39 results on '"Leavis, Helen L"'
Search Results
2. Clinical Symptoms, Laboratory Parameters and Long-Term Follow-up in a National DADA2 Cohort
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Andriessen, Marie Valérie E., Legger, G. Elizabeth, Bredius, Robbert G. M., van Gijn, Marielle E., Hak, A. Elisabeth, Muller, Petra C. E. Hissink, Kamphuis, Sylvia, Klouwer, Femke C. C., Kuijpers, Taco W., Leavis, Helen L., Nierkens, Stefan, Rutgers, Abraham, van der Veken, Lars T., van Well, Gijs T. J., Mulders-Manders, Catharina M., and van Montfrans, Joris M.
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- 2023
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3. Pulmonary Computed Tomography Screening Frequency in Primary Antibody Deficiency
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Smits, Bas M., Boland, Sharisa L., Hol, Marjolein E., Dandis, Rana, Leavis, Helen L., de Jong, Pim A., Prevaes, Sabine M.P.J., Mohamed Hoesein, Firdaus A.A., van Montfrans, Joris M., and Ellerbroek, Pauline M.
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- 2024
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4. Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus
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Kaan, Ellen D., Brunekreef, Tammo E., Drylewicz, Julia, van den Hoogen, Lucas L., van der Linden, Maarten, Leavis, Helen L., van Laar, Jacob M., van der Vlist, Michiel, Otten, Henny G., and Limper, Maarten
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- 2024
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5. Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.
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Leavis, Helen L, Daele, Paul L A van, Mulders-Manders, Catharina, Michels, Renée, Rutgers, Abraham, Legger, Elizabeth, Bijl, Marc, Hak, Elisabeth A, Lam-Tse, Wai-Kwan, Bonte-Mineur, Femke, Fretter, Peter, Simon, Anna, Paassen, Pieter van, Goes, Marlies C van der, Flendrie, Marcel, Vercoutere, Ward, Lieshout, Antoine W T van, Leek, Arjen, Vastert, Sebastiaan J, and Tas, Sander W
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RHEUMATOID arthritis diagnosis , *BIOTHERAPY , *RHEUMATOID arthritis treatment , *CONSENSUS (Social sciences) , *WORLD Wide Web , *RESEARCH funding , *QUESTIONNAIRES , *METHOTREXATE , *TREATMENT effectiveness , *DESCRIPTIVE statistics , *EVIDENCE-based medicine , *DELPHI method , *RHEUMATOLOGISTS , *GLUCOCORTICOIDS , *EVALUATION - Abstract
Objectives Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. Methods The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Results Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. Conclusion In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Chronically Activated T-cells Retain Their Inflammatory Properties in Common Variable Immunodeficiency
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Berbers, Roos-Marijn, van der Wal, M. Marlot, van Montfrans, Joris M., Ellerbroek, Pauline M., Dalm, Virgil A. S. H., van Hagen, P. Martin, Leavis, Helen L., and van Wijk, Femke
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- 2021
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7. Targeted Proteomics Reveals Inflammatory Pathways that Classify Immune Dysregulation in Common Variable Immunodeficiency
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Berbers, Roos-Marijn, Drylewicz, Julia, Ellerbroek, Pauline M., van Montfrans, Joris M., Dalm, Virgil A. S. H., van Hagen, P. Martin, Keller, Baerbel, Warnatz, Klaus, van de Ven, Annick, van Laar, Jaap M., Nierkens, Stefan, and Leavis, Helen L.
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- 2021
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8. Neurological phenotype of adenosine deaminase 2 deficient patients: a cohort study.
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Verschoof, Merelijne A., van Meenen, Laura C. C., Andriessen, M. Valérie E., Brinkman, Daniëlle M. C., Kamphuis, Sylvia, Kuijpers, Taco W., Leavis, Helen L., Legger, G. Elizabeth, Mulders‐Manders, Catharina M., de Pagter, Anne P. J., Rutgers, Abraham, van Well, Gijs T. J., Coutinho, Jonathan M., Hak, A. Elisabeth, van Montfrans, Joris M., and Klouwer, Femke C. C.
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ADENOSINE deaminase ,TRANSIENT ischemic attack ,ISCHEMIC stroke ,HEMORRHAGIC stroke ,TUMOR necrosis factors ,STROKE - Abstract
Background and purpose: Patients with adenosine deaminase 2 (ADA2) deficiency can present with various neurological manifestations due to vasculopathies and autoinflammation. These include ischaemic and hemorrhagic stroke, but less clearly defined neurological symptoms have also been reported. Methods: In this cohort study, patients with confirmed ADA2 deficiency from seven university hospitals in the Netherlands were included. The frequency and recurrence rates of neurological manifestations before and after initiation of tumor necrosis factor α (TNF‐α) inhibiting therapy were analyzed. Results: Twenty‐nine patients were included with a median age at presentation of 5 years (interquartile range 1–17). Neurological manifestations occurred in 19/29 (66%) patients and were the presenting symptom in 9/29 (31%) patients. Transient ischaemic attack (TIA)/ischaemic stroke occurred in 12/29 (41%) patients and was the presenting symptom in 8/29 (28%) patients. In total, 25 TIAs/ischaemic strokes occurred in 12 patients, one after initiation of TNF‐α inhibiting therapy and one whilst switching between TNF‐α inhibitors. None was large‐vessel occlusion stroke. Two hemorrhagic strokes occurred: one aneurysmatic subarachnoid hemorrhage and one spontaneous intracerebral hemorrhage. Most neurological symptoms, including cranial nerve deficits, vertigo, ataxia and seizures, were caused by TIAs/ischaemic strokes and seldom recurred after initiation of TNF‐α inhibiting therapy. Conclusions: Neurological manifestations, especially TIA/ischaemic stroke, are common in patients with ADA2 deficiency and frequently are the presenting symptom. Because it is a treatable cause of young stroke, for which antiplatelet and anticoagulant therapy are considered contraindicated, awareness amongst neurologists and pediatricians is important. Screening for ADA2 deficiency in young patients with small‐vessel ischaemic stroke without an identified cause should be considered. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Lipoteichoic acid synthesis inhibition in combination with antibiotics abrogates growth of multidrug-resistant Enterococcus faecium
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Paganelli, Fernanda L., van de Kamer, Tim, Brouwer, Ellen C., Leavis, Helen L., Woodford, Neil, Bonten, Marc J.M., Willems, Rob J.L., and Hendrickx, Antoni P.A.
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- 2017
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10. Microbial Dysbiosis in Common Variable Immune Deficiencies: Evidence, Causes, and Consequences
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Berbers, Roos-Marijn, Nierkens, Stefan, van Laar, Jacob M., Bogaert, Debby, and Leavis, Helen L.
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- 2017
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11. Genome-wide Screening Identifies Phosphotransferase System Permease BepA to Be Involved in Enterococcus faecium Endocarditis and Biofilm Formation
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Paganelli, Fernanda L., Huebner, Johannes, Singh, Kavindra V., Zhang, Xinglin, van Schaik, Willem, Wobser, Dominique, Braat, Johanna C., Murray, Barbara E., Bonten, Marc J. M., Willems, Rob J. L., and Leavis, Helen L.
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- 2016
12. Roux-Y Gastric Bypass and Sleeve Gastrectomy directly change gut microbiota composition independent of surgery type
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Paganelli, Fernanda L., Luyer, Misha, Hazelbag, C. Marijn, Uh, Hae-Won, Rogers, Malbert R. C., Adriaans, Danielle, Berbers, Roos-Marijn, Hendrickx, Antoni P. A., Viveen, Marco C., Groot, James A., Bonten, Marc J. M., Fluit, Ad C., Willems, Rob J. L., and Leavis, Helen L.
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- 2019
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13. CCR9/CXCR5 Co-Expressing CD4 T Cells Are Increased in Primary Sjögren's Syndrome and Are Enriched in PD-1/ICOS-Expressing Effector T Cells.
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Hinrichs, Anneline C., Kruize, Aike A., Lafeber, Floris P. J. G., Leavis, Helen L., and van Roon, Joel A. G.
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SJOGREN'S syndrome ,B cells ,T cells ,MONONUCLEAR leukocytes ,T helper cells ,CELL populations ,CHEMOKINE receptors ,T cell receptors - Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disease characterised by B cell hyperactivity. CXCR5+ follicular helper T cells (Tfh), CXCR5-PD-1hi peripheral helper T cells (Tph) and CCR9+ Tfh-like cells have been implicated in driving B cell hyperactivity in pSS; however, their potential overlap has not been evaluated. Our aim was to study the overlap between the two CXCR5- cell subsets and to study their PD-1/ICOS expression compared to "true" CXCR5/PD-1/ICOS-expressing Tfh cells. CXCR5- Tph and CCR9+ Tfh-like cell populations from peripheral blood mononuclear cells of pSS patients and healthy controls (HC) were compared using flow cytometry. PD-1/ICOS expression from these cell subsets was compared to each other and to CXCR5+ Tfh cells, taking into account their differentiation status. CXCR5- Tph cells and CCR9+ Tfh-like cells, both in pSS patients and HC, showed limited overlap. PD-1/ICOS expression was higher in memory cells expressing CXCR5 or CCR9. However, the highest expression was found in CXCR5/CCR9 co-expressing T cells, which are enriched in the circulation of pSS patients. CXCR5- Tph and CCR9+ Tfh-like cells are two distinct cell populations that both are enriched in pSS patients and can drive B cell hyperactivity in pSS. The known upregulated expression of CCL25 and CXCL13, ligands of CCR9 and CXCR5, at pSS inflammatory sites suggests concerted action to facilitate the migration of CXCR5+CCR9+ T cells, which are characterised by the highest frequencies of PD-1/ICOS-positive cells. Hence, these co-expressing effector T cells may significantly contribute to the ongoing immune responses in pSS. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren's syndrome that show potential to predict and monitor clinical response.
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Hamkour, Safae, van der Heijden, Eefje H. M., Lopes, Ana P., Blokland, Sofie L. M., Bekker, Cornelis P. J., Van Helden-Meeuwsen, Cornelia G., Versnel, Marjan A., Kruize, Aike A., Radstake, Timothy R. D. J., Leavis, Helen L., Hillen, Maarten R., and van Roon, Joel A. G.
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- 2023
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15. Optimizing future treatment of enterococcal infections: attacking the biofilm?
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Paganelli, Fernanda L., Willems, Rob J., and Leavis, Helen L.
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- 2012
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16. In patients with primary Sjögren's syndrome innate-like MAIT cells display upregulated IL-7R, IFN-γ, and IL-21 expression and have increased proportions of CCR9 and CXCR5-expressing cells.
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Hinrichs, Anneline C., Kruize, Aike A., Leavis, Helen L., and van Roon, Joel A. G.
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SJOGREN'S syndrome ,CHEMOKINE receptors ,T helper cells ,T cells ,B cells ,INTERLEUKIN-21 - Abstract
Introduction: Mucosal-associated invariant T (MAIT) cells might play a role in B cell hyperactivity and local inflammation in primary Sjögren's syndrome (pSS), just like previously studied mucosa-associated CCR9+ and CXCR5+ T helper cells. Here, we investigated expression of CCR9, CXCR5, IL-18R and IL-7R on MAIT cells in pSS, and assessed the capacity of DMARDs to inhibit the activity of MAIT cells. Methods: Circulating CD161+ and IL-18Ra+ TCRVa7.2+ MAIT cells from pSS patients and healthy controls (HC) were assessed using flow cytometry, and expression of CCR9, CXCR5, and IL-7R on MAIT cells was studied. Production of IFN-γ and IL-21 by MAIT cells was measured upon IL-7 stimulation in the presence of leflunomide (LEF) and hydroxychloroquine (HCQ). Results: The numbers of CD161+ and IL-18Rα+ MAIT cells were decreased in pSS patients compared to HC. Relative increased percentages of CD4 MAIT cells in pSS patients caused significantly higher CD4/CD8 ratios in MAIT cells. The numbers of CCR9 and CXCR5-expressing MAIT cells were significantly higher in pSS patients. IL-7R expression was higher in CD8 MAIT cells as compared to all CD8 T cells, and changes in IL-7R expression correlated to several clinical parameters. The elevated production of IL-21 by MAIT cells was significantly inhibited by LEF/HCQ treatment. Conclusion: Circulating CD161+ and IL-18Ra+ MAIT cell numbers are decreased in pSS patients. Given their enriched CCR9/CXCR5 expression this may facilitate migration to inflamed salivary glands known to overexpress CCL25/CXCL13. Given the pivotal role of IL-7 and IL-21 in inflammation in pSS this indicates a potential role for MAIT cells in driving pSS immunopathology. [ABSTRACT FROM AUTHOR]
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- 2022
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17. Case report: Up‐front allogeneic stem cell transplantation in a patient with the VEXAS syndrome.
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van Leeuwen‐Kerkhoff, Nathalie, de Witte, Moniek A., Heijstek, Marloes W., and Leavis, Helen L.
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STEM cell transplantation ,POSITRON emission tomography computed tomography ,STILL'S disease ,HEMATOPOIETIC stem cell transplantation - Abstract
Future studies and experiences are needed in order to determine the best strategy for allo-HSCT in patients with the VEXAS syndrome. Recently, a cohort of six patients who were retrospectively diagnosed with the VEXAS syndrome was reported and received allo-HSCT for severe inflammatory syndromes ( I n i = 4) or MDS ( I n i = 2).4 Of these patients, three showed long-term complete remission. Recently, Beck et al. reported a novel monogenic auto-inflammatory syndrome called the VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome).1 A cohort of 25 men was found to have a myeloid lineage-restricted somatic mutation in I UBA1 i , a gene located on the X chromosome encoding the ubiquitin-activating enzyme 1. Azacitidine for patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry. [Extracted from the article]
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- 2022
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18. Clinical features and immune-related protein patterns of anti-MDA5 positive clinically amyopathic dermatomyositis Dutch patients.
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Hensgens, Marjolein P M, Delemarre, Eveline M, Drylewicz, Julia, Voortman, Mareye, Krol, Roline M, Dalm, Virgil A S H, Miedema, Jelle R, Wiertz, Ivo, Grutters, Jan, Limper, Maarten, Nierkens, Stefan, and Leavis, Helen L
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PROTEINS ,BIOMARKERS ,INTERLEUKINS ,DERMATOMYOSITIS ,RESPIRATORY insufficiency ,MELANOMA ,INTERSTITIAL lung diseases ,RETROSPECTIVE studies ,ACQUISITION of data ,RISK assessment ,INTERFERONS ,CELLULAR signal transduction ,SEVERITY of illness index ,MEDICAL records ,DISEASE risk factors ,DISEASE complications ,SYMPTOMS - Abstract
Objectives The presence of melanoma differentiation-associated protein 5 (MDA5) antibodies in patients with DM is associated with the development of a rapidly progressive interstitial lung disease (RPILD), unresponsive to conventional treatment. We characterize patients and provide more insight into potential biomarkers to identify patients with RPILD. Methods Patients diagnosed with anti-MDA5 positive DM between December 2015 and November 2017 were included in this study. Clinical data were retrospectively retrieved from medical records. A total of 180 immune-related markers were measured in sera of 16 patients and 15 healthy controls using proximity extension assay-based technology. Results Twenty patients were included, with a median time from symptoms till diagnosis of 4 months. All patients had clinically amyopathic DM. Interstitial lung disease (ILD) was present at diagnosis in 94% of the patients, 45% presented with RPILD. The mortality rate was 35% within 4 months after diagnosis and respiratory failure was the main cause of death in these patients. Furthermore, unsupervised analysis revealed that patients with RPILD show clearly different inflammatory serum profiles than healthy controls. In addition, in comparison to healthy controls, the IFN, IL1, IL10 and IL18 signalling pathways are different regulated in anti-MDA5 positive patients. Conclusion In this Dutch anti-MDA5 positive clinically amyopathic DM (CADM) cohort, one-third of the patients died due to RPILD soon after diagnosis, which underlines the severity of this disease. In addition, we have found several possible pathways that are differentially regulated in RPILD vs no RPILD DM and healthy controls. These markers await further validation before clinical use. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Heterozygous Variants in the DNA-binding Domain of c-Myb May Affect Normal B/T Cell Development.
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Smits, Bas M., Hartley, Taila, Dünnebach, Ester, Bartels, Marije, Boycott, Kim M., Kernohan, Kirstin D., Dyment, David A., Giltay, Jacques C., Haddad, Elie, Jarinova, Olga, van Montfrans, Joris, van Royen-Kerkhof, Annet, van der Veken, Lars T., de Witte, Moniek, Nierkens, Stefan, Pham-Huy, Anne, and Leavis, Helen L.
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- 2022
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20. Immunogenicity of the mRNA-1273 COVID-19 vaccine in adult patients with inborn errors of immunity.
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van Leeuwen, Leanne P.M., GeurtsvanKessel, Corine H., Ellerbroek, Pauline M., de Bree, Godelieve J., Potjewijd, Judith, Rutgers, Abraham, Jolink, Hetty, van de Veerdonk, Frank, van Gorp, Eric C.M., de Wilt, Faye, Bogers, Susanne, Gommers, Lennert, Geers, Daryl, Bruns, Anke H.W., Leavis, Helen L., van Haga, Jelle W., Lemkes, Bregtje A., van der Veen, Annelou, de Kruijf-Bazen, S.F.J., and van Paassen, Pieter
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Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2–specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations. [ABSTRACT FROM AUTHOR]
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- 2022
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21. CCL5 Release by CCR9+ CD8 T Cells: A Potential Contributor to Immunopathology of Primary Sjögren's Syndrome.
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Hinrichs, Anneline C., Blokland, Sofie L. M., Kruize, Aike A., Lafeber, Floris P. J., Leavis, Helen L., and van Roon, Joel A. G.
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SJOGREN'S syndrome ,T cells ,CHEMOKINE receptors ,CD8 antigen ,IMMUNOPATHOLOGY - Abstract
Introduction: Increased CCL5 expression and CD8 T cells have been shown to be pivotal regulators of immunopathology in primary Sjögren's syndrome (pSS) and pSS-like disease. Increased CCL5 expression by CCR9+ CD4 T cells has previously been implicated as a contributor to immunopathology in pSS. The role of CD8 T cells and in particular CCR9+ CD8 T cells and their potential to secrete CCL5 has not previously been studied in pSS. In this study we investigated both CCR9 and CCL5 expression by CD8 T cells in pSS patients compared to healthy controls (HC). Methods: CCR9 expression on CD8 T cells from peripheral blood was compared between patients with pSS and HC by flow cytometry. Intracellular CCL5 expression by naive, memory and effector CCR9- and CCR9+ CD8 T cells was assessed. In addition, the capacity and pace of CCL5 release upon T cell activation was determined for all subsets and compared with CD4 T cells. Results: The frequency of circulating CCR9+ CD8 T cells in pSS patients is increased compared to HC. Antigen-experienced CD8 T cells, especially CCR9+ effector CD8 T cells, express the highest CCL5 levels, and release the highest levels of CCL5 upon activation. Memory and effector CD8 T cells of pSS patients express significantly less CCL5 and subsequently release less CCL5 upon stimulation compared to HC. CCR9+ CD8 T cells rapidly release CCL5 and significantly more than CCR9+ CD4 T cells. Conclusion: CCR9+ CD8 T cells express more CCL5 than CCR9- CD8 T cells. CCL5 is rapidly released upon activation, resulting in reduced intracellular expression. Reduced CCL5 expression by an elevated number of antigen-experienced CCR9-expressing CD8 T cells in pSS patients points towards increased release in vivo. This suggests that CCL5 release by CCR9+ CD8 T cells contributes to immunopathology in pSS. [ABSTRACT FROM AUTHOR]
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- 2022
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22. Epidemic and nonepidemic multidrug-resistant Enterococcus faecium
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Leavis, Helen L., Willems, Rob J.L., Top, Janetta, Spalburg, Emile, Mascini, Ellen M., Fluit, Ad C., Hoepelman, Andy, de Neeling, Albert J., and Bonten, Mark J.M.
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Drug resistance -- Physiological aspects ,Drug resistance -- Genetic aspects ,Enterococcal infections -- Genetic aspects ,Enterococcal infections -- Development and progression ,Enterococcal infections -- Care and treatment - Abstract
The epidemiology of vancomycin-resistant Enterococcus faecium (VREF) in Europe is characterized by a large community reservoir. In contrast, nosocomial outbreaks and infections (without a community reservoir) characterize VREF in the [...]
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- 2003
23. Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity: A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers.
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Elsink, Kim, Huibers, Manon M. H., Hollink, Iris H. I. M., Simons, Annet, Zonneveld-Huijssoon, Evelien, van der Veken, Lars T., Leavis, Helen L., Henriet, Stefanie S. V., van Deuren, Marcel, van de Veerdonk, Frank L., Potjewijd, Judith, Berghuis, Dagmar, Dalm, Virgil A. S. H., Vermont, Clementien L., van de Ven, Annick A. J. M., Lambeck, Annechien J. A., Abbott, Kristin M., van Hagen, P. Martin, de Bree, Godelieve J., and Kuijpers, Taco W.
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NUCLEOTIDE sequencing ,CHILD patients ,COHORT analysis ,IMMUNOLOGIC diseases ,GENETIC testing ,GENETIC disorder diagnosis ,MOLECULAR diagnosis - Abstract
Objective: Inborn errors of immunity (IEI) are a heterogeneous group of disorders, affecting different components of the immune system. Over 450 IEI related genes have been identified, with new genes continually being recognized. This makes the early application of next-generation sequencing (NGS) as a diagnostic method in the evaluation of IEI a promising development. We aimed to provide an overview of the diagnostic yield and time to diagnosis in a cohort of patients suspected of IEI and evaluated by an NGS based IEI panel early in the diagnostic trajectory in a multicenter setting in the Netherlands. Study Design: We performed a prospective observational cohort study. We collected data of 165 patients with a clinical suspicion of IEI without prior NGS based panel evaluation that were referred for early NGS using a uniform IEI gene panel. The diagnostic yield was assessed in terms of definitive genetic diagnoses, inconclusive diagnoses and patients without abnormalities in the IEI gene panel. We also assessed time to diagnosis and clinical implications. Results: For children, the median time from first consultation to diagnosis was 119 days versus 124 days for adult patients (U=2323; p=0.644). The median turn-around time (TAT) of genetic testing was 56 days in pediatric patients and 60 days in adult patients (U=1892; p=0.191). A definitive molecular diagnosis was made in 25/65 (24.6%) of pediatric patients and 9/100 (9%) of adults. Most diagnosed disorders were identified in the categories of immune dysregulation (n=10/25; 40%), antibody deficiencies (n=5/25; 20%), and phagocyte diseases (n=5/25; 20%). Inconclusive outcomes were found in 76/165 (46.1%) patients. Within the patient group with a genetic diagnosis, a change in disease management occurred in 76% of patients. Conclusion: In this cohort, the highest yields of NGS based evaluation for IEI early in the diagnostic trajectory were found in pediatric patients, and in the disease categories immune dysregulation and phagocyte diseases. In cases where a definitive diagnosis was made, this led to important disease management implications in a large majority of patients. More research is needed to establish a uniform diagnostic pathway for cases with inconclusive diagnoses, including variants of unknown significance. [ABSTRACT FROM AUTHOR]
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- 2021
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24. Broad Virus Detection and Variant Discovery in Fecal Samples of Hematopoietic Transplant Recipients Using Targeted Sequence Capture Metagenomics.
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Jansen, Suze A., Nijhuis, Wouter, Leavis, Helen L., Riezebos-Brilman, Annelies, Lindemans, Caroline A., and Schuurman, Rob
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NOROVIRUSES ,NOROVIRUS diseases ,METAGENOMICS ,HEMATOPOIETIC stem cell transplantation ,VIRAL gastroenteritis ,VIRUS diseases ,GRAFT versus host disease ,DIAGNOSTIC use of polymerase chain reaction - Abstract
Pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients often suffer from gastro-intestinal (GI) disease caused by viruses, Graft-versus-Host Disease (GVHD) or a combination of the two. Currently, the GI eukaryotic virome of HSCT recipients remains relatively understudied, which complicates the understanding of its role in GVHD pathogenicity. As decisions regarding immunosuppressive therapy in the treatment of virus infection or GVHD, respectively, can be completely contradicting, it is crucial to better understand the prevalence and relevance of viruses in the GI tract in the HSCT setting. A real time PCR panel for a set of specific viruses widely used to diagnose the most common causes of GI viral gastroenteritis is possibly insufficient to grasp the full extent of viruses present. Therefore, we applied the targeted sequence capture method ViroCap to residual fecal samples of 11 pediatric allogeneic HSCT recipients with GI symptoms and a suspicion of GVHD, to enrich for nucleic acids of viruses that are known to infect vertebrate hosts. After enrichment, NGS was applied to broadly detect viral sequences. Using ViroCap, we were able to detect viruses such as norovirus and adenovirus (ADV), that had been previously detected using clinical diagnostic PCR on the same sample. In addition, multiple, some of which clinically relevant viruses were detected, including ADV, human rhinovirus (HRV) and BK polyomavirus (BKV). Interestingly, in samples in which specific PCR testing for regular viral GI pathogens did not result in a diagnosis, the ViroCap pipeline led to the detection of viral sequences of human herpesvirus (HHV)-7, BKV, HRV, KI polyomavirus and astrovirus. The latter was an only recently described variant and showed extensive sequence mismatches with the applied real time PCR primers and would therefore not have been detected if tested. Our results indicate that target enrichment of viral nucleic acids through ViroCap leads to sensitive and broad possibly clinically relevant virus detection, including the detection of newer variants in clinical HSCT recipient samples. As such, ViroCap could be a useful detection tool clinically, but also in studying the associations between viral presence and GVHD. [ABSTRACT FROM AUTHOR]
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- 2020
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25. Severe thrombotic microangiopathy after autologous stem cell transplantation in systemic sclerosis: a case report.
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Sharif, Maryam O., Leavis, Helen L., Paassen, Pieter van, Rhenen, Anna van, Timmermans, Sjoerd A. M. E. G., Ton, Evelien, Laar, Jacob M. van, and Spierings, Julia
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GLUCOCORTICOIDS , *HISPANIC Americans , *HEMOLYSIS & hemolysins , *SYSTEMIC scleroderma , *SEVERITY of illness index , *CARDIAC tamponade , *LACTATE dehydrogenase , *THROMBOCYTOPENIA , *HEMATOPOIETIC stem cell transplantation - Abstract
The article describes the case of a 64-year-old White female who presented experienced severe thrombotic microangiopathy following autologous stem cell transplantation in systemic sclerosis (SSc). Topics covered include the medical history of the patient, the diagnostic challenges and dramatic course of haematopoietic stem cell transplantation-thrombotic microangiopathy (HSCT-TMA) in SSc as illustrated by the case, and patient outcome following treatment.
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- 2021
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26. Low IgA Associated With Oropharyngeal Microbiota Changes and Lung Disease in Primary Antibody Deficiency.
- Author
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Berbers, Roos-Marijn, Mohamed Hoesein, Firdaus A. A., Ellerbroek, Pauline M., van Montfrans, Joris M., Dalm, Virgil A. S. H., van Hagen, P. Martin, Paganelli, Fernanda L., Viveen, Marco C., Rogers, Malbert R. C., de Jong, Pim A., Uh, Hae-Won, Willems, Rob J. L., and Leavis, Helen L.
- Subjects
LUNG diseases ,INTERSTITIAL lung diseases ,IMMUNOLOGICAL deficiency syndromes ,IMMUNOGLOBULIN A ,IMMUNOGLOBULINS ,ALPHA 1-antitrypsin deficiency - Abstract
Common Variable Immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are primary antibody deficiencies characterized by hypogammaglobulinemia and recurrent infections, which can lead to structural airway disease (AD) and interstitial lung disease (ILD). We investigated associations between serum IgA, oropharyngeal microbiota composition and severity of lung disease in these patients. In this cross-sectional multicentre study we analyzed oropharyngeal microbiota composition of 86 CVID patients, 12 XLA patients and 49 healthy controls (HC) using next-generation sequencing of the 16S rRNA gene. qPCR was used to estimate bacterial load. IgA was measured in serum. High resolution CT scans were scored for severity of AD and ILD. Oropharyngeal bacterial load was increased in CVID patients with low IgA (p = 0.013) and XLA (p = 0.029) compared to HC. IgA status was associated with distinct beta (between-sample) diversity (p = 0.039), enrichment of (Allo)prevotella , and more severe radiographic lung disease (p = 0.003), independently of recent antibiotic use. AD scores were positively associated with Prevotella, Alloprevotella , and Selenomonas , and ILD scores with Streptococcus and negatively with Rothia. In clinically stable patients with CVID and XLA, radiographic lung disease was associated with IgA deficiency and expansion of distinct oropharyngeal bacterial taxa. Our findings highlight IgA as a potential driver of upper respiratory tract microbiota homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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27. Behçet's Disease Under Microbiotic Surveillance? A Combined Analysis of Two Cohorts of Behçet's Disease Patients.
- Author
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van der Houwen, Tim B., van Laar, Jan A. M., Kappen, Jasper H., van Hagen, Petrus M., de Zoete, Marcel R., van Muijlwijk, Guus H., Berbers, Roos-Marijn, Fluit, Ad C., Rogers, Malbert, Groot, James, Hazelbag, C. Marijn, Consolandi, Clarissa, Severgnini, Marco, Peano, Clelia, D'Elios, Mario M., Emmi, Giacomo, and Leavis, Helen L.
- Subjects
BEHCET'S disease ,FECAL analysis ,COHORT analysis ,GUT microbiome - Abstract
Background: In Behçet's disease (BD), an auto-inflammatory vasculitis, an unbalanced gut microbiota can contribute to pro-inflammatory reactions. In separate studies, distinct pro- and anti-inflammatory bacteria associated with BD have been identified. Methods: To establish disease-associated determinants, we performed gut microbiome profiling in BD patients from the Netherlands (n = 19) and Italy (n = 13), matched healthy controls (HC) from the Netherlands (n = 17) and Italy (n = 15) and oral microbiome profiling in Dutch BD patients (n = 18) and HC (n = 15) by 16S rRNA gene sequencing. In addition, we used fecal IgA-SEQ analysis to identify specific IgA coated bacterial taxa in Dutch BD patients (n = 13) and HC (n = 8). Results: In BD stool samples alpha-diversity was conserved, whereas beta-diversity analysis showed no clustering based on disease, but a significant segregation by country of origin. Yet, a significant decrease of unclassified Barnesiellaceae and Lachnospira genera was associated with BD patients compared to HC. Subdivided by country, the Italian cohort displays a significant decrease of unclassified Barnesiellaceae and Lachnospira genera, in the Dutch cohort this decrease is only a trend. Increased IgA-coating of Bifidobacterium spp., Dorea spp. and Ruminococcus bromii species was found in stool from BD patients. Moreover, oral Dutch BD microbiome displayed increased abundance of Spirochaetaceae and Dethiosulfovibrionaceae families. Conclusions: BD patients show decreased fecal abundance of Barnesiellaceae and Lachnospira and increased oral abundance of Spirochaetaceae and Dethiosulfovibrionaceae. In addition, increased fecal IgA coating of Bifidobacterium, Ruminococcus bromii and Dorea may reflect retention of anti-inflammatory species and neutralization of pathosymbionts in BD, respectively. Additional studies are warranted to relate intestinal microbes with the significance of ethnicity, diet, medication and response with distinct pro- and inflammatory pathways in BD patients. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
28. Identification of a novel genomic island specific to hospital-acquired clonal complex 17 Enterococcus faecium isolates
- Author
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Heikens, Esther, van Schaik, Willem, Leavis, Helen L., Bonten, Marc J.M., and Willems, Rob J.L.
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Carbohydrate metabolism -- Analysis ,Enterococcus -- Genetic aspects ,Enterococcus -- Physiological aspects ,Polymerase chain reaction -- Usage ,Biological sciences - Abstract
The [delta][rho]-Web model, PCR, and dot blotting methods are used to identify anomalous GeCs in the genome of Enterococcus faecium DO, a clonal complex 17 (CC17) E. faecium strains that might contribute towards increased fitness and enhanced survival of CC17 E. faecium. A genomic island identified in CC17 E. faecium tentatively encoding a metabolic pathway involved in carbohydrate transport and metabolism might provide a competitive advantage over the E. faecium microbiota.
- Published
- 2008
29. First Report of IgG4 Related Disease Primary Presenting as Vertebral Bone Marrow Lesions.
- Author
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van den Elshout-den Uyl, Debby, Spoto, Clothaire P. E., de Boer, Mirthe, Leiner, Tim, Leavis, Helen L., and Leguit, Roos J.
- Subjects
BONE marrow ,PLASMA cells ,SCARS ,FIBROSIS ,MORPHOGENESIS ,EDEMA ,DISEASES - Abstract
IgG4-related disease is a fibro-inflammatory disorder characterized by swelling of tissues and affected organs accompanied by the development of scar tissue (fibrosis) and infiltration by IgG4 positive plasma cells. Almost any organ can be affected, including, but rarely, bone marrowinvolvement. Here we present a case of a 76-year-old male with IgG4-related disease presenting primarily with vertebral bone marrow lesions. Histopathology showed the typical features of storiform fibrosis, and increased IgG4 positive plasma cells. Treatment with corticosteroids significantly improved wellbeing and resolved lesion size on MRI. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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30. Lymphopenia in atopic dermatitis patients treated with oral immunosuppressive drugs.
- Author
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Bakker, Daphne S., Garritsen, Floor M., Leavis, Helen L., van der Schaft, Jorien, Bruijnzeel-Koomen, Carla A.F.M., van den Broek, Marcel P.H., and de Bruin-Weller, Marjolein S.
- Subjects
CYCLOSPORINE ,LYMPHOPENIA ,PREDNISONE ,AZATHIOPRINE ,ANTIFUNGAL agents - Abstract
Introduction: Oral immunosuppressive drugs are commonly used in the treatment of atopic dermatitis (AD). In patients with autoimmune- and rheumatic diseases, these drugs have been associated with lymphopenia. Lymphopenia is related to an increased risk of opportunistic infections. The incidence of lymphopenia in patients with AD treated with oral immunosuppressive drugs is yet unknown. Objective: To evaluate the occurrence of recurrent lymphopenia in patients with AD treated with oral immunosuppressive drugs and to make recommendations for screening in daily practice. Methods: Patients with recurrent lymphopenia (i.e. >5 times lymphocyte counts below 0.8 × 10
9 /L) during treatment with oral immunosuppressive drugs were included from our immunosuppressive drugs database and further analyzed. Results: A total of 360 AD patients, treated with oral immunosuppressive drugs, were screened. A recurrent lymphopenia during treatment was found in 11 patients. In 8/11 patients, recurrent lymphopenia was observed during concomitant treatment with prednisone. No serious infections were observed. Conclusion: Lymphopenia is occasionally seen in AD patients treat with oral immunosuppressive drugs. Concomitant treatment with prednisone seems to be a risk factor. We suggest to include monitoring of lymphocyte counts in the standard follow-up for all AD patients treated with oral immunosuppressive drugs. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
31. A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease.
- Author
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Aeschlimann, Florence A., Batu, Ezgi D., Canna, Scott W., Go, Ellen, Gül, Ahmet, Hoffmann, Patrycja, Leavis, Helen L., Ozen, Seza, Schwartz, Daniella M., Stone, Deborah L., van Royen-Kerkof, Annet, Kastner, Daniel L., Aksentijevich, Ivona, and Laxer, Ronald M.
- Subjects
IMMUNOSUPPRESSIVE agents ,COMPARATIVE studies ,GENETIC disorders ,INFLAMMATION ,RESEARCH methodology ,MEDICAL cooperation ,GENETIC mutation ,RESEARCH ,PHENOTYPES ,DNA-binding proteins ,EVALUATION research ,DISEASE progression - Abstract
Objectives: The association between mutations in TNFAIP3, encoding the NF-kB regulatory protein A20, and a new autoinflammatory disease has recently been recognised. This study aims at describing the clinical phenotypes and disease course of patients with A20 haploinsufficiency (HA20).Methods: Data for all cases from the initial publication, and additional cases identified through collaborations since, were collected using standardised data collection forms.Results: A total of 16 patients (13 female) from seven families with a genetic diagnosis of HA20 were included. The disease commonly manifested in early childhood (range: first week of life to 29 years of age). The main clinical symptoms were recurrent oral, genital and/or gastrointestinal ulcers (16/16), musculoskeletal (9/16) and gastrointestinal complaints (9/16), cutaneous lesions (8/16), episodic fever (7/16), and recurrent infections (7/16). Clinical phenotypes varied considerably, even within families. Relapsing-remitting disease course was most common, and one patient died. Laboratory abnormalities included elevated acute-phase reactants and fluctuating presence of various autoantibodies such as antinuclear antibodies (4/10 patients tested) and anti-dsDNA (2/5). Tissue biopsy of different sites revealed non-specific chronic inflammation (6/12 patients tested), findings consistent with class V lupus nephritis in one patient, and pustules and normal results in two patients each. All patients were treated: 4/16 received colchicine and 12/16 various immunosuppressive agents. Cytokine inhibitors effectively suppressed systemic inflammation in 7/9 patients.Conclusions: Early-onset recurrent oral, genital and/or gastrointestinal ulcers are the hallmark feature of HA20. Frequency and intensity of other clinical manifestations varied highly. Treatment regimens should be based on disease severity, and cytokine inhibitors are often required to control relapses. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
32. Stimulating severe COVID-19: the potential role of GM-CSF antagonism.
- Author
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Leavis, Helen L, van de Veerdonk, Frank L, and Murthy, Srinivas
- Subjects
GRANULOCYTE-macrophage colony-stimulating factor ,COVID-19 - Published
- 2022
- Full Text
- View/download PDF
33. Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS.
- Author
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van der Made, Caspar I., Potjewijd, Judith, Hoogstins, Annemiek, Willems, Huub P.J., Kwakernaak, Arjan J., de Sevaux, Ruud G.L., van Daele, Paul L.A., Simons, Annet, Heijstek, Marloes, Beck, David B., Netea, Mihai G., van Paassen, Pieter, Elizabeth Hak, A., van der Veken, Lars T., van Gijn, Marielle E., Hoischen, Alexander, van de Veerdonk, Frank L., Leavis, Helen L., and Rutgers, Abraham
- Abstract
A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS. This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease. A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS. A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%. VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
34. The Enterococcus faecium Enterococcal Biofilm Regulator, EbrB, Regulates the esp Operon and Is Implicated in Biofilm Formation and Intestinal Colonization
- Author
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Top, Janetta, Paganelli, Fernanda L., Zhang, Xinglin, van Schaik, Willem, Leavis, Helen L., van Luit-Asbroek, Miranda, van der Poll, Tom, Leendertse, Masja, Bonten, Marc J. M., and Willems, Rob J. L.
- Subjects
ENTEROCOCCUS faecium ,BIOFILMS ,NOSOCOMIAL infections ,PATHOGENIC microorganisms ,COLONIZATION (Ecology) ,BACTERIAL operons ,MOBILE genetic elements - Abstract
Nowadays, Enterococcus faecium is one of the leading nosocomial pathogens worldwide. Strains causing clinical infections or hospital outbreaks are enriched in the enterococcal surface protein (Esp) encoding ICEEfm1 mobile genetic element. Previous studies showed that Esp is involved in biofilm formation, endocarditis and urinary tract infections. In this study, we characterized the role of the putative AraC type of regulator (locus tag EfmE1162_2351), which we renamed ebrB and which is, based on the currently available whole genome sequences, always located upstream of the esp gene, and studied its role in Esp surface exposure during growth. A markerless deletion mutant of ebrB resulted in reduced esp expression and complete abolishment of Esp surface exposure, while Esp cell-surface exposure was restored when this mutant was complemented with an intact copy of ebrB. This demonstrates a role for EbrB in esp expression. However, during growth, ebrB expression levels did not change over time, while an increase in esp expression at both RNA and protein level was observed during mid-log and late-log phase. These results indicate the existence of a secondary regulation system for esp, which might be an unknown quorum sensing system as the enhanced esp expression seems to be cell density dependent. Furthermore, we determined that esp is part of an operon of at least 3 genes putatively involved in biofilm formation. A semi-static biofilm model revealed reduced biofilm formation for the EbrB deficient mutant, while dynamics of biofilm formation using a flow cell system revealed delayed biofilm formation in the ebrB mutant. In a mouse intestinal colonization model the ebrB mutant was less able to colonize the gut compared to wild-type strain, especially in the small intestine. These data indicate that EbrB positively regulates the esp operon and is implicated in biofilm formation and intestinal colonization. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
35. Allogeneic stem cell transplantation in a patient with myelodysplastic syndrome and polyarteritis nodosa: a case report and systematic review.
- Author
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Stavenga, Mirte, Leavis, Helen, de Witte, Theo, Raymakers, Reinier, Leavis, Helen L, de Witte, Theo M, and Raymakers, Reinier A P
- Subjects
MYELODYSPLASTIC syndromes treatment ,POLYARTERITIS nodosa ,STEM cell transplantation ,PREDNISONE ,TACROLIMUS ,THERAPEUTICS ,HEMATOPOIETIC stem cell transplantation ,CASE studies ,MYELODYSPLASTIC syndromes ,SYSTEMATIC reviews ,DISEASE complications ,DIAGNOSIS - Abstract
The article discusses the case of a patient with co-occurring myelodysplastic syndrome (MDS) and polyarteritis nodosa (PAN). Topics discussed include the clinical presentation of the patient, allogeneic stem cell transplantation (SCT) performed on the patient, and treatment with prednisone and tacrolimus.
- Published
- 2016
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36. Insertion Sequence--Driven Diversification Creates a Globally Dispersed Emerging Multiresistant Subspecies of E. faecium.
- Author
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Leavis, Helen L., Willems, Rob J. L., van Wamel, Willem J. B., Schuren, Frank H., Caspers, Martien P. M., and Bonten, Marc J. M.
- Subjects
- *
PATHOGENIC bacteria , *INTENSIVE care units , *GENOMES , *GENETIC transformation , *DNA microarrays , *HOSPITALS - Abstract
Enterococcus faecium, an ubiquous colonizer of humans and animals, has evolved in the last 15 years from an avirulent commensal to the third most frequently isolated nosocomial pathogen among intensive care unit patients in the United States. E. faecium combines multidrug resistance with the potential of horizontal resistance gene transfer to even more pathogenic bacteria. Little is known about the evolution and virulence of E. faecium, and genomic studies are hampered by the absence of a completely annotated genome sequence. To further unravel its evolution, we used a mixed whole-genome microarray and hybridized 97 E. faecium isolates from different backgrounds (hospital outbreaks (n = 18), documented infections (n = 34) and asymptomatic carriage of hospitalized patients (n = 15), and healthy persons (n = 15) and animals (n = 21)). Supported by Bayesian posterior probabilities (PP = 1.0), a specific clade containing all outbreak-associated strains and 63% of clinical isolates was identified. Sequencing of 146 of 437 clade-specific inserts revealed mobile elements (n = 74), including insertion sequence (IS) elements (n = 42), phage genes (n = 6) and plasmid sequences (n = 26), hypothetical (n = 58) and membrane proteins (n = 10), and antibiotic resistance (n = 9) and regulatory genes (n = 11), mainly located on two contigs of the unfinished E. faecium DO genome. Split decomposition analysis, varying guanine cytosine content, and aberrant codon adaptation indices all supported acquisition of these genes through horizontal gene transfer with IS16 as the predicted most prominent insert (98% sensitive, 100% specific). These findings suggest that acquisition of IS elements has facilitated niche adaptation of a distinct E. faecium subpopulation by increasing its genome plasticity. Increased genome plasticity was supported by higher diversity indices (ratio of average genetic similarities of pulsed-field gel electrophoresis and multi locus sequence typing) for clade-specific isolates. Interestingly, the previously described multi locus sequence typing-based clonal complex 17 largely overlapped with this clade. The present data imply that the global emergence of E. faecium, as observed since 1990, represents the evolution of a subspecies with a presumably better adaptation than other E. faecium isolates to the constraints of a hospital environment. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
37. Identification of high-risk enterococcal clonal complexes: global dispersion and antibiotic resistance
- Author
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Leavis, Helen L, Bonten, Marc JM, and Willems, Rob JL
- Subjects
- *
ENTEROCOCCUS , *VANCOMYCIN resistance , *HOSPITALS , *EPIDEMICS - Abstract
Vancomycin-resistant Enterococcus faecium spread dramatically in hospital settings in the USA in the 1990s and reached endemicity at the turn of the century. Similarly, rising prevalence rates are currently observed in several European countries, with prevalence rates of greater than 10% reported in seven of these. On the basis of multilocus sequence typing (MLST), the population structure of E. faecium was elucidated and the existence of a distinct high-risk enterococcal clonal complex, designated clonal complex-17 (CC17), which is associated with the majority of hospital outbreaks and clinical infections in five continents, was revealed. This complex is correlated with ampicillin and quinolone resistance and with the presence of a putative pathogenicity island. Preliminary MLST data suggest that similar hospital-adapted complexes might also exist in E. faecalis. [Copyright &y& Elsevier]
- Published
- 2006
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- View/download PDF
38. Targeted Sequence Capture Metagenomics (ViroCap) to Detect Viruses in Stool Samples of Hematopoietic Stem Cell Transplantation Patients.
- Author
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Jansen, Suze A., Nijhuis, Wouter, Leavis, Helen L., Riezebos-Brilman, Annelies, Lindemans, Caroline A., and Schuurman, Rob
- Subjects
- *
HEMATOPOIETIC stem cell transplantation , *CHLOROPLAST DNA , *METAGENOMICS , *DNA viruses , *VIRUSES , *HEMATOPOIETIC system - Abstract
Gastro-intestinal (GI) symptoms in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients are common and may be caused by viruses, Graft-Versus-Host-Disease (GVHD) or both. Currently, little is known about the GI viriome in SCT patients, hindering the study of the pathogenicity and role in GVHD. We used ViroCap, a viral target enrichment method, in combination with Next Generation Sequencing (NGS) to detect viruses in stool samples of HSCT patients and compared to PCR results. Using ViroCap, nucleic acid of a broad range of RNA and DNA viruses infecting vertebrate hosts was enriched in banked stool samples of HSCT patients. Upon enrichment, samples were sequenced by NGS on an Illumina MiSeq system and detected viral sequences were analyzed using the automated Genome Detective pipeline (GD) and/or directly aligned (DA) to a reference sequence of a specific virus, using Genious software. Where possible, presence of newly detected viral pathogens was confirmed by virus-specific qPCR. Stool samples of 11 patients, age range 1-17, that had undergone HSCT for a variety of indications were selected for ViroCap analysis. All selected patients suffered from GI-symptoms. Ten were diagnosed with grade I-IV GI-GVHD according to consensus guidelines. In 6 samples adenovirus (ADV), norovirus or both had been previously detected by clinical diagnostic qPCRs (Diagnosis D), while in 5 samples no viral GI pathogens were found (No diagnosis ND). In all D samples the presence of the initially found virus could be confirmed upon ViroCap analysis. ADV was most commonly found and Ct values grossly correlated with the number of sequence specific reads upon ViroCap GD and DA analysis. In addition, ViroCap led to the detection of multiple, possibly clinically relevant viral pathogens in D samples, including human herpesvirus-6B (HHV6B) (n=1), BK polyomavirus (BKV) (n=2), ADV (n=1) and human rhinovirus (HRV) (n=1). Presence of BKV and HRV was confirmed by qPCR. Furthermore, in 4/5 ND samples viral pathogens were detected. These included human herpes Virus 7 (HHV7) (n=1), BKV (n=1), HRV (n=2) and Astrovirus (AV) (n=1). HRV presence was confirmed by qPCR, HHV7 was not tested. BKV could not be confirmed, but other clinical samples from the same patient taken closely before/after the specific stool sample were BKV positive. Further analysis of the AV sequences revealed that the routine PCR failed to detect this virus due to extensive sequence mismatches in the primer/probe binding regions. This AV clade was classified as an AV VA3 (JX857868.1). In summary, application of viral target enrichment strategies with limited pathogen detection bias, such as ViroCap, increase the sensitivity of NGS for virus detection and can lead to discovery of novel variants. As such, it might be a useful screening tool to study associations of viral pathogens with GI-symptoms and GVHD. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
39. Air pollution from livestock farms and the oropharyngeal microbiome of COPD patients and controls.
- Author
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van Kersen, Warner, Bossers, Alex, de Steenhuijsen Piters, Wouter A.A., de Rooij, Myrna M.T., Bonten, Marc, Fluit, Ad C., Heederik, Dick, Paganelli, Fernanda L., Rogers, Malbert, Viveen, Marco, Bogaert, Debby, Leavis, Helen L., and Smit, Lidwien A.M.
- Subjects
- *
AIR pollution , *LIVESTOCK farms , *CHRONIC obstructive pulmonary disease , *AIR pollutants - Abstract
[Display omitted] Air pollution from livestock farms is known to affect respiratory health of patients with chronic obstructive pulmonary disease (COPD). The mechanisms behind this relationship, however, remain poorly understood. We hypothesise that air pollutants could influence respiratory health through modulation of the airway microbiome. Therefore, we studied associations between air pollution exposure and the oropharyngeal microbiota (OPM) composition of COPD patients and controls in a livestock-dense area. Oropharyngeal swabs were collected from 99 community-based (mostly mild) COPD cases and 184 controls (baseline), and after 6 and 12 weeks. Participants were non-smokers or former smokers. Annual average livestock-related outdoor air pollution at the home address was predicted using dispersion modelling. OPM composition was analysed using 16S rRNA-based sequencing in all baseline samples and 6-week and 12-week repeated samples of 20 randomly selected subjects (n = 323 samples). A random selection of negative control swabs, taken every sampling day, were also included in the downstream analysis. Both farm-emitted endotoxin and PM 10 levels were associated with increased OPM richness in COPD patients (p < 0.05) but not in controls. COPD case-control status was not associated with community structure, while correcting for known confounders (multivariate PERMANOVA p > 0.05). However, members of the genus Streptococcus were more abundant in COPD patients (Benjamini-Hochberg adjusted p < 0.01). Moderate correlation was found between ordinations of 20 subjects analysed at 0, 6, and 12 weeks (Procrustes r = 0.52 to 0.66; p < 0.05; Principal coordinate analysis of Bray-Curtis dissimilarity), indicating that the OPM is relatively stable over a 12 week period and that a single sample sufficiently represents the OPM. Air pollution from livestock farms is associated with OPM richness of COPD patients, suggesting that the OPM of COPD patients is susceptible to alterations induced by exposure to air pollutants. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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