69 results on '"Khatamzas E"'
Search Results
2. Definition of the early HIV-1 signalosome in dendritic cells
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Khatamzas, E, Simmons, A, and Rowland-Jones, S
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Immunology ,HIV/AIDS - Abstract
DCs are critical to the early events of HIV-1 infection. They are the first cells that HIV-1 encounters at mucosal surfaces and as sentinel antigen-presenting cells of the immune system these should alarm the immune system and activate innate immune defences to recruit effective adaptive immunity and viral clearance. A peculiar characteristic of HIV – in contrast to other ssRNA viruses – is its ability to completely evade host innate recognition pathways. Additionally, it has the unique ability to manipulate the endo-lysosomal system of DCs and promote transmission via trans-infection to CD4+ T cells across virological synapses. However, it is largely unknown how HIV-1 is sensed by the innate immune system. Here, a multipronged experimental approach based on phosphoproteomics, transcriptomics and custom RNAi screen was developed to characterize the early signaling complex induced by HIV-1 in DCs. A novel method of phosphoproteomics to identify the HIV-1 phosphoproteome in DCs showed that 342 proteins were differentially phosphorylated following 10 min of HIV-1 infection compared to time-matched mock-infected DCs. Functional analysis of these phosphoproteins showed enrichments in several cellular pathways, including vesicular trafficking, cytoskeletal rearrangements and the secretory pathway and a relative paucity of signaling molecules involved in inflammatory pathways. Proteomics analysis of HIV-1 virions was undertaken to identify host molecules hijacked by HIV-1 during viral replication and revealed a close interaction between the virus and the endo-lysosomal system. Transcriptomics analysis of HIV-1 infected DCs showed a muted immune response with no detectable differentially regulated genes. The results of the phoshoproteomic screen provided the basis for a custom RNAi screen to identify host proteins that are differentially phosphorylated by the virus and required for efficient trans-infection from DCs to CD4+ lymphocytes. The results of this screen showed that 54 of the 120 host factors tested were required for efficient viral transfer to CD4+ T cells and characterize the compartment that HIV-1 is internalized in on a molecular level. Two host factors identified within the HIV-1 phosphoproteome were chosen for further studies. Studies of BLOC-1 (biogenesis of lysosome-related organelles complex-1) and its subunits identified a role for snapin in HIV-1 trans-infection and HIV-1 and TLR8 sensing. Snapin may act as determinant of sorting of HIV-1 intraluminal vesicles to non-degradative, non-immunogenic compartments by activating mammalian target of rapamycin, mTOR, and inhibiting autophagy. Furthermore, HIV-1 triggered dephosphorylation of the cytosolic tyrosine phosphatase possibly via the interaction of host CD47 incorporated in the virion and the transmembrane glycoprotein SIRPα expressed on DCs. Blocking of this interaction with an inhibitory CD47 antibody resulted in a reduction of HIV-1 replication. Taken together, this multipronged approach reveals the complexity of the interaction of HIV-1 with the host cell machinery and identifies novel mechanism of the immune evasion tactics usurped by HIV-1.
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- 2016
3. Pattern recognition receptor mediated downregulation of microRNA-650 fine-tunes MxA expression in dendritic cells infected with Influenza A virus
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Pichulik T, Khatamzas E, Liu X, Brain O, Delmiro Garcia M, Leslie A, Danis B, Mayer A, Baban D, Ragoussis J, An, Weber, and Alison Simmons
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MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, which have been shown to fine-tune innate immune responses downstream of pattern recognition receptor (PRR) signaling. This study identifies miR-650 as a novel PRR-responsive miRNA which is downregulated upon stimulation of primary human monocyte-derived dendritic cells (MDDCs) with a variety of different microbe-associated molecular patterns (MAMPs). A comprehensive target search combining in silico analysis, transcriptional profiling and reporter assays reveals that miR-650 regulates several well-known interferon-stimulated genes (ISGs), including IFIT2 and MXA. In particular, downregulation of miR-650 in Influenza A-infected MDDCs enhances the expression of MxA and may therefore contribute to the establishment of an antiviral state. Together these findings reveal a novel link between miR-650 and the innate immune response in human MDDCs.
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- 2016
4. Early Phosphorylation Events Induced in Dendritic Cells by the HIV Derived TLR8 Ligand ssRNA40
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Leslie, A, Pichulik, T, Khatamzas, E, Mayer, A, McMichael, A, and Simmons, A
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- 2011
5. The role of macrophages and dendritic cells in Dengue infection
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Howells, A, Sinclair, M, Miller, J, Khatamzas, E, Rowland-Jones, S, McMichael, A, and Luhn, K
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- 2010
6. Cytomegalovirus (CMV) phosphoprotien 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals
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Kern, F, Bunde, T, Faulhaber, N, kiecker, F, Khatamzas, E, Rudawski, I-M, Pruss, A, Gratama, JW (S.), Volmer-Engert, R, Ewert, R, Reinke, P, Volk, H-D, Picker, LJ, and Medical Oncology
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- 2002
7. P017 The miRNA-29 family regulates NOD2-dependent IL-23 expression in human DCs and limits intestinal pathology in a mouse model of mucosal inflammation
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Brain, O., primary, Owens, B., additional, Sun, M.-Y., additional, Schonefeldt, S., additional, Allan, P., additional, Pichulik, T., additional, Khatamzas, E., additional, Jewell, D., additional, Liston, A., additional, and Simmons, A., additional
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- 2013
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8. P063 Investigation of the function of NOD2 in Crohn's disease using phosphoproteomics
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Allan, P., primary, Brain, O., additional, Baker, J., additional, Owens, B., additional, Steevels, T., additional, Simpson, P., additional, Pichulik, T., additional, Khatamzas, E., additional, Leslie, A., additional, Kessler, B., additional, and Simmons, A., additional
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- 2012
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9. NOD2 regulation of micrornas
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Brain, O., primary, Allan, P., additional, Pichulik, T., additional, Khatamzas, E., additional, Simpson, P., additional, Jewell, D., additional, and Simmons, A., additional
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- 2011
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10. NOD2 signalling in Crohn's disease
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Allan, P., primary, Brain, O., additional, Baker, J., additional, Simpson, P., additional, Pichulik, T., additional, Khatamzas, E., additional, Reenares, C., additional, Leslie, A., additional, Kessler, B., additional, and Simmons, A., additional
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- 2011
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11. S18 Mechanism of NOD2 mediated autophagy
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Brain, O., primary, Baker, J., additional, Cooney, R., additional, Allan, P., additional, Pichulik, T., additional, Khatamzas, E., additional, Ternette, N., additional, Kessler, B., additional, and Simmons, A., additional
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- 2010
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12. The increasing prevalence of listeriosis--what are we missing?
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Khatamzas, E., primary, Hughes, H., additional, Grant, K. A., additional, Mclauchlin, J., additional, and Bowler, I. C. J. W., additional
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- 2009
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13. Use of overlapping peptide mixtures as antigens for cytokine flow cytometry
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Maecker, H. T., Dunn, H. S., Suni, M. A., Khatamzas, E., Pitcher, C. J., Bunde, T., Persaud, N., Trigona, W., Fu, T. M., and Sinclair, E.
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- 2001
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14. Severe hypercalcaemia and lymphoma in an HTLV-1 positive Jamaican woman: a case report
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Lyell Veronica, Khatamzas Elham, and Allain Theresa
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Medicine - Abstract
Abstract Human T cell lymphotrophic virus type-1 infection is endemic in the Afro-Caribbean community in Britain, with carriage rates of about 3%. Although there is a long latency, carriers have a 1–5% chance of developing adult T cell leukaemia/lymphoma, a condition frequently complicated by marked and refractory hypercalcaemia, and with a poor prognosis. We present the case of an elderly Jamaican woman with severe hypercalcaemia and a raised PTHrP who was found to have lymphoma and was positive for HTLV-1.
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- 2007
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15. Effectiveness, barriers and facilitating factors of strategies for active delabelling of patients with penicillin allergy labels: a systematic review protocol.
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Nürnberg H, Khatamzas E, Denkinger C, Krause T, Oetken L, Rauer S, Rapp A, Hoppe-Tichy T, and Morath B
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- Humans, Research Design, Systematic Reviews as Topic, Penicillins adverse effects, Drug Hypersensitivity
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Introduction: Up to 15% of adult patients in the clinical setting report to be allergic to penicillin. However, in most cases, penicillin allergy is not confirmed. Due to the negative aspects associated with erroneous penicillin allergy, the implementation of active delabelling processes for penicillin allergy is an important part of antibiotic stewardship programmes. Depending on the clinical setting, different factors need to be considered during implementation. This review examines the effectiveness of different delabelling interventions and summarises components and structures that facilitate, support or constrain structured penicillin allergy delabelling., Methods and Analysis: This review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The databases MEDLINE (via PubMed), EMBASE and Cochrane Library were searched for studies reporting on any intervention to identify, assess or rule out uncertain penicillin allergy. To improve completeness, two further databases are also searched for grey literature. Study design, intervention type, professional groups involved, effectiveness, limitations, barriers, facilitating factors, clinical setting and associated regulatory factors will be extracted and analysed. In addition, exclusion criteria for participation in the delabelling intervention and criteria for not delabelling penicillin allergy will be summarised. In case of failed protocols, these are highlighted and quantitatively analysed if possible. Two independent reviewers will perform the screening process and data extraction. Discordant decisions will be resolved through review by a third reviewer. Bias assessment of the individual studies will be performed using the Newcastle Ottawa Scale., Ethics and Dissemination: Because individual patient-related data are not analysed, an ethical approval is not required. The review will be published in a peer-reviewed scientific journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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16. Corrigendum to 'Nivolumab induces long-term remission in a patient with fusariosis' [Eur J Cancer 173 (2022) 91-94].
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Khatamzas E, Mellinghoff SC, Thelen M, Schlößer HA, Kunz WG, Buerkle C, Dichtl K, Guenther M, Ormanns S, and von Bergwelt-Baildon M
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- 2023
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17. Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection.
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Khatamzas E, Antwerpen MH, Rehn A, Graf A, Hellmuth JC, Hollaus A, Mohr AW, Gaitzsch E, Weiglein T, Georgi E, Scherer C, Stecher SS, Gruetzner S, Blum H, Krebs S, Reischer A, Leutbecher A, Subklewe M, Dick A, Zange S, Girl P, Müller K, Weigert O, Hopfner KP, Stemmler HJ, von Bergwelt-Baildon M, Keppler OT, Wölfel R, Muenchhoff M, and Moosmann A
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- CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte genetics, Humans, Immunization, Passive, Mutation, Nucleoproteins genetics, Peptides genetics, SARS-CoV-2, Spike Glycoprotein, Coronavirus genetics, COVID-19 Serotherapy, COVID-19 therapy, Lymphoma, Vaccines
- Abstract
Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design., (© 2022. The Author(s).)
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- 2022
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18. Nivolumab induces long-term remission in a patient with fusariosis.
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Khatamzas E, Mellinghoff SC, Thelen M, Schlößer HA, Kunz WG, Buerkle C, Dichtl K, Ormanns S, and von Bergwelt-Baildon M
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- Humans, Immunocompromised Host, Nivolumab therapeutic use, Remission Induction, Fusariosis
- Abstract
Competing Interests: Conflict of interest statement SCM reports consultancy for Octapharma. She received research grants from the UoC (KoelnFortune) as mentioned above, from DMyKG (Manfred-Plempel-Stiftung) and from DZIF (Clinical Leave Stipend). PH is an advisor or received lecture honoraria from Johnson & Johnson. MBB has been a consultant to MSD Sharp & Dohme, Novartis, Roche, KITE/Gilead, Bristol-Myers Squibb, Astellas, Mologen, and Miltenyi. He has received research funding and honoraria from the aforementioned companies. The remaining authors have nothing to declare.
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- 2022
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19. [Management of infection in immunocompromised patients].
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Mellinghoff SC, Stemler J, Forkl S, Khatamzas E, and Classen AY
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- Anti-Bacterial Agents therapeutic use, Humans, Immunocompromised Host, Quality of Life, Bacterial Infections drug therapy, Neoplasms drug therapy
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The number of immunosuppressed patients continues to increase worldwide. The main reasons are the demographic development and improved long-term survival, also for patients under immunosuppression. A major cause of hospitalization and mortality among these patients are infections. Their management, including prevention and adequate treatment, plays a crucial role in survival and quality of life, but also with regard to economic factors.Infection management in immunocompromised patients faces new challenges today. Not only the increasing number, but also new groups of patients at risk and an increasingly aging and comorbid population pose problems for the treating physicians. While cancer medicine is no longer determined solely by radiotherapy and chemotherapy, new targeted substances are playing an increasingly important role. In addition, new targeted substances complicate adequate infection prophylaxis due to potential interactions. The worldwide increase in antibiotic-resistant pathogens complicates treatment of bacterial infections, which is associated with increased mortality, especially in the immunocompromised patient population. Further, the disruption of the microbiome shows negative antibiotic-associated effects. Hence the reasonable use of anti-infectives in prophylaxis and therapy is of great importance.There are many recommendations and guidelines for clinicians regarding the management of infections in immunocompromised patients. Overlaps of infectiology, hygiene as well as hematology and oncology sometimes lead to different recommendations. This article provides an overview of the currently existing evidence and guidelines for infection management in immunosuppressed patients., Competing Interests: Mellinghoff: Octapharma (Beratungtätigkeit), Gilead (Reisekosten und Fortbildung);Stemler: Bundesministerium für Bildung und Forschung – Forschungsgelder; Basilea Pharmaceuticals Inc. – Frschungsgelder Pfizer Inc. – Vortragshonorar; Deutsche Gesellschaft für Infektiologie (DGI e.V.) – Reisekosten; Meta-Alexander Foundation – ReisekostenClassen: Deutsches Zentrum für Infektionsforschung (Forschungsgelder und Reisekosten); Akademie für Infektionsmedizin (Dozentenhonorar); Ärtzekammer Nordhrein Westfalen (Dozentenhonorar); Gilead (Reisekosten und Fortbildung), (Thieme. All rights reserved.)
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- 2022
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20. Intracerebral mucormycosis after COVID-19: illustrative cases.
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Nohman AI, Ivren M, Klein S, Khatamzas E, Unterberg A, and Giese H
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Background: In this case report the authors present two female patients with intracranial mucormycosis after coronavirus disease 2019 (COVID-19)., Observations: The first patient was a 30-year-old woman with no past medical history or allergies who presented with headaches and vomiting. Magnetic resonance imaging (MRI) and computed tomography of the skull showed an endonasal infection, which had already destroyed the frontal skull base and caused a large frontal intracranial abscess. The second patient was a 29-year-old woman with multiple pre-existing conditions, who was initially admitted to the hospital due to a COVID-19 infection and later developed a hemiparesis of the right side. Here, the MRI scan showed an abscess configuration in the left motor cortex. In both cases, rapid therapy was performed by surgical clearance and abscess evacuation followed by antifungal, antidiabetic, and further supportive treatment for several weeks., Lessons: Both cases are indicative of a possible correlation of mucormycosis in the setting of severe immunosuppression involved with COVID-19, both iatrogenic with the use of steroids and previous medical history. Furthermore, young and supposedly healthy patients can also be affected by this rare disease., Competing Interests: Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper., (© 2022 The authors.)
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- 2022
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21. Unexpected community-acquired co-infections during an ongoing pandemic: (one) too many diagnoses at once.
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Cordas Dos Santos DM, Fischer L, von Bergwelt-Baildon M, and Khatamzas E
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- Hospitalization, Humans, Longitudinal Studies, Pandemics prevention & control, Coinfection diagnosis, Coinfection epidemiology, Community-Acquired Infections diagnosis, Community-Acquired Infections epidemiology
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- 2022
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22. Should routine risk reduction procedures for the prevention and control of pandemics become a standard in all oncological outpatient clinics? The prospective COVID-19 cohort study: protect-CoV.
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Fey T, Erickson N, Stahler A, Muenchhoff M, Keppler OT, Ruehlmann K, Krauss-Pfeiffer G, Steinberg H, Graf A, Krebs S, Blum H, Khatamzas E, Seynstahl S, Casuscelli J, Markwardt D, Forstpointner R, Schinköthe T, von Bergwelt-Baildon M, and Heinemann V
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- Ambulatory Care Facilities, Cohort Studies, Humans, Prospective Studies, Risk Reduction Behavior, SARS-CoV-2, COVID-19, Pandemics prevention & control
- Abstract
Limited knowledge exists on the effectiveness of preventive preparedness plans for the care of outpatient cancer patients during epidemics or pandemics. To ensure adequate, timely and continuous clinical care for this highly vulnerable population, we propose the establishment of preventive standard safety protocols providing effective early phase identification of outbreaks at outpatient cancer facilities and communicating adapted standards of care. The prospective cohort study Protect-CoV conducted at the LMU Klinikum from mid-March to June 2020 investigated the effectiveness of a rapid, proactive and methodical response to protect patients and interrupt SARS-CoV-2 transmission chains during the first pandemic wave. The implemented measures reduced the risk of infection of individual cancer patients and ensured safe adjunctive infusion therapy in an outpatient setting during the early COVID-19 pandemic. In addition to the immediate implementation of standard hygiene procedures, our results underscore the importance of routine PCR testing for the identification of asymptomatic or pre-symptomatic COVID-19 cases and immediate tracing of positive cases and their contacts. While more prospective controlled studies are needed to confirm these results, our study illustrates the importance of including preventative testing and tracing measures in the standard risk reduction procedures at all out patient cancer centers., (© 2022. The Author(s).)
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- 2022
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23. Presence of optrA- mediated linezolid resistance in multiple lineages and plasmids of Enterococcus faecalis revealed by long read sequencing.
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McHugh MP, Parcell BJ, Pettigrew KA, Toner G, Khatamzas E, El Sakka N, Karcher AM, Walker J, Weir R, Meunier D, Hopkins KL, Woodford N, Templeton KE, Gillespie SH, and Holden MTG
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- Animals, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial genetics, Enterococcus faecalis genetics, Linezolid pharmacology, Microbial Sensitivity Tests, Multilocus Sequence Typing, Plasmids genetics, Enterococcus faecium genetics, Gram-Positive Bacterial Infections
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Transferable linezolid resistance due to optrA , poxtA , cfr and cfr -like genes is increasingly detected in enterococci associated with animals and humans globally. We aimed to characterize the genetic environment of optrA in linezolid-resistant Enterococcus faecalis isolates from Scotland. Six linezolid-resistant E. faecalis isolated from urogenital samples were confirmed to carry the optrA gene by PCR. Short read (Illumina) sequencing showed the isolates were genetically distinct (>13900 core SNPs) and belonged to different MLST sequence types. Plasmid contents were examined using hybrid assembly of short and long read (Oxford Nanopore MinION) sequencing technologies. The optrA gene was located on distinct plasmids in each isolate, suggesting that transfer of a single plasmid did not contribute to optrA dissemination in this collection. pTM6294-2, BX5936-1 and pWE0438-1 were similar to optrA -positive plasmids from China and Japan, while the remaining three plasmids had limited similarity to other published examples. We identified the novel Tn 6993 transposon in pWE0254-1 carrying linezolid ( optrA ), macrolide ( ermB ) and spectinomycin [ANT(9)-Ia] resistance genes. OptrA amino acid sequences differed by 0-20 residues. We report multiple variants of optrA on distinct plasmids in diverse strains of E. faecalis . It is important to identify the selection pressures driving the emergence and maintenance of resistance against linezolid to retain the clinical utility of this antibiotic.
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- 2022
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24. Pulmonary function impairment of asymptomatic and persistently symptomatic patients 4 months after COVID-19 according to disease severity.
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Munker D, Veit T, Barton J, Mertsch P, Mümmler C, Osterman A, Khatamzas E, Barnikel M, Hellmuth JC, Münchhoff M, Walter J, Ghiani A, Munker S, Dinkel J, Behr J, Kneidinger N, and Milger K
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- Humans, Lung, Prospective Studies, SARS-CoV-2, Severity of Illness Index, COVID-19
- Abstract
Objective: Evaluation of pulmonary function impairment after COVID-19 in persistently symptomatic and asymptomatic patients of all disease severities and characterisation of risk factors., Methods: Patients with confirmed SARS-CoV-2 infection underwent prospective follow-up with pulmonary function testing and blood gas analysis during steady-state cycle exercise 4 months after acute illness. Pulmonary function impairment (PFI) was defined as reduction below 80% predicted of DLCOcSB, TLC, FVC, or FEV1. Clinical data were analyzed to identify risk factors for impaired pulmonary function., Results: 76 patients were included, hereof 35 outpatients with mild disease and 41 patients hospitalized due to COVID-19. Sixteen patients had critical disease requiring mechanical ventilation, 25 patients had moderate-severe disease. After 4 months, 44 patients reported persisting respiratory symptoms. Significant PFI was prevalent in 40 patients (52.6%) occurring among all disease severities. The most common cause for PFI was reduced DLCOcSB (n = 39, 51.3%), followed by reduced TLC and FVC. The severity of PFI was significantly associated with mechanical ventilation (p < 0.001). Further risk factors for DLCO impairment were COPD (p < 0.001), SARS-CoV-2 antibody-Titer (p = 0.014) and in hospitalized patients CT score. A decrease of paO2 > 3 mmHg during cycle exercise occurred in 1/5 of patients after mild disease course., Conclusion: We characterized pulmonary function impairment in asymptomatic and persistently symptomatic patients of different severity groups of COVID-19 and identified further risk factors associated with persistently decreased pulmonary function. Remarkably, gas exchange abnormalities were revealed upon cycle exercise in some patients with mild disease courses and no preexisting pulmonary condition., (© 2021. The Author(s).)
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- 2022
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25. Results from a national survey on COVID-19-associated mucormycosis in Germany: 13 patients from six tertiary hospitals.
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Seidel D, Simon M, Sprute R, Lubnow M, Evert K, Speer C, Seeßle J, Khatamzas E, Merle U, Behrens C, Blau IW, Enghard P, Haas CS, Steinmann J, Kurzai O, and Cornely OA
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- Antifungal Agents therapeutic use, Germany epidemiology, Humans, Tertiary Care Centers, COVID-19 complications, Mucormycosis diagnosis, Mucormycosis drug therapy, Mucormycosis epidemiology
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Background: Most COVID-19-associated mucormycosis (CAM) cases are reported from India and neighbouring countries. Anecdotally cases from Europe have been presented., Objective: To estimate the disease burden and describe the clinical presentation of CAM in Germany., Methods: We identified cases through German mycology networks and scientific societies, and collected anonymised clinical information via FungiScope®., Results: We identified 13 CAM cases from six tertiary referral hospitals diagnosed between March 2020 and June 2021. Twelve patients had severe or critical COVID-19, eleven were mechanically ventilated for a median of 8 days (range 1-27 days) before diagnosis of CAM. Eleven patients received systemic corticosteroids. Additional underlying medical conditions were reported for all but one patient, five were immunocompromised because of malignancy or organ transplantation, three were diabetic. Eleven patients developed pneumonia. Mortality was 53.8% with a median time from diagnosis of mucormycosis to death of 9 days (range 0-214 days) despite treatment with liposomal amphotericin B and/or isavuconazole in 10 of 13 cases. CAM prevalence amongst hospitalised COVID-19 patients overall (0.67% and 0.58% in two centres) and those admitted to the intensive care unit (ICU) (1.47%, 1.78% and 0.15% in three centres) was significantly higher compared to non-COVID-19 patients (P < .001 for respective comparisons)., Conclusion: COVID-19-associated mucormycosis is rare in Germany, mostly reported in patients with comorbidities and impaired immune system and severe COVID-19 treated in the ICU with high mortality compared to mainly rhino-orbito-cerebral CAM in patients with mild COVID-19 in India. Risk for CAM is higher in hospitalised COVID-19 patients than in other patients., (© 2021 The Authors. Mycoses published by Wiley-VCH GmbH.)
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- 2022
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26. Sensitivity of two SARS-CoV-2 variants with spike protein mutations to neutralising antibodies.
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Müller K, Girl P, Giebl A, Gruetzner S, Antwerpen M, Khatamzas E, Wölfel R, and von Buttlar H
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- Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Antibodies, Neutralizing therapeutic use, Antibodies, Viral therapeutic use, COVID-19 immunology, Humans, SARS-CoV-2 chemistry, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 virology, Mutation, SARS-CoV-2 genetics, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus genetics
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SARS-CoV-2 infections elicit a humoral immune response capable of neutralising the virus. However, multiple variants have emerged with mutations in the spike protein amongst others, the key target of neutralising antibodies. We evaluated the neutralising efficacy of 89 serum samples from patients, infected with SARS-CoV-2 in the beginning of 2020, against two virus variants isolated from acutely infected patients and harbouring spike protein mutations. One isolate was assigned to lineage B.1.351 (MUC-IMB-B.1.351) whilst the other (MUC-484) was isolated from an immunocompromised patient, sharing some but not all mutations with B.1.351 and representing a transitional variant. Both variants showed a significant reduction in neutralisation sensitivity compared to wild-type SARS-CoV-2 with MUC-IMB-B.1.351 being almost completely resistant to neutralisation. The observed reduction in neutralising activity of wild-type-specific antibodies against both variants suggests that individual mutations in the spike protein are sufficient to confer a potent escape from the humoral immune response. In addition, the effect of escape mutations seems to accumulate, so that more heavily mutated variants show a greater loss of sensitivity to neutralisation up to complete insensitivity as observed for MUC-IMB-B.1.351. From a clinical point of view, this might affect the efficacy of (monoclonal) antibody treatment of patients with prolonged infections as well as patients infected with variants other than the donor. At the same, this could also negatively influence the efficacy of current vaccines (as they are based on wild-type spike protein) emphasising the need to thoroughly surveil the emergence and distribution of variants and adapt vaccines and therapeutics accordingly., (© 2021. The Author(s).)
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- 2021
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27. Genomic epidemiology reveals multiple introductions of SARS-CoV-2 followed by community and nosocomial spread, Germany, February to May 2020.
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Muenchhoff M, Graf A, Krebs S, Quartucci C, Hasmann S, Hellmuth JC, Scherer C, Osterman A, Boehm S, Mandel C, Becker-Pennrich AS, Zoller M, Stubbe HC, Munker S, Munker D, Milger K, Gapp M, Schneider S, Ruhle A, Jocham L, Nicolai L, Pekayvaz K, Weinberger T, Mairhofer H, Khatamzas E, Hofmann K, Spaeth PM, Bender S, Kääb S, Zwissler B, Mayerle J, Behr J, von Bergwelt-Baildon M, Reincke M, Grabein B, Hinske CL, Blum H, and Keppler OT
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- Genome, Viral, Genomics, Germany epidemiology, Hospitals, Humans, Phylogeny, SARS-CoV-2, COVID-19, Cross Infection epidemiology
- Abstract
BackgroundIn the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data.AimWe applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata.MethodsWe investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission.ResultsWe identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions.ConclusionsEarly spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.
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- 2021
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28. An algorithm for safe de-labelling of antibiotic allergy in adult hospital in-patients.
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Sneddon J, Cooper L, Ritchie N, Steele C, Spears M, McEwen J, Dempsey Z, Sutherland R, Khatamzas E, and Seaton RA
- Subjects
- Adult, Hospitals, Humans, Algorithms, Anti-Bacterial Agents adverse effects, Drug Hypersensitivity diagnosis, Penicillins adverse effects
- Published
- 2021
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29. Dynamics of SARS-CoV-2 shedding in the respiratory tract depends on the severity of disease in COVID-19 patients.
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Munker D, Osterman A, Stubbe H, Muenchhoff M, Veit T, Weinberger T, Barnikel M, Mumm JN, Milger K, Khatamzas E, Klauss S, Scherer C, Hellmuth JC, Giessen-Jung C, Zoller M, Herold T, Stecher S, de Toni EN, Schulz C, Kneidinger N, Keppler OT, Behr J, Mayerle J, and Munker S
- Subjects
- Humans, RNA, Viral, Respiratory System, Severity of Illness Index, Virus Shedding, COVID-19, SARS-CoV-2
- Abstract
A fraction of COVID-19 patients progress to a severe disease manifestation with respiratory failure and the necessity of mechanical ventilation. Identifying patients at risk is critical for optimised care and early therapeutic interventions. We investigated the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding relative to disease severity.We analysed nasopharyngeal and tracheal shedding of SARS-CoV-2 in 92 patients with diagnosed COVID-19. Upon admission, standardised nasopharyngeal swab or sputum samples were collected. If patients were mechanically ventilated, endotracheal aspirate samples were additionally obtained. Viral shedding was quantified by real-time PCR detection of SARS-CoV-2 RNA.45% (41 out of 92) of COVID-19 patients had a severe disease course with the need for mechanical ventilation (severe group). At week 1, the initial viral shedding determined from nasopharyngeal swabs showed no significant difference between nonsevere and severe cases. At week 2, a difference could be observed as the viral shedding remained elevated in severely ill patients. A time-course of C-reactive protein, interleukin-6 and procalcitonin revealed an even more protracted inflammatory response following the delayed drop of virus shedding load in severely ill patients. A significant proportion (47.8%) of patients showed evidence of prolonged viral shedding (>17 days), which was associated with severe disease courses (73.2%).We report that viral shedding does not differ significantly between severe and nonsevere COVID-19 cases upon admission to the hospital. Elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between the second and third week, and prolonged viral shedding are associated with a more severe disease course., Competing Interests: Conflict of interest: D. Munker has nothing to disclose. Conflict of interest: A. Osterman has nothing to disclose. Conflict of interest: H. Stubbe has nothing to disclose. Conflict of interest: M. Muenchhoff has nothing to disclose. Conflict of interest: T. Veit has nothing to disclose. Conflict of interest: T. Weinberger has nothing to disclose. Conflict of interest: M. Barnikel has nothing to disclose. Conflict of interest: J-N. Mumm has nothing to disclose. Conflict of interest: K. Milger has nothing to disclose. Conflict of interest: E. Khatamzas has nothing to disclose. Conflict of interest: S. Klauss has nothing to disclose. Conflict of interest: C. Scherer has nothing to disclose. Conflict of interest: J.C. Hellmuth has nothing to disclose. Conflict of interest: C. Giessen-Jung has nothing to disclose. Conflict of interest: M. Zoller has nothing to disclose. Conflict of interest: T. Herold has nothing to disclose. Conflict of interest: S. Stecher has nothing to disclose. Conflict of interest: E.N. De Toni has nothing to disclose. Conflict of interest: C. Schulz has nothing to disclose. Conflict of interest: N. Kneidinger has nothing to disclose. Conflict of interest: O.T. Keppler has nothing to disclose. Conflict of interest: J. Behr has nothing to disclose. Conflict of interest: J. Mayerle has nothing to disclose. Conflict of interest: S. Munker has nothing to disclose., (Copyright ©ERS 2021.)
- Published
- 2021
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30. [Update 2021: COVID-19 from the perspective of infectious diseases specialty].
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Khatamzas E and Kroidl I
- Subjects
- COVID-19 complications, COVID-19 prevention & control, Humans, Interferon Type I blood, Post-Acute COVID-19 Syndrome, Antibodies, Viral blood, COVID-19 immunology, Infectious Disease Medicine, SARS-CoV-2 immunology
- Abstract
From an infectious disease perspective, there have been outstanding findings since January 2020 far beyond the knowledge gained about SARS-CoV, which hopefully will help us to manage future pandemics. Positive highlights include the increased public awareness of infectious disease epidemiology, the increase in immunological knowledge, and the successful use of existing vaccine development platforms and technologies. This article presents a personal selection of interesting developments in recent months., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)
- Published
- 2021
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31. COVID-19 in Patients Receiving CD20-depleting Immunochemotherapy for B-cell Lymphoma.
- Author
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Gaitzsch E, Passerini V, Khatamzas E, Strobl CD, Muenchhoff M, Scherer C, Osterman A, Heide M, Reischer A, Subklewe M, Leutbecher A, Tast B, Ruhle A, Weiglein T, Stecher SS, Stemmler HJ, Dreyling M, Girl P, Georgi E, Wölfel R, Mateyka L, D'Ippolito E, Schober K, Busch DH, Kager J, Spinner CD, Treiber M, Rasch S, Lahmer T, Iakoubov R, Schneider J, Protzer U, Winter C, Ruland J, Quante M, Keppler OT, von Bergwelt-Baildon M, Hellmuth J, and Weigert O
- Abstract
The clinical and immunological impact of B-cell depletion in the context of coronavirus disease 2019 (COVID-19) is unclear. We conducted a prospectively planned analysis of COVID-19 in patients who received B-cell depleting anti-CD20 antibodies and chemotherapy for B-cell lymphomas. The control cohort consisted of age- and sex-matched patients without lymphoma who were hospitalized because of COVID-19. We performed detailed clinical analyses, in-depth cellular and molecular immune profiling, and comprehensive virological studies in 12 patients with available biospecimens. B-cell depleted lymphoma patients had more severe and protracted clinical course (median hospitalization 88 versus 17 d). All patients actively receiving immunochemotherapy (n = 5) required ICU support including long-term mechanical ventilation. Neutrophil recovery following granulocyte colony stimulating factor stimulation coincided with hyperinflammation and clinical deterioration in 4 of the 5 patients. Immune cell profiling and gene expression analysis of peripheral blood mononuclear cells revealed early activation of monocytes/macrophages, neutrophils, and the complement system in B-cell depleted lymphoma patients, with subsequent exacerbation of the inflammatory response and dysfunctional interferon signaling at the time of clinical deterioration of COVID-19. Longitudinal immune cell profiling and functional in vitro assays showed SARS-CoV-2-specific CD8
+ and CD4+ T-effector cell responses. Finally, we observed long-term detection of SARS-CoV-2 in respiratory specimens (median 84 versus 12 d) and an inability to mount lasting SARS-CoV-2 antibody responses in B-cell depleted lymphoma patients. In summary, we identified clinically relevant particularities of COVID-19 in lymphoma patients receiving B-cell depleting immunochemotherapies., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)- Published
- 2021
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32. Equity for excellence in academic institutions: a manifesto for change.
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Wedekind L, Noé A, Mokaya J, Tamandjou C, Kapulu M, Ruecker A, Kestelyn E, Zimba M, Khatamzas E, Eziefula AC, Mackintosh CL, Nascimento R, Ariana P, Best D, Gibbs E, Dunachie S, Hadley G, Ravenswood H, Young B, Kamau C, Marsh K, McShane H, Hale R, McPhilbin E, Ovseiko PV, Surender R, Worland C, White LJ, and Matthews PC
- Abstract
Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Wedekind L et al.)
- Published
- 2021
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33. Liver transplantation in a patient after COVID-19 - Rapid loss of antibodies and prolonged viral RNA shedding.
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Niess H, Börner N, Muenchhoff M, Khatamzas E, Stangl M, Graf A, Girl P, Georgi E, Koliogiannis D, Denk G, Irlbeck M, Werner J, and Guba M
- Subjects
- COVID-19 pathology, Humans, Male, Middle Aged, RNA, Viral genetics, SARS-CoV-2, Severity of Illness Index, Antibodies, Viral blood, COVID-19 complications, End Stage Liver Disease surgery, Liver Transplantation, Virus Shedding
- Abstract
To date, little is known about the duration and effectiveness of immunity as well as possible adverse late effects after an infection with SARS-CoV-2. Thus it is unclear, when and if liver transplantation can be safely offered to patients who suffered from COVID-19. Here, we report on a successful liver transplantation shortly after convalescence from COVID-19 with subsequent partial seroreversion as well as recurrence and prolonged shedding of viral RNA., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2021
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34. Rituximab Treatment of Hairy Cell Leukemia in a Patient with Mycobacterium kansasii Infection: A Case Report.
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Mümmler C, Zhang D, Zimmermann A, Mertsch P, Fischer L, Greither M, Khatamzas E, Ormanns S, Heiß-Neumann M, Dreyling M, von Bergwelt-Baildon M, and Boeck S
- Subjects
- Humans, Middle Aged, Mycobacterium kansasii, Leukemia, Hairy Cell complications, Leukemia, Hairy Cell drug therapy, Mycobacterium Infections, Nontuberculous diagnosis, Mycobacterium Infections, Nontuberculous drug therapy, Opportunistic Infections diagnosis, Opportunistic Infections drug therapy, Rituximab therapeutic use
- Abstract
Introduction: Infectious complications represent a major cause of morbidity and mortality in hairy cell leukemia (HCL) patients. Due to the immunosuppressive nature of the disease, these patients are frequently affected by opportunistic infections and rare pathogens. Furthermore, cytotoxic chemotherapy might lead to poor or even fatal outcomes in the setting of an active infection., Case Presentation: We report the case of a 62-year-old HCL patient who presented with recurrent fever episodes, pancytopenia, and mediastinal lymphadenopathy. A treatment decision against purine analogs and for rituximab mono was made as lymph node tissue revealed disseminated Mycobacterium kansasii infection. Together with specific antimycobacterial treatment, rituximab mono led to complete hematologic remission after 6 months without aggravating the accompanying infection., Conclusion: Here, we demonstrate successful treatment of HCL with rituximab in a patient with concomitant disseminated M. kansasii infection., (© 2021 S. Karger AG, Basel.)
- Published
- 2021
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35. Urinary Frequency as a Possibly Overlooked Symptom in COVID-19 Patients: Does SARS-CoV-2 Cause Viral Cystitis?
- Author
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Mumm JN, Osterman A, Ruzicka M, Stihl C, Vilsmaier T, Munker D, Khatamzas E, Giessen-Jung C, Stief C, Staehler M, and Rodler S
- Subjects
- Aged, COVID-19, COVID-19 Testing, Clinical Laboratory Techniques, Coronavirus Infections complications, Coronavirus Infections diagnosis, Cystitis diagnosis, Cystitis physiopathology, Host-Pathogen Interactions, Humans, Male, Middle Aged, Pandemics, Pneumonia, Viral complications, Pneumonia, Viral diagnosis, Prospective Studies, Retrospective Studies, Risk Factors, SARS-CoV-2, Time Factors, Urinary Incontinence, Urge diagnosis, Urinary Incontinence, Urge physiopathology, Urinary Tract Infections diagnosis, Urinary Tract Infections physiopathology, Betacoronavirus pathogenicity, Coronavirus Infections virology, Cystitis virology, Pneumonia, Viral virology, Urinary Incontinence, Urge virology, Urinary Tract Infections virology, Urination, Urodynamics
- Abstract
The current coronavirus disease 2019 (COVID-19) pandemic is a challenge for physicians in triaging patients in emergency rooms. We found a potentially dangerous overlap of classical urinary symptoms and the as yet not fully described symptoms of COVID-19. After a patient was primarily triaged as a urosepsis case and then subsequently diagnosed with COVID-19, we focused on an increase in urinary frequency as a symptom of COVID-19 and identified this in seven males out of 57 patients currently being treated in our COVID-19 wards. In the absence of any other causes, urinary frequency may be secondary to viral cystitis due to underlying COVID-19 disease. We propose consideration of urinary frequency as an anamnestic tool in patients with infective symptoms to increase awareness among urologists during the current COVID-19 pandemic to prevent fatal implications of misinterpreting urological symptoms., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
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36. [COVID-19: Questions and answers from Infectious Diseases Specialty].
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Khatamzas E, Rothe C, and Kroidl I
- Abstract
Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.
- Published
- 2020
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37. Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT.
- Author
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Scarborough M, Li HK, Rombach I, Zambellas R, Walker AS, McNally M, Atkins B, Kümin M, Lipsky BA, Hughes H, Bose D, Warren S, Mack D, Folb J, Moore E, Jenkins N, Hopkins S, Seaton RA, Hemsley C, Sandoe J, Aggarwal I, Ellis S, Sutherland R, Geue C, McMeekin N, Scarborough C, Paul J, Cooke G, Bostock J, Khatamzas E, Wong N, Brent A, Lomas J, Matthews P, Wangrangsimakul T, Gundle R, Rogers M, Taylor A, Thwaites GE, and Bejon P
- Subjects
- Administration, Intravenous, Administration, Oral, Adult, Anti-Bacterial Agents adverse effects, Bacterial Infections microbiology, Bone Diseases, Infectious microbiology, Clinical Protocols, Cost-Benefit Analysis economics, Female, Humans, Joint Diseases microbiology, Male, Middle Aged, Quality-Adjusted Life Years, Technology Assessment, Biomedical, Treatment Outcome, United Kingdom, Anti-Bacterial Agents administration & dosage, Bacterial Infections drug therapy, Bone Diseases, Infectious drug therapy, Drug Administration Schedule, Joint Diseases drug therapy
- Abstract
Background: Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes., Objective: To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection., Design: Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%., Setting: Twenty-six NHS hospitals., Participants: Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively)., Interventions: Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm., Main Outcome Measure: The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data., Results: Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial., Limitations: The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded., Conclusions: PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy., Future Work: Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics., Trial Registration: Current Controlled Trials ISRCTN91566927., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 38. See the NIHR Journals Library website for further project information., Competing Interests: Adrian Taylor reports personal fees from Zimmer Inc., Corin Group and DePuy Synthes Companies outside the submitted work. Martin McNally reports personal fees from Bonesupport AB outside the submitted work. R Andrew Seaton reports personal fees from previous consultancy and funding for speaking at educational meetings (Novartis Pharma) and consultancy for Merck Sharp & Dohme Corp. (MSD) outside the submitted work. Harriet Hughes reports other competing interests from Gilead Sciences Inc., MSD, Biocomposites, and personal fees from Biocomposites and Cubist Pharmaceuticals outside the submitted work. Jennifer Bostock was a member of the Health Services and Delivery Research Commissioned Panel Members during this project.
- Published
- 2019
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38. Neurosurgical device-associated infections due to Candida auris - Three cases from a single tertiary center.
- Author
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Khatamzas E, Madder H, and Jeffery K
- Subjects
- Aged, Antifungal Agents administration & dosage, Candidiasis drug therapy, Candidiasis microbiology, Cerebrospinal Fluid microbiology, Humans, Male, Middle Aged, Prosthesis-Related Infections drug therapy, Prosthesis-Related Infections microbiology, Tertiary Care Centers, Candida isolation & purification, Candidiasis diagnosis, Candidiasis pathology, Prosthesis-Related Infections diagnosis, Prosthesis-Related Infections pathology, Ventriculoperitoneal Shunt adverse effects
- Published
- 2019
- Full Text
- View/download PDF
39. Oral versus Intravenous Antibiotics for Bone and Joint Infection.
- Author
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Li HK, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL, Lipsky BA, Hughes HC, Bose D, Kümin M, Scarborough C, Matthews PC, Brent AJ, Lomas J, Gundle R, Rogers M, Taylor A, Angus B, Byren I, Berendt AR, Warren S, Fitzgerald FE, Mack DJF, Hopkins S, Folb J, Reynolds HE, Moore E, Marshall J, Jenkins N, Moran CE, Woodhouse AF, Stafford S, Seaton RA, Vallance C, Hemsley CJ, Bisnauthsing K, Sandoe JAT, Aggarwal I, Ellis SC, Bunn DJ, Sutherland RK, Barlow G, Cooper C, Geue C, McMeekin N, Briggs AH, Sendi P, Khatamzas E, Wangrangsimakul T, Wong THN, Barrett LK, Alvand A, Old CF, Bostock J, Paul J, Cooke G, Thwaites GE, Bejon P, and Scarborough M
- Subjects
- Administration, Intravenous, Adolescent, Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents adverse effects, Anti-Bacterial Agents pharmacokinetics, Female, Humans, Intention to Treat Analysis, Male, Medication Adherence, Middle Aged, Treatment Outcome, Young Adult, Administration, Oral, Anti-Bacterial Agents administration & dosage, Bone Diseases, Infectious drug therapy, Joint Diseases drug therapy
- Abstract
Background: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication., Methods: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points., Results: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%)., Conclusions: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).
- Published
- 2019
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40. Mumps presenting with unilateral, synchronous parotid and submandibular gland swelling.
- Author
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Boyle C, Asimakopoulos P, Khatamzas E, and Vernham G
- Subjects
- Abscess diagnosis, Diagnosis, Differential, Female, Humans, Infectious Mononucleosis diagnosis, Mumps complications, Parotitis diagnosis, Young Adult, Edema etiology, Mumps diagnosis, Parotid Diseases etiology, Submandibular Gland Diseases etiology
- Abstract
A previously healthy 22-year-old woman presented with acute, unilateral facial and neck swelling, associated with fever and malaise. She was initially treated with intravenous antibiotics; however, CT imaging showed unilateral, synchronous swelling and inflammation of the parotid and submandibular glands, and a PCR swab from the parotid duct was positive for mumps. She was fully immunised and had no contact in the preceding period with anyone diagnosed with mumps. She responded to supportive management and her symptoms resolved over the course of her admission. Unilateral, synchronous swelling and severe inflammation of both the parotid and submandibular glands in mumps is a very unusual presentation, and not one previously reported in the literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2018
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41. Snapin promotes HIV-1 transmission from dendritic cells by dampening TLR8 signaling.
- Author
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Khatamzas E, Hipp MM, Gaughan D, Pichulik T, Leslie A, Fernandes RA, Muraro D, Booth S, Zausmer K, Sun MY, Kessler B, Rowland-Jones S, Cerundolo V, and Simmons A
- Subjects
- CD4-Positive T-Lymphocytes virology, Cell Line, HIV-1 immunology, Humans, Dendritic Cells immunology, Dendritic Cells virology, HIV-1 pathogenicity, Host-Pathogen Interactions, Signal Transduction, Toll-Like Receptor 8 metabolism, Vesicular Transport Proteins metabolism
- Abstract
HIV-1 traffics through dendritic cells (DCs) en route to establishing a productive infection in T lymphocytes but fails to induce an innate immune response. Within DC endosomes, HIV-1 somehow evades detection by the pattern-recognition receptor (PRR) Toll-like receptor 8 (TLR8). Using a phosphoproteomic approach, we identified a robust and diverse signaling cascade triggered by HIV-1 upon entry into human DCs. A secondary siRNA screen of the identified signaling factors revealed several new mediators of HIV-1 trans -infection of CD4
+ T cells in DCs, including the dynein motor protein Snapin. Inhibition of Snapin enhanced localization of HIV-1 with TLR8+ early endosomes, triggered a pro-inflammatory response, and inhibited trans -infection of CD4+ T cells. Snapin inhibited TLR8 signaling in the absence of HIV-1 and is a general regulator of endosomal maturation. Thus, we identify a new mechanism of innate immune sensing by TLR8 in DCs, which is exploited by HIV-1 to promote transmission., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2017
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42. Toscana virus encephalitis following a holiday in Sicily.
- Author
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Osborne JC, Khatamzas E, Misbahuddin A, Hart R, Sivaramakrishnan A, and Breen DP
- Subjects
- Aged, Humans, Male, Sandfly fever Naples virus, Sicily, Meningoencephalitis diagnosis, Meningoencephalitis physiopathology, Meningoencephalitis virology, Phlebotomus Fever diagnosis, Phlebotomus Fever physiopathology
- Abstract
We report a case of Toscana virus encephalitis. This emerging pathogen is among the three most common causes of meningoencephalitis in Europe during the warm season, yet remains under-recognised. Doctors should consider Toscana virus infection in patients presenting with neurological symptoms who have a relevant exposure history during the summer months., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
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43. RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomain sites resulting in functionally disparate signaling events.
- Author
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Colak E, Leslie A, Zausmer K, Khatamzas E, Kubarenko AV, Pichulik T, Klimosch SN, Mayer A, Siggs O, Hector A, Fischer R, Klesser B, Rautanen A, Frank M, Hill AV, Manoury B, Beutler B, Hartl D, Simmons A, and Weber AN
- Subjects
- Animals, HEK293 Cells, Humans, Mice, Oligoribonucleotides chemistry, Protein Structure, Tertiary, Quinolinium Compounds chemistry, RNA chemistry, Signal Transduction genetics, Signal Transduction immunology, Toll-Like Receptor 7 genetics, Toll-Like Receptor 8 genetics, Oligoribonucleotides pharmacology, Quinolinium Compounds pharmacology, RNA pharmacology, Signal Transduction drug effects, Toll-Like Receptor 7 immunology, Toll-Like Receptor 8 immunology
- Abstract
TLRs 7 and 8 are pattern recognition receptors controlling antiviral host defense or autoimmune diseases. Apart from foreign and host RNA, synthetic RNA oligoribonucleotides (ORN) or small molecules of the imidazoquinoline family activate TLR7 and 8 and are being developed as therapeutic agonists. The structure-function relationships for RNA ORN and imidazoquinoline sensing and consequent downstream signaling by human TLR7 and TLR8 are unknown. Proteome- and genome-wide analyses in primary human monocyte-derived dendritic cells here showed that TLR8 sensing of RNA ORN versus imidazoquinoline translates to ligand-specific differential phosphorylation and transcriptional events. In addition, TLR7 and 8 ectodomains were found to discriminate between RNA ORN and imidazoquinolines by overlapping and nonoverlapping recognition sites to which murine loss-of-function mutations and human naturally occurring hyporesponsive polymorphisms map. Our data suggest TLR7 and TLR8 can signal in two different "modes" depending on the class of ligand. Considering RNA ORN and imidazoquinolines have been regarded as functionally interchangeable, our study highlights important functional incongruities whose understanding will be important for developing TLR7 or 8 therapeutics with desirable effector and safety profiles for in vivo application., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
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44. The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.
- Author
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Brain O, Owens BM, Pichulik T, Allan P, Khatamzas E, Leslie A, Steevels T, Sharma S, Mayer A, Catuneanu AM, Morton V, Sun MY, Jewell D, Coccia M, Harrison O, Maloy K, Schönefeldt S, Bornschein S, Liston A, and Simmons A
- Subjects
- Activating Transcription Factor 2 metabolism, Animals, Cells, Cultured, Dendritic Cells metabolism, Escherichia coli immunology, Escherichia coli Infections immunology, Humans, Inflammation immunology, Interleukin-12 Subunit p40 metabolism, Intestinal Mucosa immunology, Mice, Mice, Knockout, MicroRNAs genetics, Nod2 Signaling Adaptor Protein genetics, Polymorphism, Single Nucleotide, Th17 Cells immunology, Crohn Disease immunology, Dendritic Cells immunology, Interleukin-23 metabolism, MicroRNAs metabolism, Nod2 Signaling Adaptor Protein metabolism
- Abstract
NOD2 is an intracellular sensor that contributes to immune defense and inflammation. Here we investigated whether NOD2 mediates its effects through control of microRNAs (miRNAs). miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2. DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn's disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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45. The increasing prevalence of listeriosis--what are we missing?
- Author
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Khatamzas E, Hughes H, Grant KA, McLauchlin J, and Bowler IC
- Subjects
- Aged, Amoxicillin therapeutic use, Anti-Bacterial Agents therapeutic use, Antibodies, Monoclonal therapeutic use, Diet, Female, Humans, Immunocompromised Host, Immunosuppressive Agents therapeutic use, Listeria monocytogenes isolation & purification, Listeriosis epidemiology, Male, Prevalence, Treatment Outcome, Antibodies, Monoclonal adverse effects, Immunosuppressive Agents adverse effects, Listeriosis etiology, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Published
- 2010
- Full Text
- View/download PDF
46. Evaluation of the frequency of virus-specific CD8+ T cells by cytokine flow cytometry.
- Author
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Hoffmeister B, Kiecker F, Surel I, Khatamzas E, Schuster V, Volk HD, and Kern F
- Subjects
- CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Cytokines analysis, CD8-Positive T-Lymphocytes metabolism, Flow Cytometry methods
- Published
- 2003
- Full Text
- View/download PDF
47. Cytomegalovirus (CMV) phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals.
- Author
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Kern F, Bunde T, Faulhaber N, Kiecker F, Khatamzas E, Rudawski IM, Pruss A, Gratama JW, Volkmer-Engert R, Ewert R, Reinke P, Volk HD, and Picker LJ
- Subjects
- Amino Acid Sequence, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Epitopes, T-Lymphocyte immunology, Humans, Molecular Sequence Data, CD4-Positive T-Lymphocytes virology, CD8-Positive T-Lymphocytes virology, Cytomegalovirus immunology, Phosphoproteins immunology, Viral Matrix Proteins immunology
- Abstract
Antigen-specific, cytokine flow cytometry was used to analyze the prevalence and frequency of CD4 and CD8 memory T cells specific for the abundantly expressed cytomegalovirus (CMV) phosphoprotein 65 (pp65) in healthy CMV IgG-seropositive individuals. Stimulation of peripheral blood mononuclear cells with peptide pools and individual peptides derived from the pp65 amino acid sequence in 40 donors revealed that 63% of donors had a detectable CD4 T cell response and that 83% of donors had a detectable CD8 T cell response against this protein. The overall frequencies of T cells directed against pp65 were analyzed for 20 donors by stimulation with peptide pools covering the complete pp65 protein and were as high as 2 in 1000 and 9 in 1000 (median) peripheral blood CD4 and CD8 T cells, respectively. In addition, a comparison between CD4 responses to a CMV lysate containing various CMV proteins and pp65-specific responses in 9 donors indicated that pp65 was a dominant target of the CMV-specific CD4 T cell response in some, but not all, donors. Several new T cell epitopes were identified.
- Published
- 2002
- Full Text
- View/download PDF
48. Clonotypic structure of the human CD4+ memory T cell response to cytomegalovirus.
- Author
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Bitmansour AD, Waldrop SL, Pitcher CJ, Khatamzas E, Kern F, Maino VC, and Picker LJ
- Subjects
- Antigens, CD biosynthesis, Antigens, Differentiation, T-Lymphocyte biosynthesis, CD4-Positive T-Lymphocytes metabolism, CD40 Ligand biosynthesis, Clone Cells, Cytokines biosynthesis, Epitopes, T-Lymphocyte biosynthesis, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, Female, Flow Cytometry methods, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, Humans, Immunodominant Epitopes biosynthesis, Immunodominant Epitopes genetics, Immunodominant Epitopes immunology, Lectins, C-Type, Male, Multigene Family immunology, Phosphoproteins immunology, Receptors, Antigen, T-Cell, alpha-beta biosynthesis, Receptors, Antigen, T-Cell, alpha-beta genetics, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocyte Subsets metabolism, Viral Matrix Proteins immunology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Cytomegalovirus immunology, Immunologic Memory genetics, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets virology
- Abstract
High steady-state frequencies of CMV-specific CD4(+) memory T cells are maintained in CMV-exposed subjects, and these cells are thought to play a key role in the immunologic control of this permanent infection. However, the essential components of this response are poorly defined. Here, we report the use of a step-wise application of flow cytometric and molecular techniques to determine the number and size of the TCR Vbeta-defined clonotypes within freshly obtained CMV-specific CD4(+) memory T cell populations of four healthy, CMV-exposed human subjects. This analysis revealed a stable clonotypic hierarchy in which 1-3 dominant clonotypes are maintained in concert with more numerous subdominant and minor clonotypes. These dominant clonotypes accounted for 10-50% of the overall CMV response, and comprised from 0.3 to 4.0% of peripheral blood CD4(+) T cells. Two subjects displayed immunodominant responses to single epitopes within the CMV matrix phosphoprotein pp65; these single epitope responses were mediated by a single dominant clonotype in one subject, and by multiple subdominant and minor clonotypes in the other. Thus, the CMV-specific CD4(+) T cell memory repertoire in normal subjects is characterized by striking clonotypic dominance and the potential for epitope focusing, suggesting that primary responsibility for immunosurveillance against CMV reactivation rests with a handful of clones recognizing a limited array of CMV determinants. These data have important implications for the understanding of mechanisms by which a genetically stable chronic viral pathogen such as CMV is controlled, and offer possible insight into the failure of such control for a genetically flexible pathogen like HIV-1.
- Published
- 2001
- Full Text
- View/download PDF
49. Analysis of CD8 T cell reactivity to cytomegalovirus using protein-spanning pools of overlapping pentadecapeptides.
- Author
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Kern F, Faulhaber N, Frömmel C, Khatamzas E, Prösch S, Schönemann C, Kretzschmar I, Volkmer-Engert R, Volk HD, and Reinke P
- Subjects
- Amino Acid Sequence, Cytomegalovirus immunology, Cytomegalovirus Infections blood, HLA-A1 Antigen immunology, HLA-A2 Antigen immunology, HLA-B7 Antigen immunology, HLA-B8 Antigen immunology, Humans, Interferon-gamma biosynthesis, Molecular Sequence Data, CD8-Positive T-Lymphocytes immunology, Cytomegalovirus Infections immunology, Immediate-Early Proteins immunology, Peptides immunology, Phosphoproteins immunology, Viral Matrix Proteins immunology, Viral Proteins
- Abstract
The frequencies of human cytomegalovirus (HCMV) protein-specific CD8 T cells, identified by the presence of intracellular IFN-gamma, were measured by flow cytometry following stimulation of freshly isolated peripheral blood mononuclear cells (PBMC) with comprehensive peptide pools. These pools spanned the entire amino acid sequences of the HCMV pp65 and major immediate early (IE-1) proteins and consisted of 15-amino acid peptides with at least nine overlaps between neighboring peptides. As a result all potential CD8 T cell epitopes contained in these proteins were provided by the complete pools and, therefore, unlike with single epitopes, testing was independent of donor HLA type. Individual stimulating peptides from the same pools were identified in parallel experiments. Thus we found that our results with the complete pools using PBMC from 26 healthy HCMV-seropositive donors were 100% sensitive and specific with respect to predicting the presence of recognized epitopes in the respective proteins. In addition, cells from 15 renal transplant patients were tested with complete pools alone. While our results confirmed our previous contention that HCMV IE-1 is an important CD8 T cell target, the technical improvement we made in order to address this question has clearly wider implications. Similar pools may be applied to examine the role of proteins from other pathogens, in autoimmune disease or following vaccination.
- Published
- 2000
- Full Text
- View/download PDF
50. Distribution of human CMV-specific memory T cells among the CD8pos. subsets defined by CD57, CD27, and CD45 isoforms.
- Author
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Kern F, Khatamzas E, Surel I, Frömmel C, Reinke P, Waldrop SL, Picker LJ, and Volk HD
- Subjects
- CD57 Antigens biosynthesis, CD8-Positive T-Lymphocytes chemistry, Flow Cytometry, Humans, Leukocyte Common Antigens biosynthesis, T-Lymphocyte Subsets chemistry, T-Lymphocyte Subsets immunology, Tumor Necrosis Factor Receptor Superfamily, Member 7 biosynthesis, Antigens, CD biosynthesis, CD8-Positive T-Lymphocytes metabolism, Cytomegalovirus immunology, Immunologic Memory immunology, T-Lymphocyte Subsets metabolism
- Abstract
Chronic antigenic stimulation has been associated with peripheral blood expansions of CD8pos. T cells characterized by CD57 expression, loss of CD27 expression, and reversal of the CD45RO(bright) /RA(dim) phenotype usually associated with immunological memory towards a CD45RO(dim) /RA(bright) phenotype. However, the relationship and functional significance of these subset(s) has remained controversial. Here, this issue was addressed using a novel flow cytometric technique that allows simultaneous detection of human cytomegalovirus (HCMV)-specific CD8pos. memory T cells by rapid (< 6 h) HCMV peptide-specific induction of cytokine synthesis, and their phenotypic characterization, including CD57, CD27 and CD45RA/RO. The vast majority of resting CD8(pos.) T cells capable of rapid induction of IFN-gamma and TNF-alpha synthesis in response to HCMV peptides were found in a subset characterized by intermediate to high expression of CD57, down-regulation/loss of CD27, and varying degrees of reversal of the classical "memory" CD45RO(bright) /RA(dim) phenotype. This subpopulation likely includes the fully differentiated memory cells responsible for the long-term immune defense against HCMV reactivation.
- Published
- 1999
- Full Text
- View/download PDF
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