitive molecular diagnostics and correct test interpretation are crucial for accurate COVID-19 diagnosis and thereby essential for good clinical practice. Furthermore, they are a key factor in outbreak control where active case finding in combination with isolation and contact tracing are crucial.AimWith the objective to inform the public health and laboratory responses to the pandemic, we reviewed current published knowledge on the kinetics of SARS-CoV-2 infection as assessed by RNA molecular detection in a wide range of clinical samples.MethodsWe performed an extensive search on studies published between 1 December 2019 and 15 May 2020, reporting on molecular detection and/or isolation of SARS-CoV-2 in any human laboratory specimen.ResultsWe compiled a dataset of 264 studies including 32,515 COVID-19 cases, and additionally aggregated data points (n = 2,777) from sampling of 217 adults with known infection timeline. We summarised data on SARS-CoV-2 detection in the respiratory and gastrointestinal tract, blood, oral fluid, tears, cerebrospinal fluid, peritoneal fluid, semen, vaginal fluid; where provided, we also summarised specific observations on SARS-CoV-2 detection in pregnancy, infancy, children, adolescents and immunocompromised individuals.ConclusionOptimal SARS-CoV-2 molecular testing relies on choosing the most appropriate sample type, collected with adequate sampling technique, and with the infection timeline in mind. We outlined knowledge gaps and directions for future well-documented systematic studies.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.10.2001134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953531PMC
March 2021

Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19).

Nat Commun 2021 01 11;12(1):267. Epub 2021 Jan 11.

Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.

Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients (17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5-11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4-17.2). Multivariate analyses identify viral loads above 7 log RNA copies/mL (odds ratio [OR] of 14.7 (CI 3.57-58.1; p < 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p < 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.
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http://dx.doi.org/10.1038/s41467-020-20568-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801729PMC
January 2021

[The pitfalls of preventive testing for SARS-CoV-2].

Ned Tijdschr Geneeskd 2020 12 15;165. Epub 2020 Dec 15.

Erasmus MC, Rotterdam: Afd. Viroscience.

The Dutch test capacity to detect the SARS-CoV-2 virus has increased enormously since the start of the COVID-19 pandemic. As a consequence of ongoing spreading of the virus, tests are also increasingly being carried out among people without COVID-19 related symptoms. Preventive testing for SARS-CoV-2 is especially performed in sectors in which early detection of the virus is essential, for instance in the professional sports sector. The guideline of the RIVM states that people who have tested positive for SARS-CoV-2 but without COVID-19 related symptoms are advised to stay in isolation for five days from time of the test. However, this guideline is not suitable for people who are diagnosed in a very early stage of the infection as a result of preventive testing. They are likely to leave isolation during the most contagious phase of the infection. In this paper, we argue that people who are positive for SARS-CoV-2, but without COVID-19 related symptoms, after a preventive test should be advised to isolate longer than five days.
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December 2020

Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss.

Aliment Pharmacol Ther 2021 01 21;53(2):314-320. Epub 2020 Nov 21.

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Serum hepatitis B virus (HBV) RNA may reflect intrahepatic HBV replication. Novel anti-viral drugs have shown potent HBV RNA decline without concomitant hepatitis B surface antigen (HBsAg) decrease. How this relates to off-treatment response is yet unclear.

Aim: To study the degree of on-treatment viral antigen decline among patients with pronounced HBV RNA decrease in relation to off-treatment sustained response and HBsAg loss.

Methods: HBV RNA, HBsAg and hepatitis B core-related antigen (HBcrAg) were quantified in patients with chronic hepatitis B who participated in two randomised controlled trials of peginterferon-based therapy. Sustained response (HBV DNA <2000 IU/mL) and/or HBsAg loss were assessed in patients with and without on-treatment HBV RNA response (either >2 log HBV RNA decline or >1 log decline resulting in an undetectable value at on-treatment week 24), stratified by concomitant HBsAg decline (<0.5/0.5-1/>1 log).

Results: We enrolled 279 patients; 176 were hepatitis B e antigen (HBeAg)-positive, and 103 were HBeAg-negative. Sustained response was achieved in 20.4% of patients. At on-treatment week 24, HBV RNA response was associated with higher sustained response rates (27.4% vs 13.0% in non-responders, P =  0.004). However, among patients with an HBV RNA response (n = 135), 56.4% did not experience >0.5 log HBsAg decline. Among HBV RNA responders, sustained response was achieved in 47.6% of those with >1 log HBsAg decline (n = 20/42), vs 16.0% with <0.5 log decline (n = 12/75, P = 0.001). Similar results were obtained with HBcrAg and when response was defined as HBsAg loss.

Conclusions: In this cohort, many patients with HBV RNA response during peginterferon-based treatment did not experience HBsAg and/or HBcrAg decline. The absence of concomitant decline in these viral antigens was associated with low rates of treatment response and HBsAg loss. Future trials should therefore consider kinetics of combined biomarkers to assess anti-viral efficacy. Trial registration, ClinicalTrials.gov: NCT00114361, NCT00146705.
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http://dx.doi.org/10.1111/apt.16172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839551PMC
January 2021

Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans.

Science 2021 01 10;371(6525):172-177. Epub 2020 Nov 10.

Department of Viroscience, Erasmus MC, WHO Collaborating Centre for Arbovirus and Viral Hemorrhagic Fever Reference and Research, Rotterdam, Netherlands.

Animal experiments have shown that nonhuman primates, cats, ferrets, hamsters, rabbits, and bats can be infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, SARS-CoV-2 RNA has been detected in felids, mink, and dogs in the field. Here, we describe an in-depth investigation using whole-genome sequencing of outbreaks on 16 mink farms and the humans living or working on these farms. We conclude that the virus was initially introduced by humans and has since evolved, most likely reflecting widespread circulation among mink in the beginning of the infection period, several weeks before detection. Despite enhanced biosecurity, early warning surveillance, and immediate culling of animals in affected farms, transmission occurred between mink farms in three large transmission clusters with unknown modes of transmission. Of the tested mink farm residents, employees, and/or individuals with whom they had been in contact, 68% had evidence of SARS-CoV-2 infection. Individuals for which whole genomes were available were shown to have been infected with strains with an animal sequence signature, providing evidence of animal-to-human transmission of SARS-CoV-2 within mink farms.
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http://dx.doi.org/10.1126/science.abe5901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857398PMC
January 2021

Determining the therapeutic range for ribavirin in transplant recipients with chronic hepatitis E virus infection.

J Viral Hepat 2021 Feb 15;28(2):431-435. Epub 2020 Nov 15.

Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

The aim of this study was to define the therapeutic range for ribavirin (RBV) in transplant recipients with chronic hepatitis E virus (HEV) infection. In this retrospective multicentre cohort study, data of adult transplant recipients with chronic HEV infection, who had been treated with RBV monotherapy between 01-3-2008 and 01-08-2018, were included. ROC curve analyses were performed, and the half-maximal effective RBV concentration was calculated to determine a representative therapeutic range. In 96 patients, RBV monotherapy for a median of three months resulted in a sustained virologic response in 63.5% of the patients, while 88.5% of the patients developed anaemia. RBV plasma concentrations at steady state were significantly higher in clinical responders compared with clinical non-responders: median 1.96 (IQR 1.81-2.70) versus 0.49 (IQR 0.45-0.73) mg/L, P = .0004. RBV caused a dose-dependent haemoglobin reduction with higher RBV plasma concentrations resulting in more haemoglobin reduction. The therapeutic range for RBV for chronic HEV infection in transplant recipients ranges between 1.8 and 2.3 mg/L.
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http://dx.doi.org/10.1111/jvh.13432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983011PMC
February 2021

Hepatitis B core-related antigen levels predict recurrence-free survival in patients with HBV-associated early-stage hepatocellular carcinoma: results from a Dutch long-term follow-up study.

J Viral Hepat 2021 01 14;28(1):205-208. Epub 2020 Sep 14.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Prognosis of hepatitis B (HBV)-associated hepatocellular carcinoma (HCC) is poor due to high rates of HCC recurrence and progression of underlying liver disease. We studied whether serum hepatitis B core-related antigen (HBcrAg) levels could predict HCC recurrence and outcome in HBV associated. Higher HBcrAg levels at HCC diagnosis were independently associated with reduced overall and recurrence-free survival in patients with early, but not advanced, stage HCC.
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http://dx.doi.org/10.1111/jvh.13394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756674PMC
January 2021

EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution.

Neurol Neuroimmunol Neuroinflamm 2020 11 13;7(6). Epub 2020 Aug 13.

From the Department of Neurology (J.Y.M., K.L.K.); Department of Viroscience (G.P.N., A.A.E.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, the Netherlands (J.Y.M., K.L.K.).

Objective: In multiplex MS families, we determined the humoral immune response to Epstein-Barr virus nuclear antigen 1 (EBNA-1)-specific immunoglobulin γ (IgG) titers in patients with MS, their healthy siblings, and biologically unrelated healthy spouses and investigated the role of specific genetic loci on the antiviral IgG titers.

Methods: IgG levels against EBNA-1 and varicella zoster virus (VZV) as control were measured. and tagging single-nucleotide polymorphisms (SNPs) were genotyped. We assessed the associations between these SNPs and antiviral IgG titers.

Results: OR for abundant EBNA-1 IgG was the highest in patients with MS and intermediate in their siblings compared with spouses. We confirmed that is associated with abundant EBNA-1 IgG. After stratification for , the EBNA-1 IgG gradient was still significant in patients with MS and young siblings compared with spouses. was not explanatory for EBNA-1 IgG titer gradient. No associations for VZV IgG were found.

Conclusions: In families with MS, the EBNA-1 IgG gradient being the highest in patients with MS, intermediate in their siblings, and lowest in biologically unrelated spouses indicates a genetic contribution to EBNA-1 IgG levels that is only partially explained by carriership.
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http://dx.doi.org/10.1212/NXI.0000000000000872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428359PMC
November 2020

Hepatitis B core-related antigen levels predict pegylated interferon-α therapy response in HBeAg-positive chronic hepatitis B.

Antivir Ther 2020 ;25(4):217-222

Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Serum hepatitis B core-related antigen (HBcrAg) levels reflect intrahepatic HBV replication activity. We aimed to study whether HBcrAg levels predict response to pegylated interferon (PEG-IFN) treatment in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.

Methods: We studied HBcrAg levels in 222 HBeAg-positive patients treated with PEG-IFN with or without lamivudine for 52 weeks in a global randomized trial and compared kinetics across treatment arms and types of response. Optimal HBcrAg cutoffs for stopping therapy were compared to and combined with the currently recommended hepatitis B surface antigen (HBsAg)-based stopping-rules.

Results: Baseline HBcrAg levels could not discriminate between responders and non-responders (P=0.91). HBcrAg levels of patients responding to PEG-IFN therapy showed a more pronounced on-treatment decline (mean declines 3.4 versus 1.0 log U/ml; P<0.0001), which was sustained until the end of follow-up (mean declines week 78, 3.8 versus 1.0 log U/ml; P<0.0001). In the PEG-IFN monotherapy group, HBcrAg levels of >8.35 log U/ml at week 24 identified 19 patients (19%) of whom 1 (negative predicitve value [NPV]=95%) achieved a response. The performance of this HBcrAg-based stopping rule alone was not superior to the one based on HBsAg >20,000 IU/ml. Among patients with an HBsAg <20,000 (n=56), 9 (16%) had an HBcrAg >8.35, of whom 8 achieved no response (NPV 89%).

Conclusions: HBeAg-positive CHB patients with a response to PEG-IFN therapy achieve a more pronounced HBcrAg decline. HBcrAg levels at week 24 of therapy could be used to identify non-responders in combination with the established HBsAg-based stopping-rules.
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http://dx.doi.org/10.3851/IMP3367DOI Listing
January 2020

Rapid SARS-CoV-2 whole-genome sequencing and analysis for informed public health decision-making in the Netherlands.

Nat Med 2020 09 16;26(9):1405-1410. Epub 2020 Jul 16.

ErasmusMC, Department of Viroscience, WHO Collaborating Centre for Arbovirus and Viral Hemorrhagic Fever Reference and Research, Rotterdam, the Netherlands.

In late December 2019, a cluster of cases of pneumonia of unknown etiology were reported linked to a market in Wuhan, China. The causative agent was identified as the species Severe acute respiratory syndrome-related coronavirus and was named SARS-CoV-2 (ref. ). By 16 April the virus had spread to 185 different countries, infected over 2,000,000 people and resulted in over 130,000 deaths. In the Netherlands, the first case of SARS-CoV-2 was notified on 27 February. The outbreak started with several different introductory events from Italy, Austria, Germany and France followed by local amplification in, and later also outside, the south of the Netherlands. The combination of near to real-time whole-genome sequence analysis and epidemiology resulted in reliable assessments of the extent of SARS-CoV-2 transmission in the community, facilitating early decision-making to control local transmission of SARS-CoV-2 in the Netherlands. We demonstrate how these data were generated and analyzed, and how SARS-CoV-2 whole-genome sequencing, in combination with epidemiological data, was used to inform public health decision-making in the Netherlands.
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http://dx.doi.org/10.1038/s41591-020-0997-yDOI Listing
September 2020

An evaluation of COVID-19 serological assays informs future diagnostics and exposure assessment.

Nat Commun 2020 07 6;11(1):3436. Epub 2020 Jul 6.

Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.

The world is entering a new era of the COVID-19 pandemic in which there is an increasing call for reliable antibody testing. To support decision making on the deployment of serology for either population screening or diagnostics, we present a detailed comparison of serological COVID-19 assays. We show that among the selected assays there is a wide diversity in assay performance in different scenarios and when correlated to virus neutralizing antibodies. The Wantai ELISA detecting total immunoglobulins against the receptor binding domain of SARS CoV-2, has the best overall characteristics to detect functional antibodies in different stages and severity of disease, including the potential to set a cut-off indicating the presence of protective antibodies. The large variety of available serological assays requires proper assay validation before deciding on deployment of assays for specific applications.
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http://dx.doi.org/10.1038/s41467-020-17317-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338506PMC
July 2020

Norovirus outbreak in a natural playground: A One Health approach.

Zoonoses Public Health 2020 06 9;67(4):453-459. Epub 2020 Feb 9.

Public Health Service Rotterdam-Rijnmond, Rotterdam, The Netherlands.

Norovirus constitutes the most frequently identified infectious cause of disease outbreaks associated with untreated recreational water. When investigating outbreaks related to surface water, a One Health approach is insightful. Historically, there has been a focus on potential contamination of recreational water by bird droppings and a recent publication demonstrating human noroviruses in bird faeces suggested this should be investigated in future water-related norovirus outbreaks. Here, we describe a One Health approach investigating a norovirus outbreak in a natural playground. On social media, a large amount of waterfowl were reported to defecate near these playground premises leading to speculations about their potential involvement. Surface water, as well as human and bird faecal specimens, was tested for human noroviruses. Norovirus was found to be the most likely cause of the outbreak but there was no evidence for transmission via waterfowl. Cases had become known on social media prior to notification to the public health service underscoring the potential of online media as an early warning system. In view of known risk factors, advice was given for future outbreak investigations and natural playground design.
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http://dx.doi.org/10.1111/zph.12689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318310PMC
June 2020

Performance evaluation of the Panther Fusion® respiratory tract panel.

J Clin Virol 2020 02 10;123:104232. Epub 2019 Dec 10.

Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: Respiratory tract infections are among the most common infections during winter season. Rapid diagnostics is required for clinical decision making regarding isolation of patients and appropriate therapy.

Objectives: The aim of this study was to evaluate the analytical and clinical performance characteristics of the Panther Fusion® respiratory panel using published laboratory-developed real-time PCR assays (LDT).

Study Design: Analytical sensitivity of Panther Fusion® Flu A/B/RSV was assessed by testing dilutions of cell culture isolates. Clinical performance assessment included the complete Panther Fusion® respiratory panel (Flu-A/B/RSV, PIV 1-4 and AdV/hMPV/RV) and consisted of a retrospective and a prospective study-arm. The retrospective evaluation included 201, stored (-80 °C) samples collected between February 2006 and January 2017. Prospective evaluation was performed on 1045 unselected pretreated respiratory tract samples from patients presented to our hospital between November 2017 and May 2018.

Results: Analytical sensitivity was generally slightly lower for the Panther Fusion® assays. Clinical specificity and sensitivity was between 96 %-100 % and 71.9 %-100 %, respectively. Discrepant results were found in 146 samples of which 88 samples tested LDT positive / Panther Fusion® negative and 58 samples were LDT negative / Panther Fusion® positive. A total of ten discrepant samples with Ct-values <30 were sequenced to confirm the presence of 7 RV-C not-detected by LDT and 1 RV-A and 2 ADV-2 not detected by Panther Fusion®.

Conclusions: The Panther Fusion® provides a random-access system with continuous loading and much shorter sample-to-answer times compared to LDT, albeit with a slightly less clinical sensitivity compared to the LDT.
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http://dx.doi.org/10.1016/j.jcv.2019.104232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172494PMC
February 2020

Hepatitis E Virus Shows More Genomic Alterations in Cell Culture than In Vivo.

Pathogens 2019 11 22;8(4). Epub 2019 Nov 22.

Department of Viroscience, Erasmus University Medical Center, Postbus 2040 3000 CA Rotterdam, The Netherlands.

Hepatitis E Virus (HEV) mutations following ribavirin treatment have been associated with treatment non-response and viral persistence, but spontaneous occurring genomic variations have been less well characterized. We here set out to study the HEV genome composition in 2 patient sample types and 2 infection models. Near full HEV genome Sanger sequences of serum- and feces-derived HEV from two chronic HEV genotype 3 (gt3) patients were obtained. In addition, viruses were sequenced after in vitro or in vivo expansion on A549 cells or a humanized mouse model, respectively. We show that HEV acquired 19 nucleotide mutations, of which 7 nonsynonymous amino acids changes located in Open Reading Frame 1 (ORF1), ORF2, and ORF3 coding regions, after prolonged in vitro culture. In vivo passage resulted in selection of 8 nucleotide mutations with 2 altered amino acids in the X domain and Poly-proline region of ORF1. Intra-patient comparison of feces- and serum-derived HEV gt3 of two patients showed 7 and 2 nucleotide mutations with 2 and 0 amino acid changes, respectively. Overall, the number of genomic alterations was up to 1.25× per 1000 nucleotides or amino acids in in vivo samples, and up to 2.84× after in vitro expansion of the same clinical HEV strain. In vitro replication of a clinical HEV strain is therefore associated with more mutations, compared to the minor HEV genomic alterations seen after passage of the same strain in an immune deficient humanized mouse; as well as in feces and blood of 2 immunosuppressed chronically infected HEV patients. These data suggest that HEV infected humanized mice more closely reflect the HEV biology seen in solid organ transplant recipients.
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http://dx.doi.org/10.3390/pathogens8040255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963849PMC
November 2019

Causes of Hypertensive Anterior Uveitis in Thailand.

Ocul Immunol Inflamm 2020 May 7;28(4):559-565. Epub 2019 Nov 7.

Department of Ophthalmology, Erasmus Medical Centre , Rotterdam, the Netherlands.

Purpose: To determine the prevalence of viral infections in patients with hypertensive anterior uveitis in Thailand from polymerase chain reaction (PCR) of aqueous humor.

Methods: Thirty-one patients with anterior uveitis with intraocular pressure (IOP) above 25 mmHg were included for PCR analysis for cytomegalovirus (CMV), herpes simplex (HSV), varicella-zoster (VZV), rubella, chikungunya and Zika virus.

Results: The prevalence of PCR-positive results was 32%, including 19% for CMV, 10% for HSV, and 3% for VZV; PCR for other tested viruses demonstrated negative results. PCR-positive patients exhibited satisfactory IOP control with antiviral and anti-glaucomatous treatment compared to PCR-negative patients, and more than half of PCR-negative patients required glaucoma surgery within 12 months ( = .01).

Conclusion: PCR evidence of infection with herpes group viruses was found in one-third of patients with hypertensive anterior uveitis; CMV being the most common pathogen. The PCR-positive group generally responded well to a combination of antiviral and anti-glaucoma treatment.
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http://dx.doi.org/10.1080/09273948.2019.1678651DOI Listing
May 2020

Relationship between hepatitis B core-related antigen levels and sustained HBeAg seroconversion in patients treated with nucleo(s)tide analogues.

J Viral Hepat 2019 07 16;26(7):828-834. Epub 2019 Apr 16.

Department of Viroscience, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Hepatitis B e antigen (HBeAg) seroconversion experienced during nucleo(s)tide analogue (NUC) therapy is often not sustained. We aimed to study whether hepatitis B core-related antigen (HBcrAg) levels predict sustained HBeAg seroconversion in patients treated with NUCs. We studied HBeAg-positive patients treated with NUCs for at least 6 months. We quantified HBcrAg at baseline and at the time of HBeAg seroconversion and studied the relationship with HBeAg seroconversion and subsequent relapse. HBcrAg was quantified at baseline in 196 patients; levels varied significantly by HBV genotype and correlated with HBsAg, HBV DNA and HBeAg. Baseline HBcrAg levels were lower in patients who achieved HBeAg seroconversion than in those who did not; the unadjusted hazard ratio (HR) was 0.802 (95% CI: 0.656-0.980, P = 0.031); and this association was not sustained in multivariate analysis. HBcrAg remained detectable in all patients at the time of HBeAg seroconversion. Higher HBcrAg at the time of seroconversion was an independent predictor of relapse (adjusted HR: 1.855 (95% CI: 1.099-3.133, P = 0.021), and none of the patients with HBcrAg < 4.90 log U/mL experienced relapse. Baseline HBcrAg is not an independent predictor of HBeAg seroconversion during NUC therapy. HBcrAg remains detectable in patients after HBeAg seroconversion. Patients with lower levels at the time of seroconversion have a higher probability of sustained HBeAg seroconversion.
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http://dx.doi.org/10.1111/jvh.13097DOI Listing
July 2019

Diagnostic and analytical performance of the hepatitis B core related antigen immunoassay in hepatitis B patients.

J Clin Virol 2019 05 4;114:1-5. Epub 2019 Mar 4.

Department of Viroscience, Erasmus MC, University Medical Center Rotterdam, the Netherlands. Electronic address:

Background: Novel serological markers for Hepatitis B virus (HBV) infection are needed for prognosis and guidance of therapy.

Objective: We evaluated the diagnostic performance of the Fujirebio Lumipulse G HBcrAg immunoassay on the Fujirebio LUMIPULSE G1200 analyzer.

Study Design: Analytical performance was examined using three HBeAg positive HBV samples. Diagnostic specificity was assessed using subpanels of 54 confirmed acute HAV, HCV, HEV, B19, CMV and EBV infections. Diagnostic sensitivity was investigated in well-defined HBV positive patient groups, both treated and untreated, including immunocompromised patients.

Results: The Lumipulse G HBcrAg immunoassay provided a linear measurement at a dilution between 1:100 and1:10,000. Six out of 54 samples showed non-specific reactivity in sera from acute CMV, EBV and HEV infections, of which 2 of them >3 log U/ml. The highest levels of HBcrAg were measured in HBeAg positive patients, in both treated and untreated as well as in immunocompromised patients. Untreated patients had relatively low serum HBcrAg levels in the inactive carrier phase, which increased upon progression into the HBeAg-negative hepatitis phase. Also, we showed that the applicability of HBcrAg to distinguish between patients with resolved HBV infection and false-positive reactivity to solitary anti-HBc is limited.

Conclusions: Our study demonstrated significant differences in HBcrAg levels depending on HBeAg status, the clinical phase, as well as the treatment status. Specificity of the assay is good; only 2 out of 54 samples showed reactivity above 3 log U/ml. Before implementing the assay in clinical practice, additional research in larger patient cohorts should be carried out.
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http://dx.doi.org/10.1016/j.jcv.2019.03.003DOI Listing
May 2019

Genomic sequence of yellow fever virus from a Dutch traveller returning from the Gambia-Senegal region, the Netherlands, November 2018.

Euro Surveill 2019 Jan;24(4)

Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands.

In November 2018, yellow fever was diagnosed in a Dutch traveller returning from a bicycle tour in the Gambia-Senegal region. A complete genome sequence of yellow fever virus (YFV) from the case was generated and clustered phylogenetically with YFV from the Gambia and Senegal, ruling out importation into the Netherlands from recent outbreaks in Brazil or Angola. We emphasise the need for increased public awareness of YFV vaccination before travelling to endemic countries.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.4.1800684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351999PMC
January 2019

Acute-onset chronic inflammatory demyelinating polyneuropathy after Zika virus infection.

J Neurol Neurosurg Psychiatry 2018 10 24;89(10):1118-1119. Epub 2017 Nov 24.

Department of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1136/jnnp-2017-317346DOI Listing
October 2018

Whole-Genome Next-Generation Sequencing to Study Within-Host Evolution of Norovirus (NoV) Among Immunocompromised Patients With Chronic NoV Infection.

J Infect Dis 2017 12;216(12):1513-1524

Department of Viroscience, Erasmus Medical Center, Bilthoven, the Netherlands.

Background: The genus Norovirus comprises large genetic diversity, and new GII.4 variants emerge every 2-3 years. It is unknown in which host these new variants originate. Here we study whether prolonged shedders within the immunocompromised population could be a reservoir for newly emerging strains.

Methods: Sixty-five fecal samples from 16 immunocompromised patients were retrospectively selected. Isolated viral RNA was enriched by hybridization with a custom norovirus whole-genome RNA bait set and deep sequenced on the Illumina MiSeq platform.

Results: Patients shed virus for average 352 days (range, 76-716 days). Phylogenetic analysis showed distinct GII.4 variants in 3 of 13 patients (23%). The viral mutation rates were variable between patients but did not differ between various immune status groups. All within-host GII.4 viral populations showed amino acid changes at blocking epitopes over time, and the majority of VP1 amino acid mutations were located at the capsid surface.

Conclusions: This study found viruses in immunocompromised hosts that are genetically distinct from viruses circulating in the general population, and these patients therefore may contain a reservoir for newly emerging strains. Future studies need to determine whether these new strains are of risk to other immunocompromised patients and the general population.
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http://dx.doi.org/10.1093/infdis/jix520DOI Listing
December 2017

Hepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre study.

J Hepatol 2017 11 20;67(5):925-932. Epub 2017 Jul 20.

Department of Neurology and Immunology, Erasmus MC, University Medical Centre Rotterdam, The Netherlands.

Background & Aims: Hepatitis E virus (HEV) has been associated with a number of neurological syndromes, but causality has not yet been established. The aim of this study was to explore the relationship between HEV and neurological illness by prospective HEV testing of patients presenting with acute non-traumatic neurological injury.

Methods: Four hundred and sixty-four consecutive patients presenting to hospital with acute non-traumatic neurological illnesses were tested for HEV by serology and PCR from four centres in the UK, France and the Netherlands.

Results: Eleven of 464 patients (2.4%) had evidence of current/recent HEV infection. Seven had HEV RNA identified in serum and four were diagnosed serologically. Neurological cases in which HEV infection was found included neuralgic amyotrophy (n=3, all PCR positive); cerebral ischemia or infarction (n=4); seizure (n=2); encephalitis (n=1); and an acute combined facial and vestibular neuropathy (n=1). None of these cases were clinically jaundiced and median ALT at presentation was 24IU/L (range 8-145). Cases of HEV-associated neuralgic amyotrophy were found in each of the participating countries: all were middle-aged males with bilateral involvement of the brachial plexus.

Conclusions: In this cohort of patients with non-traumatic neurological injury, 2.4% had evidence of HEV infection. Symptoms of hepatitis were mild or absent and no patients were jaundiced. The cases of HEV-associated neuralgic amyotrophy had similarities with other HEV-associated cases described in a large retrospective study. This observation supports a causal relationship between HEV and neuralgic amyotrophy. To further understand the relevance of HEV infection in patients with acute neurological illnesses, case-control studies are warranted. Lay summary: Hepatitis E virus (HEV), as its name suggests, is a hepatotropic virus, i.e. it causes damage to the liver (hepatitis). Our findings show that HEV can also be associated with a range of injury to the nervous system.
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http://dx.doi.org/10.1016/j.jhep.2017.07.010DOI Listing
November 2017

HCV antigen instead of RNA testing to diagnose acute HCV in patients treated in the Dutch Acute HCV in HIV Study.

J Int AIDS Soc 2017 06;20(1):21621

Department of Internal Medicine, Division of Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Introduction: Affordable and sensitive screening methods for acute hepatitis C (HCV) are necessary to successfully intervene in the current HCV epidemic among HIV-positive men having sex with men. HCV core antigen (Ag) testing has been proven effective in diagnosing chronic HCV-infected patients at low costs. We studied the characteristics of HCV Ag testing in acute HCV-infected HIV-positive patients. Plasma samples were selected from acutely HCV genotype 1-infected patients treated with peginterferon, ribavirin and boceprevir in the Dutch Acute HCV in HIV Study. The control group consisted of HIV-positive patients with a newly raised alanine aminotransferase (ALT) (>41 U/L) in whom HCV RNA was undetectable and who were tested for HCV Ag. Spearman correlation coefficient between HCV RNA and HCV Ag was calculated together with the sensitivity and specificity of HCV Ag testing at acute HCV diagnosis.

Results And Discussion: Upon acute HCV diagnosis, HCV Ag was identified in 39 out of 44 patients with detectable HCV RNA levels. In all 23 control patients without detectable HCV RNA in plasma, HCV Ag was undetectable as well. This resulted in a sensitivity and specificity of HCV Ag of respectively 89% (95% CI 75-96) and 100% (95% CI 82-100). The correlation between HCV Ag and HCV RNA was 0.97 ( < 0.001) upon diagnosis.

Conclusion: The data presented in this study suggest that HCV Ag testing is a sensitive and specific method that can be used in diagnosing AHCV in HIV-infected patients.
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http://dx.doi.org/10.7448/IAS.20.1.21621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515013PMC
June 2017

Hepatitis E virus: A potential threat for patients with liver disease and liver transplantation.

Best Pract Res Clin Gastroenterol 2017 Apr 12;31(2):143-150. Epub 2017 Apr 12.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address:

Immunocompromised patients are at risk of acquiring acute hepatitis E virus infection (HEV), leading to chronicity. Chronic HEV infection is associated with persistent viraemia, raised transaminase activity, histological features associated with chronic hepatitis and evidence of rapid development of cirrhosis. Extrahepatic manifestations have been associated with HEV. Most frequently reported are neurological disorders with predominantly involvement of the peripheral nervous system. In patients using immunosuppressive drugs antibody production is often delayed and HEV RNA detection is superior to serology to detect infection. Therapeutic options for chronic HEV includes tapering immunosuppressive and secondly ribavirin, pegylated interferon alpha (PEG-IFN). Present recommendation is to treat chronic HEV patients for 3 months, asses serum HEV RNA and stool HEV RNA and stop therapy if both are undetectable. Studies are required to determine which other antiviral agents than ribavirin and (PEG-)IFN are of clinical utility in treating HEV in the minority of patients who do not respond to ribavirin.
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http://dx.doi.org/10.1016/j.bpg.2017.03.006DOI Listing
April 2017

Re-evaluation of routine dengue virus serology in travelers in the era of Zika virus emergence.

J Clin Virol 2017 07 3;92:25-31. Epub 2017 May 3.

Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address:

Background: Diagnostic requests for both Zika virus (ZIKV) and dengue virus (DENV) infections in returning travelers have significantly increased during the recent ZIKV outbreak in the Americás. These flaviviruses have overlapping clinical syndromes and geographical distribution, but diagnostic differentiation is important because of different clinical consequences. As flaviviruses are known to have a short viremic period, diagnostics often rely on serological methods, which are challenging due to extensive cross-reactive antibodies.

Objective: To re-evaluate the performance of DENV serological assays in laboratory confirmed ZIKV-infected travelers.

Study Design: The extent of cross-reactivity of the DENV NS1 antigen, IgM and IgG ELISA was analyzed in 152 clinical blood samples collected from 69 qRT-PCR and 24 virus neutralization titer (VNT) confirmed ZIKV-infected travelers.

Results: The majority of travelers in the presented cohort returned to the Netherlands from Suriname and presented with symptoms of fever and rash. Twenty-three percent of the female travelers were pregnant. None of the 39 ZIKV RNA positive blood samples were cross-reactive in the DENV NS1 antigen ELISA. The rates of cross-reactivity of the DENV IgM and IgG ELISÁs were 31% and 54%, respectively, after excluding travelers with (potential) previous DENV exposure.

Conclusions: Although the DENV NS1 antigen assay was highly specific in this cohort of laboratory confirmed ZIKV-infected travelers, we demonstrate high percentages of cross-reactivity of DENV IgM and IgG ELISÁs of which diagnostic laboratories should be aware. In addition, the high rate of DENV IgG background of >25% complicates a proper serological diagnosis in this group.
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http://dx.doi.org/10.1016/j.jcv.2017.05.001DOI Listing
July 2017

Hepatitis E virus: Western Cape, South Africa.

World J Gastroenterol 2016 Nov;22(44):9853-9859

Richie G Madden, Sebastian Wallace, Glynn W Webb, Joanne Palmer, Harry R Dalton, Royal Cornwall Hospital Trust and European Centre for Environment and Human Health, University of Exeter, TR1 3LJ Truro, United Kingdom.

Aim: To conduct a prospective assessment of anti-hepatitis E virus (HEV) IgG seroprevalence in the Western Cape Province of South Africa in conjunction with evaluating risk factors for exposure.

Methods: Consenting participants attending clinics and wards of Groote Schuur, Red Cross Children's Hospital and their affiliated teaching hospitals in Cape Town, South Africa, were sampled. Healthy adults attending blood donor clinics were also recruited. Patients with known liver disease were excluded and all major ethnic/race groups were included to broadly represent local demographics. Relevant demographic data was captured at the time of sampling using an interviewer-administered confidential questionnaire. Human immunodeficiency virus (HIV) status was self-disclosed. HEV IgG testing was performed using the Wantai assay.

Results: HEV is endemic in the region with a seroprevalence of 27.9% ( = 324/1161) 95%CI: 25.3%-30.5% (21.9% when age-adjusted) with no significant differences between ethnic groups or HIV status. Seroprevalence in children is low but rapidly increases in early adulthood. With univariate analysis, age ≥ 30 years old, pork and bacon/ham consumption suggested risk. In the multivariate analysis, the highest risk factor for HEV IgG seropositivity (OR = 7.679, 95%CI: 5.38-10.96, < 0.001) was being 30 years or older followed by pork consumption (OR = 2.052, 95%CI: 1.39-3.03, < 0.001). A recent clinical case demonstrates that HEV genotype 3 may be currently circulating in the Western Cape.

Conclusion: Hepatitis E seroprevalence was considerably higher than previously thought suggesting that hepatitis E warrants consideration in any patient presenting with an unexplained hepatitis in the Western Cape, irrespective of travel history, age or ethnicity.
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http://dx.doi.org/10.3748/wjg.v22.i44.9853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124991PMC
November 2016

Pre-implementation guidelines for infectious disease point-of-care testing in medical institutions.

Future Microbiol 2017 01 6;12:51-58. Epub 2016 Dec 6.

Department of Medical Microbiology & Infectious Diseases, Erasmus University Medical Center Rotterdam (Erasmus MC), Rotterdam, the Netherlands.

Infectious disease point-of-care test (ID-POCT) devices are becoming widely available, and in this respect, international quality standards and guidelines are available for consultation once ID-POCT has been implemented into medical institutions. However, specific guidelines for consultation during the initial pre-implementation decision-making process are currently lacking. Further, there exist pre-implementation issues specific to ID-POCT. Here we present pre-implementation guidelines for consultation when considering the implementation of ID-POCT in medical institutions.
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http://dx.doi.org/10.2217/fmb-2016-0120DOI Listing
January 2017

Hepatitis E virus: Infection beyond the liver?

J Hepatol 2017 05 29;66(5):1082-1095. Epub 2016 Nov 29.

Department of Viroscience, Erasmus MC University Medical Center Rotterdam, Netherlands.

Hepatitis E virus (HEV) infections are not limited to the liver but may also affect other organs. Several diseases, including Guillain-Barré syndrome, neuralgic amyotrophy, glomerulonephritis, cryoglobulinemia, pancreatitis, lymphoma, thrombopenia, meningitis, thyroiditis and myocarditis have been observed in the context of hepatitis E. To date, the definite pathophysiological links between HEV and extrahepatic manifestations are not yet established. However, it is suggested that HEV infection might be causative based on serological studies, case series, in vitro data and animal models. In particular, neuronal and renal diseases as well as pancreatitis seem to be caused by HEV, while a causative relationship between HEV and other diseases is more doubtful. Either direct cytopathic tissue damage by extrahepatic replication, or immunological processes induced by an overwhelming host immune response, are possible origins of HEV-associated extrahepatic manifestations. Hepatologists should be aware of the possibility that acute or chronically HEV-infected patients could develop extrahepatic manifestations. Neurologists, nephrologists, rheumatologists and other groups of physicians should consider HEV infection as a potential differential diagnosis when observing one of the diseases described in this review. Ribavirin and steroids have been used in small groups of patients with extrahepatic manifestations of HEV, but the efficacy of these drugs still needs to be verified by large, multicenter studies. This article comprehensively reviews the published literature regarding HEV and extrahepatic manifestations. We discuss the probability of specific extrahepatic diseases being caused by previous or ongoing HEV infection, and summarize the published knowledge about antiviral treatment in extrahepatic disorders.
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http://dx.doi.org/10.1016/j.jhep.2016.11.016DOI Listing
May 2017

Humoral and cellular response after varicella vaccination in VZV IgG seronegative kidney transplant candidates.

Vaccine 2017 01 26;35(1):71-76. Epub 2016 Nov 26.

Internal Medicine - Nephrology & Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: In immunocompromised patients, primary infection with VZV may have a disastrous clinical course. Vaccination of VZV-seronegative patients on the waiting list for renal transplantation may prevent severe disease. However, the immunologic response of end-stage renal disease patients to peptide vaccines is far from optimal. Our question was whether end-stage renal disease patients with undetectable VZV-IgG levels were able to mount an adequate humoral and cellular response to a live attenuated varicella vaccine.

Methods: Kidney transplant candidates with undetectable VZV levels were vaccinated twice with a live attenuated varicella vaccine at an interval of 6weeks. VZV IgG levels were analysed till 2years after vaccination. The VZV-specific T-cell reactivity was determined prior to vaccination and after transplantation.

Results: Seventy-seven percent (40/52) of the vaccinees reached positive VZV-IgG levels after vaccination (responders). Eighty-two percent (9/11) showed an increase in VZV-specific CD4 memory T-cells (both central and effector memory cells). The percentage VZV-specific CD8 memory T-cells did not increase. None of the non-responders suffered from primary VZV after transplantation. No severe vaccine-related adverse events were reported, only spontaneously resolving local skin irritation.

Conclusion: The live attenuated varicella vaccine evokes positive VZV IgG-levels and VZV-specific memory T-cells in VZV-seronegative potential kidney transplant candidates.
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http://dx.doi.org/10.1016/j.vaccine.2016.11.043DOI Listing
January 2017